Omega-3 Supplementation and Its Effects on Osteoarthritis

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<p>Citation: Shawl, M.; Geetha, T.;</p><p>Burnett, D.; Babu, J.R. Omega-3</p><p>Supplementation and Its Effects on</p><p>Osteoarthritis. Nutrients 2024, 16, 1650.</p><p>https://doi.org/10.3390/nu16111650</p><p>Academic Editor: Chun-De Liao</p><p>Received: 13 April 2024</p><p>Revised: 16 May 2024</p><p>Accepted: 23 May 2024</p><p>Published: 28 May 2024</p><p>Copyright: © 2024 by the authors.</p><p>Licensee MDPI, Basel, Switzerland.</p><p>This article is an open access article</p><p>distributed under the terms and</p><p>conditions of the Creative Commons</p><p>Attribution (CC BY) license (https://</p><p>creativecommons.org/licenses/by/</p><p>4.0/).</p><p>nutrients</p><p>Review</p><p>Omega-3 Supplementation and Its Effects on Osteoarthritis</p><p>Megan Shawl 1, Thangiah Geetha 1,2 , Donna Burnett 1 and Jeganathan Ramesh Babu 1,2,*</p><p>1 Department of Nutritional Sciences, Auburn University, Auburn, AL 36849, USA</p><p>2 Boshell Metabolic Diseases and Diabetes Program, Auburn University, Auburn, AL 36849, USA</p><p>* Correspondence: jeganrb@auburn.edu</p><p>Abstract: Osteoarthritis (OA) is a degenerative joint disease characterized by the destruction of the</p><p>articular cartilage, resulting in a pro-inflammatory response. The progression of OA is multifactorial</p><p>and is influenced by the underlying cause of inflammation, which includes but is not limited to</p><p>trauma, metabolism, biology, comorbidities, and biomechanics. Although articular cartilage is the</p><p>main tissue affected in osteoarthritis, the chronic inflammatory environment negatively influences</p><p>the surrounding synovium, ligaments, and subchondral bone, further limiting their functional</p><p>abilities and enhancing symptoms of OA. Treatment for osteoarthritis remains inconsistent due to</p><p>the inability to determine the underlying mechanism of disease onset, severity of symptoms, and</p><p>complicating comorbidities. In recent years, diet and nutritional supplements have gained interest</p><p>regarding slowing the disease process, prevention, and treatment of OA. This is due to their anti-</p><p>inflammatory properties, which result in a positive influence on pain, joint mobility, and cartilage</p><p>formation. More specifically, omega-3 polyunsaturated fatty acids (PUFA) have demonstrated an</p><p>influential role in the progression of OA, resulting in the reduction of cartilage destruction, inhibition</p><p>of pro-inflammatory cytokine cascades, and production of oxylipins that promote anti-inflammatory</p><p>pathways. The present review is focused on the assessment of evidence explaining the inflammatory</p><p>processes of osteoarthritis and the influence of omega-3 supplementation to modulate the progression</p><p>of osteoarthritis.</p><p>Keywords: osteoarthritis; omega-3; supplementation; anti-inflammatory; inflammation</p><p>1. Introduction</p><p>Osteoarthritis (OA) is defined as a degenerative joint disease in which there is chronic</p><p>destruction of the articular cartilage secondary to micro and macro injury, resulting in a pro-</p><p>inflammatory response [1]. OA is multifactorial, and its disease progression is influenced</p><p>based on the extent of inflammation and factors including but not limited to trauma,</p><p>metabolism, biology, and biomechanics [2]. Articular cartilage is the smooth cartilage at</p><p>joint surfaces, providing a low friction surface and enhanced transmission of loads with</p><p>joint articulations. Although articular cartilage is the main tissue impacted in OA, the</p><p>resultant inflammation can impact the adjacent synovium, ligaments, and subchondral</p><p>bone and subsequently lead to active synovitis and systemic inflammation. For some,</p><p>this results in joint pain, mainly affecting the joints of our hands, hips, knees, lumbar and</p><p>cervical spine. Typically, a diagnosis is made upon imaging, X-ray, or MRI, demonstrating</p><p>loss of joint space, damage to the bone, bone remodeling, and bone spurs [3].</p><p>Treatment for symptomatic OA varies widely based on the joint involved, severity</p><p>of symptoms, and comorbidities. According to the Osteoarthritis Research Society In-</p><p>ternational (OARSI), the first line of treatment for OA is education, land-based exercise</p><p>programs, and, in some cases, weight-management programs, followed by pharmacologi-</p><p>cal treatment [4]. However, due to the extent of comorbidities commonly associated with</p><p>osteoarthritis, there is an increased complexity of care through the administration of medi-</p><p>cation and potential adverse responses to manage symptoms. It has been found that 67%</p><p>of individuals with OA have at least one other chronic condition, which is 20% greater than</p><p>Nutrients 2024, 16, 1650. https://doi.org/10.3390/nu16111650 https://www.mdpi.com/journal/nutrients</p><p>https://doi.org/10.3390/nu16111650</p><p>https://creativecommons.org/</p><p>https://creativecommons.org/licenses/by/4.0/</p><p>https://creativecommons.org/licenses/by/4.0/</p><p>https://www.mdpi.com/journal/nutrients</p><p>https://www.mdpi.com</p><p>https://orcid.org/0000-0001-6358-0012</p><p>https://doi.org/10.3390/nu16111650</p><p>https://www.mdpi.com/journal/nutrients</p><p>https://www.mdpi.com/article/10.3390/nu16111650?type=check_update&version=1</p><p>Nutrients 2024, 16, 1650 2 of 22</p><p>someone without [5]. Upper gastrointestinal, psychological, cardiovascular, and endocrine</p><p>systems were most likely to be affected, with the main comorbidities associated with OA,</p><p>including stroke, peptic ulcer, and metabolic syndrome. Metabolic syndrome is described</p><p>as a combination of dyslipidemia, hypertension, and diabetes. It has been classified as a</p><p>state of low-grade inflammation in the body and has been shown to have a 5-fold increased</p><p>chance of also having OA, likely due to the associated reductions in activity tolerance and</p><p>lifestyle changes that follow [6]. In vivo and in vitro studies have shown direct negative</p><p>effects of hyperglycemia, dyslipidemia, and chronic low-grade inflammation on cartilage</p><p>metabolism, resulting in the progression of the OA disease process.</p><p>Most pharmacological and physical approaches do not consistently address the under-</p><p>lying degenerative process of the arthritic joint and are considered palliative, which begs</p><p>the question: are there other treatment methods to address the disease process of OA? Diet</p><p>and nutritional supplements have been gaining interest in recent years regarding disease</p><p>process, prevention, and treatment. Specific to OA, diet modifications and nutritional</p><p>supplements have demonstrated a positive influence on inflammation, pain, joint stiffness,</p><p>and cartilage formation [7]. Omega-3 polyunsaturated fatty acids (PUFA) are recognized</p><p>for having anti-inflammatory properties and have demonstrated an influential role in the</p><p>inflammatory and catabolic process that contributes to the disease progression of OA [8].</p><p>The purpose of this review is to assess recent research on the efficacy of omega-3</p><p>PUFAs in modulating the progression of osteoarthritis.</p><p>2. Osteoarthritis</p><p>2.1. Prevalence</p><p>Osteoarthritis is the leading cause of disability globally, with an increase of 0.32%</p><p>(95% CI, 0.28, 0.36) in aged-standardized incidence rates, or a 9% increase from 1990 to</p><p>2017 [9]. In a recent review, it was found that the number of impairments with activities of</p><p>daily living was 1.12–1.35 times greater in those with OA, and typically substantially more</p><p>health care consultations, medication use, and net disability days were required [10,11].</p><p>Due to the complexity of OA, many associated risk factors can lead to its presentation</p><p>and risk of progression [1]. Such factors include occupation, joint injury, joint alignment,</p><p>obesity, physical activity, age, gender, and genetics, to name a few. Aging is the single</p><p>greatest risk factor for the development of OA in both radiographic and symptomatic</p><p>presentations. According to the Framingham OA study, a large-scale, population-based,</p><p>longitudinal study of knee OA, progressive disease occurs commonly in elder years and</p><p>more commonly in women than men [11]. Of those studied, 27% of those aged 63 to</p><p>70 years old had radiographic evidence of knee OA, which increased to 44% after the age</p><p>of 80. Hip OA, although less common than knee OA, also demonstrated an increased</p><p>incidence with age from 0.7% in the 40–44 years age group to 14% in those over the age of</p><p>85 years [12]. Additionally,</p><p>that dietary supplements providing ≤5 g/d</p><p>of EPA or DHA are considered safe if used as recommended [105,108]. Looking at the</p><p>studies explained above, most utilized a supplement value under 5 g/day, with only a</p><p>Nutrients 2024, 16, 1650 17 of 22</p><p>few that exceeded this amount; however, they were performed in short duration with no</p><p>adverse responses reported. Further evaluation of current research on omega 3’s influence</p><p>on OA symptom management would be beneficial in determining the optimal dosage of</p><p>supplementation and allowing improvements in future research.</p><p>8. Limitations</p><p>Limitations in current evidence for omega-3 PUFA supplementation include many</p><p>factors. The dosing of supplementation, as well as the ratio of n-6/n-3, or DHA to EPA,</p><p>remains unstandardized, bringing about variable responses. The amount of research</p><p>utilizing human subjects is minimal. Most studies are performed on animal models, and</p><p>despite positive results, they have yet to have the same profound response in human tissues.</p><p>This is likely secondary to the complexity of variables in humans, including the onset and</p><p>state of progression of the osteoarthritic joint, the subject’s dietary habits and comorbid</p><p>status, and the ability of a human to produce compensatory mechanisms at a cellular level.</p><p>Additionally, the type of supplementation used, plant versus animal sources, will affect the</p><p>bioavailability and thus influence the potential outcomes.</p><p>9. Conclusions</p><p>Osteoarthritis is characterized by alterations in molecular, anatomical, and physiologi-</p><p>cal processes, with influencing factors of progression from trauma, metabolism, biology,</p><p>and biomechanics [86]. The underlying etiology of osteoarthritis is not well understood;</p><p>however, the common theme of inflammation remains omnipresent. Research has demon-</p><p>strated a positive effect on the modulation of OA symptoms through diet and exercise</p><p>to promote an anti-inflammatory environment. More specifically, omega-3 PUFAs have</p><p>demonstrated a reduction in inflammatory biomarkers and cartilage degradation, counter-</p><p>acting the natural disease state of OA. In addition to their chondroprotective role, omega-3</p><p>supplementation has been shown to have indirect positive effects on muscle tissue recovery</p><p>following exercise, which is necessary to prevent the progression of OA and maintain an</p><p>independent, healthy lifestyle. The effects of omega-3 supplementation on the disease</p><p>state of OA and its symptoms remain inconclusive. Further clinical trials utilizing hu-</p><p>man participants are warranted to provide a conclusive recommendation on standardized</p><p>supplementation of omega-3 for the modulation of osteoarthritis.</p><p>Author Contributions: M.S.: writing—original draft preparation, review, and editing. T.G.: review</p><p>and editing. D.B.: review and editing. J.R.B.: supervision, review, and editing. All authors have read</p><p>and agreed to the published version of the manuscript.</p><p>Funding: This research received no external funding.</p><p>Conflicts of Interest: The authors declare no conflicts of interest.</p><p>References</p><p>1. Abramoff, B.; Caldera, F.E. Osteoarthritis: Pathology, Diagnosis, and Treatment Options. Med. Clin. N. Am. 2020, 104, 293–311.</p><p>[CrossRef] [PubMed]</p><p>2. Martel-Pelletier, J.; Boileau, C.; Pelletier, J.; Roughley, P.J. 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[CrossRef] [PubMed]</p><p>https://doi.org/10.1002/jor.24688</p><p>https://www.ncbi.nlm.nih.gov/pubmed/32270890</p><p>https://doi.org/10.1016/j.jacl.2018.03.080</p><p>https://www.ncbi.nlm.nih.gov/pubmed/29752179</p><p>https://doi.org/10.1016/j.joca.2007.12.013</p><p>https://doi.org/10.3945/ajcn.114.105833</p><p>https://www.ncbi.nlm.nih.gov/pubmed/25994567</p><p>https://doi.org/10.1590/S1807-59322010001200006</p><p>https://doi.org/10.1007/s00421-016-3373-3</p><p>https://doi.org/10.1186/s12970-017-0176-9</p><p>https://www.ncbi.nlm.nih.gov/pubmed/28717347</p><p>https://doi.org/10.1186/s12970-021-00411-x</p><p>https://doi.org/10.1186/ar2891</p><p>https://www.ncbi.nlm.nih.gov/pubmed/20015358</p><p>https://doi.org/10.2147/DDDT.S327378</p><p>https://www.ncbi.nlm.nih.gov/pubmed/34754179</p><p>https://doi.org/10.1093/rap/rkaa036</p><p>https://www.ncbi.nlm.nih.gov/pubmed/32968708</p><p>https://doi.org/10.1002/14651858.CD002946.pub2</p><p>https://www.ncbi.nlm.nih.gov/pubmed/15846645</p><p>https://doi.org/10.1007/s12325-009-0060-3</p><p>https://www.ncbi.nlm.nih.gov/pubmed/19756416</p><p>https://doi.org/10.1002/art.41416</p><p>https://doi.org/10.1001/jama.2022.21893</p><p>https://www.ncbi.nlm.nih.gov/pubmed/36511925</p><p>https://doi.org/10.1007/s00394-022-03017-4</p><p>https://www.ncbi.nlm.nih.gov/pubmed/36183308</p><p>https://doi.org/10.1155/2022/7275192</p><p>https://doi.org/10.22540/JFSF-02-045</p><p>https://doi.org/10.1007/s12603-016-0806-y</p><p>https://www.ncbi.nlm.nih.gov/pubmed/28448087</p><p>https://doi.org/10.1093/rheumatology/kel409</p><p>https://www.ncbi.nlm.nih.gov/pubmed/17387119</p><p>https://ods.od.nih.gov/factsheets/Omega3FattyAcids-HealthProfessional/</p><p>https://ods.od.nih.gov/factsheets/Omega3FattyAcids-HealthProfessional/</p><p>https://doi.org/10.1016/j.jada.2008.04.020</p><p>https://www.ncbi.nlm.nih.gov/pubmed/18589030</p><p>Nutrients 2024, 16, 1650 22 of 22</p><p>107. Shahidi, F.; Ambigaipalan, P. Omega-3 Polyunsaturated Fatty Acids and Their Health Benefits. Annu. Rev. Food Sci. Technol. 2018,</p><p>9, 345–381. [CrossRef]</p><p>108. National Institute of Health—Office of Dietary Supplements. Omega-3 Fatty Acids Fact Sheet for Consumers. Internet. Available</p><p>online: https://ods.od.nih.gov/pdf/factsheets/Omega3FattyAcids-Consumer.pdf (accessed on 15 March 2024).</p><p>Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual</p><p>author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to</p><p>people or property resulting from any ideas, methods, instructions or products referred to in the content.</p><p>https://doi.org/10.1146/annurev-food-111317-095850</p><p>https://ods.od.nih.gov/pdf/factsheets/Omega3FattyAcids-Consumer.pdf</p><p>Introduction</p><p>Osteoarthritis</p><p>Prevalence</p><p>Genetics</p><p>Normal Cartilage</p><p>Osteoarthritic Cartilage</p><p>Joint Tissues Involved in Osteoarthritis</p><p>Inflammatory Process of Osteoarthritis</p><p>Pro-Inflammatory Cytokines</p><p>Pro-Inflammatory Chemokines</p><p>Anti-Inflammatory Process of Osteoarthritis</p><p>Fatty Acids</p><p>Omega-3 and Omega-6 Fatty Acids</p><p>Anti-Inflammatory Processes of Omega-3 PUFAs</p><p>Supplementation</p><p>Fatty Acid Composition: Ratio of Omega-6 to Omega-3</p><p>Omega-3 Supplementation and Synovial Fluid</p><p>Omega-3 Supplementation and Chondrocytes</p><p>Omega-3 Supplementation and Pain, Stiffness, and Physical Function</p><p>Omega-3 Supplementation for OA with Comorbidities</p><p>Omega-3 Supplementation and Its Indirect Effects on OA</p><p>Omega-3 Supplementation in Combination with Other Nutraceuticals in OA</p><p>Diet Rich in Omega-3 and Osteoarthritis</p><p>Dietary Sources of Omega-3</p><p>Limitations</p><p>Conclusions</p><p>References</p><p>in women, typically after menopausal age, the risk of hand OA</p><p>peaks and then plateaus, eventually reducing in older years [13]. When correlating hand,</p><p>hip, and knee OA, researchers have found a correlation explaining there is a greater risk of</p><p>hip and knee OA with a history of hand OA, and previous hip OA is associated with an</p><p>increased risk of knee OA and vice versa.</p><p>2.2. Genetics</p><p>As OA affects a large majority of the population, studies have been conducted to</p><p>assess if there is a correlation between genetics and OA. A genome-wide meta-analysis</p><p>performed over 826,690 individuals, 177,517 of whom with OA, found 100 independently</p><p>associated risk variants across 11 OA phenotypes, 52 of which are newly identified [14]. The</p><p>genetic variances include genetic differences in weight-bearing versus non-weight-bearing,</p><p>sex-specific, and early age-at-onset risks. There are also genetic correlations for pain, main</p><p>disease symptoms, and casual genes linked to neuronal processes. Knee, hip, and hand</p><p>OA are thought to be genetic, with 10–30%, 50%, and 70% risks, respectively [15]. In</p><p>recent years, the growth and differentiation factor 5 gene (GDF5) has shown a consistent</p><p>Nutrients 2024, 16, 1650 3 of 22</p><p>genetic association with OA, most notably a single nucleotide polymorphism at the 3′</p><p>untranslated region of GDF5. GDF5 is an extracellular signaling molecule in the TGF-β</p><p>family, thus defining its role in immune regulation and development, maintenance, and</p><p>repair of synovial joint tissues [16]. A reduction in GDF5 mRNA protein can result in a</p><p>presentation similar to OA.</p><p>2.3. Normal Cartilage</p><p>Articular cartilage is an avascular and aneural connective tissue made up of chondro-</p><p>cytes that acts as a load-bearing tissue, absorbs impact, and sustains shear forces applied by</p><p>articulating joints [2]. Chondrocytes are specialized, as they contain proteoglycans, collagen</p><p>fibers, and a large amount of water within their extracellular matrix to provide frictionless</p><p>joint articulation. Chondrocytes maintain cartilage matrix homeostasis by constant matrix</p><p>synthesis and degradation. Collagen represents about 50% of the cartilage tissue, with</p><p>specialized type II fibers to provide tensile stiffness and strength. Proteoglycans are made</p><p>up of hyaluronic acid with multiple monomers attached laterally. These supramolecular</p><p>aggregates allow for hydration and swelling abilities of the cartilage, enhancing the tissues’</p><p>ability to withstand compressive forces [17]. Water has the highest concentration, mainly</p><p>located near the surface of the cartilage, with decreasing concentrations as you progress</p><p>deeper towards the bone [2]. It is most responsible for the maintenance of the tissue, as</p><p>well as the lubrication and nutritional status of the cartilage. Within the water component</p><p>of the tissue, inorganic salts are dissolved and allow for nutrients to move throughout the</p><p>layers of cartilage. This movement is necessary to provide nutrition to the deeper layers</p><p>that contain more chondrocytes, which maintain the integrity of the cartilage.</p><p>2.4. Osteoarthritic Cartilage</p><p>Osteoarthritis has been shown to have a multitude of clinical presentations, making</p><p>it difficult to determine an exact definition [18]. OA can be subcategorized into primary</p><p>and secondary OA. Primary OA is idiopathic with potential influences from genetics,</p><p>age, and ethnicity, whereas secondary OA includes post-traumatic, dysplastic, infectious,</p><p>inflammatory, or biochemical etiologies. Furthermore, OA has demonstrated challenges to</p><p>clinicians in classifying and diagnosing due to the vast symptoms and limited correlation</p><p>of symptoms to radiological findings. Kellgren and Lawrence were the first to attempt</p><p>radiological classification in 1957 by studying rheumatism in coal miners in Northwest</p><p>England. They were able to assess intra- and inter-rater reliability by assessing eight</p><p>joints, including the hand (distal interphalangeal joint, metacarpophalangeal joint, first</p><p>metacarpophalangeal joint), wrist, cervical spine, lumbar spine, hips, and knees. They</p><p>found that the tibiofemoral joint of the knee had the highest interobserver correlation</p><p>coefficient (r = 0.83) and second highest interobserver correlation (r = 0.83) among the</p><p>diarthrodial joints examined, which would eventually lead to a classification of OA-specific</p><p>to the knee and would be the most widely used clinical tool in the radiographic diagnosis</p><p>of OA. Using anterior-posterior knee radiographs, Kellgren and Lawrence assigned a grade</p><p>of 0 to 4 to classify the severity of knee OA as in Table 1 [18].</p><p>Table 1. Radiological features of osteoarthritis.</p><p>Grade Classification</p><p>0 No evidence of OA, normal radiographic findings</p><p>1 Doubtful narrowing of the joint space with possible osteophyte formation</p><p>2 Possible narrowing of joint space with definite osteophyte formation</p><p>3 Definite narrowing of joint space, moderate osteophyte formation, some</p><p>sclerosis, and possible deformity of bony ends</p><p>4 Large osteophyte formation, severe narrowing of the joint space, with</p><p>marked sclerosis and definite deformity of bone ends</p><p>Nutrients 2024, 16, 1650 4 of 22</p><p>2.5. Joint Tissues Involved in Osteoarthritis</p><p>The exact cause of osteoarthritis is not well understood. Many studies have exam-</p><p>ined metabolites within the serum, synovial fluid, and joint tissue to determine potential</p><p>correlations to the severity of OA progression and its symptomatic presentation [19].</p><p>Serum metabolites measured in knee OA, greater than or equal to the Kellgren and</p><p>Lawrence Grade 2, have demonstrated a reduction in glycine, histidine, lysophospholipid</p><p>(LPC), and Branched Chain Amino Acids (BCAA) [19,20]. Glycine and histidine, after</p><p>conversion to histamine, have both been associated with collagen synthesis and proliferative</p><p>effects on chondrocytes, respectively, and were further reduced upon the progression of</p><p>knee OA from Grade 2 to 3 and from Grade 3 to 4. Also, in this disease state, there was</p><p>an observed increase in serum hypoxanthine, homocysteine, urate, tryptophan, and an</p><p>increased ratio of lysophosphatidylcholine (lyosPC) to phosphatidylcholine (PC). This</p><p>increased ratio of lysoPC to PC via phospholipase A2 is associated with a reduction of</p><p>cartilage volume over time and is considered a prognostic biomarker of symptomatic</p><p>presentation and disease progression to anti-inflammatory treatments.</p><p>Evidence has demonstrated that multiple types of immune cells, such as CD14+</p><p>monocytes and macrophages, mast cells, and CD4+ T helper cells, invade the synovium [19].</p><p>With macrophages being the most abundant immune cell in the synovium, the polarization</p><p>of M2 anti-inflammatory macrophages to M1 pro-inflammatory macrophages has been</p><p>demonstrated to aid in the progression of OA, as well as become a disease predictor.</p><p>Synovial fluid has demonstrated an alteration in >50 metabolites in subjects with OA</p><p>as compared to a control; however, only about 5% of those metabolites that were also found</p><p>in serum were correlated with synovial fluid changes [19,21]. Those metabolites include</p><p>BCAA, glycine, glycerophospholipids, and creatinine. There is limited evidence in metabo-</p><p>lite biomarkers assessed from joint tissue due to challenges in sample collection [19,22].</p><p>However, researchers found a reduction in glycine, leucine, valine, methionine, citrate,</p><p>malate, and 3-hydroxybutyrate in femoral heads of adult mice as compared to its juvenile</p><p>counterpart, resulting in a reduction in substrate availability required for the maintenance</p><p>of chondrocyte homeostasis.</p><p>Chondrocytes rely on the metabolism of glucose via glycolysis to generate ATP [19].</p><p>However, approximately 80% of the glucose metabolized is converted to lactate to produce</p><p>ATP in low oxidation states because of the varying avascular nature of cartilage. The</p><p>deeper layers of chondrocytes, located in the closest proximity to the subchondral bone, are</p><p>estimated to have about 1% oxygen partial pressure, as compared to about 7–10% partial</p><p>pressure in the superficial layers [23]. Chondrocytes isolated from human OA joints</p><p>have</p><p>demonstrated a reduction in mitochondrial electrical transport chain complexes II and</p><p>III and a reduction in mitochondrial membrane potential. When studied in guinea pigs</p><p>with progressive OA, there is a reduction in mitochondrial reserve capacity, resulting in a</p><p>reduction in ATP and mitochondrial superoxide dismutase enzymes (SOD2) production,</p><p>all contributing to further mitochondrial dysfunction [24]. Additionally, acute mechanical</p><p>injury from high-impact loading produces reactive oxygen species (ROS), mitochondrial</p><p>swelling, changes in mitochondrial membrane polarization, impairs cellular respiratory</p><p>activity, and increased proton leakage, which can lead to load-induced chondrocyte death</p><p>and post-traumatic OA.</p><p>Impaired chondrocyte metabolism, as related to OA, is also involved in the limitations</p><p>of energy-sensing signaling pathways [19]. AMP-activated protein kinase (AMPK) is</p><p>impaired in OA chondrocytes. When impaired, AMPK will facilitate the production</p><p>of pro-inflammatory factors and cartilage degradation, as well as reduce the capacity for</p><p>mitochondrial biogenesis, which would otherwise be activated by the AMPK-SIRT1-PCG1α</p><p>pathway and reduce the risk of development of OA. Conversely, the inflammatory processes</p><p>associated with OA will activate the mammalian/mechanistic target of rapamycin (mTOR),</p><p>which is a serine/threonine protein kinase that functions as a catalytic subunit for two</p><p>protein complexes, mTORC1 and mTORC2. These pathways have been shown to enhance</p><p>chondrocyte inflammation and apoptosis, enhancing the effects of OA.</p><p>Nutrients 2024, 16, 1650 5 of 22</p><p>3. Inflammatory Process of Osteoarthritis</p><p>Despite the variable presentation and progression of OA, the underlying pathol-</p><p>ogy of inflammation remains consistent. Inflammation of the articular cartilage is due</p><p>to a change in the balance of cytokines that enhances a pro-inflammatory response and,</p><p>thus, the progression of osteoarthritis [25]. Pro-inflammatory cytokines, including IL-6,</p><p>TNF-α, and IL-1β, will also stimulate a multitude of chemokines to cause a migration of</p><p>additional pro-inflammatory cells to activate catabolic enzymes, including matrix metallo-</p><p>proteinases (MMPs) and a disintegrin-like and metalloproteinase with thrombospondin</p><p>motif (ADAMTS).</p><p>3.1. Pro-Inflammatory Cytokines</p><p>Pro-inflammatory cytokine, IL-1β, is one of the most abundant in the pathogenesis of</p><p>OA, as well as many other diseases [25]. It is a member of the IL-1 superfamily, including</p><p>IL-1Ra (IL-1 receptor agonist). It produces its inflammatory effects by binding to the IL-1</p><p>receptor I (IL-1RI), which is a transmembrane receptor that also allows the binding of</p><p>IL-1Ra and is found on many cells within the body, including chondrocytes, synoviocytes,</p><p>osteoblasts, osteoclasts, and macrophages. Upon binding of IL-1β to IL-1RI, there is a</p><p>cascade of signaling pathway activations that progress the pathogenesis of OA. Of these</p><p>cascades, the mitogen-activated protein kinase (MAPK) signaling has been demonstrated</p><p>as a predominant catabolic pathway of cartilage degradation in OA.</p><p>MAPK activates a subfamily of kinases that down-regulate aggrecan gene expression</p><p>and type II collagen, contributing to the disease process of reduction in extracellular</p><p>matrix production [25]. More specifically, extracellular signal-related kinases (ERKs), c-</p><p>Jun N-terminal kinases (JNKs), and p38 MAPKs, when activated by MAPK signaling,</p><p>down-regulate type II collagen, and aggrecan gene expression, and thus, a reduction in</p><p>chondrocyte synthesis. ERKs are also activated by prostaglandin E2 (PGE2), nitric oxide</p><p>(NO), and cycloxygenase-2 (COX-2), which are inflammatory mediators also stimulated</p><p>by IL-1β. ERKs, JNKs, and p38 MAPK activate MMPs and ADAMTS, which stimulate</p><p>aggrecanases and collagenases to reduce extracellular matrix synthesis and proteoglycan</p><p>production, and eventually chondrocyte hypertrophy, dedifferentiation, and apoptosis. P38</p><p>MAPK and JNKs also reduce SRY-related protein-9 (SOX9), which is a master director of</p><p>chondrocyte homeostasis, mediating MMP and ADAMTS, and when upregulated, is seen</p><p>as a potential treatment in the early stages of OA [26].</p><p>In addition to MAPK, IL-1β has demonstrated upregulation of nuclear factor kappa-</p><p>light-chain-enhancer of activated B cells (NF-κB), a pro-inflammatory mediator [27]. NF-κB</p><p>upregulates COX-2, PGE2, and NO to further enhance ERK activity and reduce proteogly-</p><p>can synthesis [25]. It mediates the activity of the MMP family ADAMTS-5 and ADAMTS-4,</p><p>resulting in proteoglycan degradation and disruption of collagen formation while sup-</p><p>pressing SOX9 activation, further reducing collagen synthesis as seen with JNK activation.</p><p>Finally, NF-κB upregulates IL-8 and chemokines, CCL2 and CCL5, which, in addition to</p><p>IL-6 and TNF-α (also stimulated by JNK and p38 MAPK), provide a positive feedback</p><p>mechanism to IL-1β to further enhance its pro-inflammatory response.</p><p>TNF-α, a member of the tumor necrosis factor family, is a pleiotropic cytokine involved</p><p>in homeostasis and disease pathology [28]. Initially, TNF-α was viewed as a cytotoxic</p><p>molecule due to its activity in necrotic regression of certain tumor cells; however, due</p><p>to its pleiotropic nature, it can also promote tissue regeneration, host defense, and cell</p><p>survival [26]. In relation to OA, when stimulated by the pro-inflammatory cytokines, TNF-</p><p>α will contribute to proteoglycan degradation and collagen disruption and inhibit collagen</p><p>synthesis via cell differentiation, proliferation, and apoptosis. TNF-α is a protein secreted in</p><p>two forms: membrane-bound (tmTNF-α) and the more biologically active soluble (sTNF-α)</p><p>form. Tumor necrosis factor receptor 1 (TNFR1) is a membrane receptor that can be activated</p><p>by both soluble and membrane-bound forms, while tumor necrosis factor receptor 2 (TNFR-</p><p>2) is stimulated by membrane-bound form; each receptor has unique structural formations</p><p>that result in differing signal pathways. Depending on the ligand attachment, TNFR1 can</p><p>Nutrients 2024, 16, 1650 6 of 22</p><p>initiate one of two signaling pathways. The first, complex 1, increases the expression of</p><p>pro-inflammatory genes and TNFR-1-associated death domain protein (TRADD), which</p><p>in turn activates the binding of receptor-interacting protein-1 (RIP-1) and TNF receptor-</p><p>associated factor-2 (TRAF-2). The binding of these two adaptor proteins results in the</p><p>stimulation of NF-κB, MAPK and its subfamilies, and activated protein-1 (AP-1), which</p><p>causes proteoglycan degradation, collagen disruption, and inhibition of collagen and</p><p>proteoglycan synthesis [29]. Conversely, complex 2 is associated with programmed cell</p><p>death via protein activation of Fas-associated death domain protein (FADD), procaspase</p><p>8/10, and finally, caspase 3 [30]. Last, TNFR2, when bound by TNFα, stimulates the</p><p>pro-inflammatory cascade of JNK and NF-κB, similar to complex 1 of TNFR1, producing</p><p>inhibited synthesis and degradation of proteoglycans and collagen. Due to the heightened</p><p>inflammatory response resulting from TNFα and signaling cascades, there will be greater</p><p>activation of pro-inflammatory cytokines and chemokines, furthering a positive feedback</p><p>mechanism to progress OA.</p><p>Interleukin 6 (IL-6) is another cytokine known to contribute to the inflammatory</p><p>response of OA; however, it has also been shown to participate in anti-inflammatory</p><p>processes [31]. IL-6 is highly active in the immune system and expressed in chondrocytes,</p><p>osteoblasts, macrophages, and adipocytes in response to IL-1β and TNF-α circulation. Its</p><p>activity is initiated through binding to the IL-6 receptors on either the cell membrane (mbIL-</p><p>6R) or soluble form (sIL-6R) in conjunction with gp130, a ubiquitously expressed protein</p><p>that activates either trans-signaling or classic-signaling [25]. IL-6 is bound to the selective</p><p>mbIL-6R and produces a classic-signaling cascade that promotes anti-inflammatory and</p><p>regenerative processes [32]. This mediation of anti-inflammatory pathways is regulated by</p><p>the activation of STAT3 (signal transducer and activator of transcription</p><p>3), which allows</p><p>for cell proliferation and inhibition of apoptosis. Conversely, trans-signaling is active on</p><p>virtually all cells due to the omnipresent pg130 and its interaction with sIL-6R, which, when</p><p>in abundance, is the determining factor of trans-signaling dominance over classic-signaling.</p><p>Research has demonstrated that in cases of OA with increased MMP10, ADAM10, and</p><p>ADAM 17, there is proteolytic cleavage of mbIL-6R via metzincin, which causes alternative</p><p>splicing of mRNA, resulting in the formation of sIL-6R. Furthermore, in patients with</p><p>high-grade OA, there are significantly greater concentrations of IL-6 in synovial fluid,</p><p>which is hypothesized to have a predictive value of progression of OA [33]. Utilizing</p><p>baseline and 3-year follow-up serum measurements, there was an increased concentration</p><p>of IL-6 and TNF-α in earlier stages of OA as compared to later stages; however, there was a</p><p>poor correlation to symptom severity. Similar to the pro-inflammatory signaling cascades</p><p>produced by TNF-α and IL-1β, IL-6 stimulates MAPK to enhance enzyme production of</p><p>the MMP family and reduce type II collagen formation [31].</p><p>3.2. Pro-Inflammatory Chemokines</p><p>In addition to cytokines, chemokines have demonstrated a large role in the pathogene-</p><p>sis of osteoarthritis [25]. Chemokines are small molecules that produce chemotaxis, or the</p><p>movement of cells within the body. These cells are known for their role in inflammation and</p><p>the recruitment of monocytes and macrophages to specific locations in the body, affecting</p><p>cellular responses, proliferation, and differentiation [34]. There are 4 families of chemokines</p><p>that are classified based on the position of the N-terminal cysteine residue, including C, CC,</p><p>CXC, and CX3C [25]. Most chemokines involved in osteoarthritis are in the CC (cysteine</p><p>residues adjacent) or the CXC (amino acid between cysteine residues) families. These small</p><p>protein ligands are activated upon binding to a G-protein coupled cell surface receptor,</p><p>which shows varying levels of binding affinity but is very selective in binding subfamily</p><p>receptors to their counterpart ligand (CCR to CCL). Upon binding to a chemokine-specific</p><p>receptor on a leukocyte, the newly formed complex will migrate to sites of inflammation</p><p>along the chemokine ligand gradient to assist in an inflammatory response. In addition to</p><p>cellular motility, chemokines are also known for helping T cell differentiation and stimu-</p><p>Nutrients 2024, 16, 1650 7 of 22</p><p>lation of function for adaptive immunity, as well as their pleiotropic effect enhancing the</p><p>disease progression of OA, including angiogenesis [35,36].</p><p>Of the CC subfamily, CCL2, CCL3, CCL4, and CCL5 are the most pertinent to OA [36].</p><p>CCL2, also known as monocyte chemoattractant protein-1 (MCP-1), is a strong chemotactic</p><p>molecule that recruits monocytes, memory T-lymphocytes, and natural killer (NK) cells</p><p>and is typically found in elevated concentrations in synovial fluid of knee OA [37]. CCL2 is</p><p>upregulated in chondrocytes, synovium, and fibroblasts secondary to inflammatory stimuli</p><p>and continues to be elevated as the disease progresses [34]. Upon recruitment to sites of in-</p><p>flammation, CCR2-expressing monocytes differentiate into pro-inflammatory macrophages</p><p>and drive local inflammation, playing a direct role in tissue damage. Additionally, CCL2</p><p>has been found to increase MMP-3 expression, causing proteoglycan loss and cartilaginous</p><p>degradation [25].</p><p>CCL3, also known as macrophage inflammatory protein 1-alpha (MIP-1α), is pro-</p><p>duced in synovial cell types, including macrophages, neutrophils, and fibroblasts, showing</p><p>enhanced expression upon inflammation [25]. In studies in murine models, it has been</p><p>found that CCL3 has a specific influence on osteoclast differentiation and enhanced bone</p><p>resorption, as when CCL3 was inhibited, there was a significant reduction in bone erosion</p><p>when OA was present [38]. CCL4, macrophage inflammatory protein 1-beta (MIP-1β), has</p><p>been defined as a unique chemokine, found to be increased in an individual’s synovial fluid</p><p>with osteoarthritis, with a 28% reduction in chemotactic activity when neutralized [39].</p><p>Researchers have hypothesized that fibroblasts do not directly express CCL4 but can be</p><p>stimulated to produce this chemokine upon exposure to TNF-α, IL-1β, or LPC. CCL5,</p><p>regulated on activation, normal T expressed, and secreted (RANTES), facilitates leukocyte</p><p>infiltration in inflamed joints of OA [40]. Researchers have demonstrated a direct corre-</p><p>lation between CCL5 and MMP-1 and MMP-13 expression/activation via JNK and ERK</p><p>protein expression, resulting in a stimulation of collagenases. Furthermore, to reduce the</p><p>development or severity of OA in a mouse model, researchers found no improvements or</p><p>no effect with the deficiency of CCL5 or CCR5 [38]. Finally, it should be noted that CCL2,</p><p>CCL3, CCL4, and CCL5 demonstrate upregulation in human chondrocytes when treated</p><p>with IL-1β [34,37,40].</p><p>Another important player in the development and progression of OA is the CXC</p><p>subfamily of chemokines [25]. More specifically, CXCL8 and CXCL12. CXCL8, also known</p><p>as IL-8, is active in the immune system, working as a chemoattractant of neutrophils, and</p><p>is expressed by CD8+T-cells, macrophages, and monocytes, as well as fibroblasts, epithelial</p><p>cells, and synoviocytes. Under pathological conditions, this protein binds to and acts on</p><p>receptors CXCR1 and CXCR2, located on leukocytes, chondrocytes, osteoclasts, fibroblasts,</p><p>and endothelial and epithelial cells of the nervous system [41]. Research has correlated</p><p>increased levels of IL-8 with pro-inflammatory processes of osteoarthritis, contributing to</p><p>the activation of MMP-13 and MMP-3 and its cascade of chondrocyte hypertrophy and</p><p>differentiation [42,43]. CXCL12, also known as stromal cell-derived factor-1 (SDF-1), is</p><p>another chemotactic protein that acts through the G-coupled protein receptor, CXCR4,</p><p>to promote tissue integrity for repair and regrowth [25,44]. When compared to healthy</p><p>controls, CXCL12 is increased 3.75-fold in the synovium of patients with OA, which in turn</p><p>enhances CXCR4+ inflammatory cells into the joint space, promoting activation of MMP1,</p><p>3, 9, and 13 and thus cartilage degradation. Additionally, CXCL12 has demonstrated a</p><p>role in stem cell homing and differentiation, resulting in osteophyte formation and bone</p><p>erosion, two contributing factors in the progression of OA [44,45].</p><p>4. Anti-Inflammatory Process of Osteoarthritis</p><p>Despite an upregulation of pro-inflammatory pathways, there is a continued anti-</p><p>inflammatory process that underlies an attempt to maintain homeostasis [25]. Of note,</p><p>two anti-inflammatory cytokines have demonstrated a role in controlling OA progression,</p><p>IL-4 and IL-10. IL-4 soluble receptor (sIL-4R) was seen to be elevated in synoviocytes and</p><p>synovial fluid of patients with hand, hip, and knee OA as compared to controls, with an</p><p>Nutrients 2024, 16, 1650 8 of 22</p><p>associated increase in CD4+T-cells [46,47]. Macrophages polarize to an M2 phenotype</p><p>with anti-inflammatory properties in response to IL-4, which causes wound healing, debris</p><p>clearance, and osteoclast inhibition [48]. IL-10’s pleiotropic effects have demonstrated</p><p>chondroprotective processes with inhibition of MMPs, a reduction in proteoglycan degrada-</p><p>tion, extracellular matrix remodeling, and matrix homeostasis via antagonist properties on</p><p>TNF-α’s caspase actions [49]. Both IL-4 and IL-10 are associated with the downregulation</p><p>of IL-1β, TNF-α, and IL-6, in addition to the secretion of secondary pro-inflammatory</p><p>mediators, PGE2, COX-2, and iNOS [25]. However, research has also shown that there are</p><p>reductions in concentrations of IL-10 in subjects with post-traumatic knee OA with main-</p><p>tained TNF-α concentrations, thus allowing the progression of OA [50]. Upon disruption</p><p>in the balance of anti-inflammatory and pro-inflammatory cytokines, a negative cascade of</p><p>positive feedback loops promotes the pathogenesis of OA, resulting in progressive joint</p><p>inflammation, cartilage degradations, and osteophyte formation.</p><p>5. Fatty Acids</p><p>In addition to mechanical loading, recent research has demonstrated a correlation</p><p>between OA and obesity, diabetes, and metabolic syndrome [51]. Obesity increases the</p><p>force on weight-bearing joints, resulting in a progressive increased risk of the development</p><p>of OA. Under the conditions of a high-fat diet, there is an upregulation of fatty acid</p><p>oxidation within cartilage as well as an increase in cholesterol uptake, increasing oxysterol</p><p>metabolites [22]. Such metabolites will induce the expression of pro-catabolic matrix</p><p>degradation enzymes. Excess intake of fat is typically accepted as an undesirable diet;</p><p>however, it seems as though the quality of fat versus the quantity of fat should be taken</p><p>into consideration.</p><p>Naturally occurring fatty acids can be classified into subcategories based on their</p><p>structure and presence of double bonds, including saturated fatty acids (SFA, no double</p><p>bond), monounsaturated fatty acids (MUFA, single double bond), and polyunsaturated</p><p>fatty acids (PUFA, multiple double bonds)) [51]. There is further subclassification based</p><p>on the location of the double bond in unsaturated fatty acids, with naming based on the</p><p>number of carbons in the chain and the position of the first double bond about the methyl</p><p>terminal (omega -ω, or n-FA) [52]. For example, all-cis-9,12,15-octadecatrienoic, also known</p><p>as α-linolenic acid, ALA, or C18:3 for its 18-carbon chain length, with 3 double bonds at</p><p>carbon 9, 12, and 15 counting from the methyl terminal. An additional classification</p><p>refers to the number of carbon atoms within the fatty acid chain; this includes long-</p><p>chain fatty acids (LCFA, ≥12 carbon atoms) and very-long-chain fatty acids (VLC-FA,</p><p>≥22 carbon atoms). Two well-known essential LCFAs that cannot be produced in the body</p><p>are the previously mentioned α-linolenic acid (ALA) and linolenic acid (LA). These two are</p><p>converted into VLC-PUFA by fatty acyl-CoA synthetases, ∆6- and ∆5-desaturases and their</p><p>relative elongases to produce all-cis-5,8,11,14,17-eicosapentaenoic (EPA, 20:5, n-3), all-cis-</p><p>7,10,13,16,19-docosapentaenoic (DPA, C22:5, n-3), all-cis-4,7,10,13,16,19-docosahexaenoic</p><p>(DHA; C22:6, n-3), and all-cis-5,8,11,14-eicosatetraenoic (arachidonic acid, ARA, C20:4, n-6),</p><p>which all play important roles within the human body.</p><p>5.1. Omega-3 and Omega-6 Fatty Acids</p><p>PUFAs are associated with positive health effects; however, n-3 and n-6 have differing</p><p>roles in metabolic functions within the human body [51]. Diets with high n-6 PUFA</p><p>are correlated with inflammation, vasoconstriction, and blood clotting, which, when in</p><p>response to acute inflammation, can protect against infection, yet when in excess, can result</p><p>in uncontrolled inflammation and an ideal environment for tumor growth. Conversely,</p><p>n-3 PUFA produces an anti-inflammatory effect, altering the function of vascular and</p><p>carcinogen biomarkers, including metabolic diseases, chronic inflammation, and conditions</p><p>that lead to a frail musculoskeletal system. The effects of PUFA can occur as a primary</p><p>event or secondary through signaling cascades utilizing bioactive signaling lipids, as well</p><p>as eicosanoids. Eicosanoids are derived from metabolites of ALA and LA, including ARA,</p><p>Nutrients 2024, 16, 1650 9 of 22</p><p>EPA, and DHA, and depending on its precursor, will determine if the eicosanoid will</p><p>produce a pro- or anti-inflammatory response.</p><p>LC-PUFAs are derived from plant and animal-based foods, mainly in the form of</p><p>triacylglycerols (TAG), phospholipids (PL), diacylglycerol (DAG), cholesterol esters (CE),</p><p>and fat-soluble vitamins esters [52]. Positioning of the LC-PUFA on its dietary form will</p><p>impact its bioavailability. For example, LC-PUFA in the form of PL (krill oil) is absorbed</p><p>more efficiently than TAGs (fish oil), as there is a greater uptake of PL within the brain.</p><p>Upon fatty acid oxidation, biosynthesis of LC-PUFA will occur within the endoplasmic</p><p>reticulum of hepatocytes, with the process initiated by ∆6-desaturation, a rate-limiting</p><p>step, adding a double bond at the 6th carbon atom from the carboxy end of LA and</p><p>ALA, producing γ-linolenic acid (GLA, C18:3, n-6) and stearidonic acid (SDA, C18:4, n-</p><p>3), respectively [53]. Next, a second 2-carbon elongation occurs via ∆6 specific elongase</p><p>yielding dihomo-γ-linolenic acid (DGLA, C20:3, n-6) and eicosatetraenoic acid (ETA, C20:4,</p><p>n-3), respectively. Last, a ∆5-desaturase adds a double bond at the 5th C—C bond and</p><p>carries out one more desaturation to produce ARA (C20:4, n-6) from SDA and EPA (C20:5,</p><p>n-3) from DGLA. EPA then undergoes two more elongations: tetracosanolpentaenoic acid</p><p>(C24:5, n-3) and tetracosahexaenoic acid (THA; C24:6, n-3). THA is subjected to β-oxidation</p><p>within the peroxisome, reducing its carbon chain by 2 atoms, achieving the final product,</p><p>VLC-PUFA docosahexaenoic acid (DHA; C22:6, n-3). Due to the utilization of the same pool</p><p>of desaturases and elongases, ALA and LA compete for bioconversion to their LC-PUFAs</p><p>and are dependent upon the ratio of consumed n-6: n-3 [53]. Interestingly, the greatest</p><p>formation of EPA and DHA occurs when there is a 1:1 ratio of LA: ALA, with a progressive</p><p>increase in n-3 status upon greater ingestion of ALA [54].</p><p>Upon synthesis, ARA, EPA, and DHA are esterified and stored in PL or neutral glycerides</p><p>and, when necessary, can be remobilized by phospholipase A2 to form eicosanoids [52]. ARA,</p><p>derived from n-6 PUFAs, are converted to pro-inflammatory cytokines, prostaglandins</p><p>(PGE2), and cyclooxygenase-2 (COX-2). By contrast, n-3 PUFAs are metabolized to anti-</p><p>inflammatory series 3 prostaglandins, series 5 leukotrienes, E-series resolvins, D-series</p><p>resolvins, protectins, and maresins. Resolvins, protectins, and maresins are all metabolites</p><p>of oxylipins classified as specialized pro-resolving lipid modulators (SPM) [55].</p><p>5.2. Anti-Inflammatory Processes of Omega-3 PUFAs</p><p>SPMs reduce pro-inflammatory immune cells, increase the production of anti-inflammatory</p><p>mediators, and counter-regulate pro-inflammatory mediators [56]. At the cellular level, this</p><p>occurs through macrophage phagocytosis of pathogens, apoptotic cells, and cellular debris,</p><p>and limits the infiltration of neutrophils and reduces chemokine and cytokine mediators to</p><p>promote tissue repair and regeneration. In a study with adults diagnosed with knee OA,</p><p>SPMs were administered for 12 weeks in the form of 500 mg soft gels; pain was significantly</p><p>reduced at both 8- and 12-week follow-ups (p = 0.039 and p = 0.031, respectively), as well as</p><p>improvements in self-reported quality of life.</p><p>Resolvins, including the E-series from EPA (RvE1, RvE4, 18S-RvE1) and D-series</p><p>from DHA (RvD1 to RvD6), act as agonists in peak periods of inflammation [57]. They</p><p>are metabolically catalyzed by lipoxygenases (LOX), cytochrome P450, and cyclooxyge-</p><p>nases (COX). Resolvins combine with G-protein-coupled receptors expressed in monocyte-</p><p>macrophages, lymphocytes, endothelial cells, vascular smooth muscle cells, and neu-</p><p>trophils, all of which are cell and organ-specific. Resolvin cellular targets depend on a</p><p>unique receptor; however, there can be common target cells for different resolvin sub-</p><p>types, yet with different imposing actions. RvE1 has been shown to regulate CD18 in</p><p>neutrophils, reduce the phosphorylation of MAPK, and inhibit superoxide production and</p><p>their migration between epithelial and endothelial cells. Additionally, RvD2 inhibits neu-</p><p>trophil chemotaxis to reduce migration and thus reduces the progression of inflammation.</p><p>Through multiple pathways, resolvins also mediate the macrophage response to inflamma-</p><p>tion. This occurs through the conversion of M1, pro-inflammatory macrophages, to M2,</p><p>anti-inflammatory macrophages, downregulation of monocyte conversion, modulation of</p><p>Nutrients 2024, 16, 1650 10 of 22</p><p>macrophage polarization, and manipulation of macrophage targeting IL-10 and 5-LOX.</p><p>Leukocytes, a key inflammatory contributor resulting in tissue damage, are regulated by</p><p>resolvins by reducing the expression of CD4+T-cells, facilitating cell migration of NK</p><p>to</p><p>remove eosinophilic granulocytes, and reducing the secretion of TNF-α and IL-6 cells. In</p><p>mouse models with osteoarthritis, researchers found RvD1 to have dampening effects on</p><p>the pro-inflammatory activity of synovial macrophages through recruitment of a greater</p><p>concentration of M2 cells, and it was able to target and reduce osteophyte formation with</p><p>an overall analgesic effect [58]. Research has also shown that RvD1 reduces the NLRP3</p><p>pathway through the inhibition of caspase-1 signaling, which would otherwise lead to</p><p>programmed cell death in chondrocytes of arthritic joints [59]. Furthermore, in humans</p><p>undergoing total knee arthroplasty, synovium, and fibroblast-like synoviocytes were ob-</p><p>tained and treated with concentrations of RvD1, finding a reduction in MMP-13 and IL-1β</p><p>secretion, suggesting a possible treatment method for late-stage OA [60]. Similarly, research</p><p>has synthesized an imidazole-derived RvD1 analog, finding greater antioxidant actions</p><p>than RvD1 derived from DHA, including scavenging ROS, thus protecting hyaluronic acid</p><p>from degradation [61].</p><p>Protectin D is derived from double lipooxygenation of DHA [55,62]. Protectin DX</p><p>(PDX) is the most widely evaluated member of the protectin family, demonstrating involve-</p><p>ment in anti-inflammation pathways in both chronic and acute inflammatory processes</p><p>through its effects on AMPK signaling. When studied in vivo and in vitro, Rat models with</p><p>knee OA, preincubated with PDX and then treated with IL-1β, demonstrated a suppression</p><p>in inflammation in chondrocytes [62]. There was a dose-dependent reduction in inhibition</p><p>of type II collagen degradation as well as an increase in AMPK phosphorylation. Activation</p><p>of AMPK through phosphorylation has been shown to reduce NF-κB nuclear translocation,</p><p>thus reducing its pro-inflammatory response, seen in this study by a reduction in expression</p><p>of MMP-3, MMP-13, ADAMTS4, iNOS, COX-2, NO, PGE2, and absent phosphorylation of</p><p>NF-κB [62,63].</p><p>Maresin-1, another metabolite of DHA, has also been shown to contribute to an</p><p>anti-inflammatory response in osteoarthritis, as well as pain hypersensitivity and post-</p><p>operative neuroinflammation [52,64]. It is produced by 12/15-lipoxygenase found in M2</p><p>macrophages and acts by restricting neutrophil infiltration, downregulating inflammatory</p><p>factors, enhancing phagocytosis, and promoting regeneration [64]. Using a rat model with</p><p>severe tibiofemoral cartilage damage through monosodium iodoacetate-induced (MIA) OA,</p><p>researchers found a positive response to the administration of maresin-1 when compared to</p><p>OA without maresin-1 treatment and a control group. There was a significant reduction in</p><p>cartilage damage with an improvement in type II collagen when compared to the untreated</p><p>and control groups. MMP13 significantly decreased in the maresin-1 treatment group</p><p>through inhibition of NF-κB and activation of the PI3K/Akt pathway, which plays an</p><p>important role in cell proliferation and survival [64,65].</p><p>6. Supplementation</p><p>Over the years, pharmacological treatments have been assessed to treat symptoms</p><p>of osteoarthritis, yet with variable success [66]. Through suppression of COX and PGEs,</p><p>NSAIDs are often used, yet with limited symptom improvement and frequently reported</p><p>side effects. Acetaminophen and opioids have been prescribed; however, there is always</p><p>the question of whether the risk of an unfavorable response outweighs the advantage of</p><p>potential pain control. With the limited success of pharmacological therapies, there has been</p><p>a growing interest in nutrition-based interventions in the treatment of OA, specifically with</p><p>the use of omega-3 PUFAs [8]. Omega-3 PUFAs are typically found in fatty fish, seafood,</p><p>and dietary supplements; however, traditional Western diets typically have a greater</p><p>concentration of omega-6 fatty acids, which compete for metabolic enzymes, potentially</p><p>reducing the positive effects of omega-3 PUFA [67].</p><p>Nutrients 2024, 16, 1650 11 of 22</p><p>6.1. Fatty Acid Composition: Ratio of Omega-6 to Omega-3</p><p>The fatty acid composition of cell membranes is altered based on the concentration</p><p>of fatty acids ingested due to their role in the formation of phospholipid bilayers, lipid-</p><p>mediated signaling, and gene expression [8]. Additionally, a high-fat diet is correlated</p><p>with weight changes and thus altered loading response of lower extremity joints and</p><p>a greater inflammatory response within joint-specific tissues [68]. Furthermore, when</p><p>osteoarthritic chondrocytes are cultured with either linoleic acid (n-6 PUFA), oleic acid</p><p>(MUFA), or palmitic acid (SFA), only linoleic acid was found to produce a pro-inflammatory</p><p>response [69]. All fatty acids were easily absorbed by the chondrocyte, resulting in a higher</p><p>concentration of intracellular lipids; however, while linoleic acid enhanced PGE2 via</p><p>TNF-α, both oleic and palmitic acid inhibited MMP1 gene expression and GAG release,</p><p>demonstrating altered influence of disease progression depending on the level of specific</p><p>fatty acids. However, when supplementation of conjugated linoleic acid (CLA) was paired</p><p>with EPA, it was found to have the greatest effect on reducing concentrations of PGE2 in</p><p>human osteoarthritic cartilage when compared to combinations of CLA with other n-6</p><p>PUFAs [70].</p><p>Looking more specifically at a ratio of n-6 to n-3, multiple variations have been</p><p>evaluated to determine if a pro-inflammatory or anti-inflammatory response dominates.</p><p>When assessed in a rat model with osteoarthritis, rats fed with a higher ratio of n-6/n-3</p><p>resulted in a greater concentration of n-6 fatty acids within the trabecular bone [71]. A ratio</p><p>of 1:1, n-6/n-3, demonstrated a significant reduction in MMP-13 expression, up to a 6:1</p><p>ratio, comparable to the control group, but no effect was seen at a ratio of 10:1. Similarly,</p><p>paw swelling significantly increased in the 365:1 treatment group (p < 0.01), while decreased</p><p>in the 1:1 and 2:1 (p < 0.01). In a human model, without supplementation, n-6/n-3 ratios</p><p>were examined in subjects with knee OA about pain and functional abilities, finding that</p><p>those with a greater ratio reported greater pain and functional limitations as compared to a</p><p>lower ratio (p < 0.04) [72].</p><p>Utilizing this information, research has assessed the correlations between dietary</p><p>intake of total fat, saturated fatty acids, MUFA, and PUFA as they relate to the specific</p><p>cellular progression of knee OA [68]. A positive association with the progression of a disease</p><p>state was found with increased total fat and saturated fat, yet a negative relationship with</p><p>MUFA and PUFA. More specifically, there was a significant reduction in joint space width in</p><p>those with greater intakes of saturated fatty acids and an associated progressive reduction</p><p>of joint space with increased total fat intake over 48 months (p = 0.02). Conversely, dietary</p><p>fat intakes with a higher ratio of MUFA and PUFA resulted in maintenance of joint space</p><p>width or a reduction in joint space loss as compared to total fat and saturated fat.</p><p>6.2. Omega-3 Supplementation and Synovial Fluid</p><p>Looking a little deeper into the joint, synovial fluid has also been examined to assess</p><p>the effects of fatty acid manifestations as related to the progression of joint inflamma-</p><p>tion [73]. Samples of synovial fluid were collected from shoulders and knees in individuals</p><p>undergoing surgery for end-stage OA. Samples of the knee displayed lower proportions of</p><p>linoleic acid (18:2, n-6), DHA (22:6, n-3), and total n-6 PUFAs when compared to a control.</p><p>However, this was not seen in samples collected from the shoulder, potentially due to the ab-</p><p>sent altered joint response to weight-bearing forces and its associated pathological cascade.</p><p>This was confirmed in an additional study assessing synovial fluid profiles of the arthritic</p><p>knee in subjects participating in the Multicenter Osteoarthritis Study (MOST) [74]. This</p><p>study demonstrated a positive association between n-6 PUFA and synovitis, yet an inverse</p><p>relationship between n-3 PUFAs and patellofemoral cartilage loss, but not tibiofemoral</p><p>cartilage loss.</p><p>6.3. Omega-3 Supplementation and Chondrocytes</p><p>Utilizing diet, researchers have compared a traditional Western diet with an n-6/n-3</p><p>ratio of 22:1 to a high n-3 diet, 1.5:1, to determine the influence of dietary supplementation</p><p>Nutrients 2024, 16, 1650 12 of 22</p><p>on OA-prone chondrocytes [75]. In a guinea pig model, a high n-3 diet allowed for a</p><p>reduction in OA disease progression (p = 0.048), achieving histological profiles similar to</p><p>those who are OA resistant. There was a significant reduction in GAG content (p = 0.003), a</p><p>reduction in denatured type II collagen, and a significant reduction in active MMP-2 levels</p><p>(p < 0.002). Supplementation with Antarctic krill oil has also been used to achieve a diet</p><p>high in omega-3 or a low n-6/n-3 ratio [76]. A diet with an n-6/n-3 ratio from 1:1 to 6:1</p><p>demonstrated significant improvement in cartilage structure and inhibition of cartilage</p><p>polysaccharide loss in mice with osteoarthritis. It was demonstrated that this ratio inhibited</p><p>the NF-κB signaling pathways and enhanced PPARγ, which inhibits inflammation and</p><p>cartilage degradation, concluding that dietary intervention could be a potential treatment</p><p>for OA. In addition to krill oil, the n-6/n-3 ratio of linseed oil (1:3.85), soybean oil (9.15:1),</p><p>and peanut oil (372.73:1) have also been tested to determine the influence on OA [77]. After</p><p>12 weeks of supplementation with linseed and soybean oil, mice with OA had increased</p><p>cartilage thickness and decreased TNF-α in both serum and chondrocytes, with no effects</p><p>seen in the peanut oil group. There were also findings of inhibited NF-κB pathway and</p><p>its resultant pro-inflammatory enzymes MMP-13 and ADAMTS-5. A human model with</p><p>IL-1β induced chondrocytes, treated with DHA, demonstrated enhanced chondrocyte</p><p>proliferation and reduced apoptosis, resulting in thicker cartilage, increased autophagy,</p><p>and reduced apoptosis through inhibition of JNK and p38 signaling pathways [78].</p><p>6.4. Omega-3 Supplementation and Pain, Stiffness, and Physical Function</p><p>Based on former findings in animal models, researchers tested the response to fish</p><p>oil on human subjects with knee OA, finding limited evidence in the short term [79].</p><p>In a randomized, double-blind trial, subjects with knee OA were provided with either</p><p>a high-dose supplement (4.5 g n-3) 15 mL/d or a low-dose (blend of fish and sunola</p><p>oil, 1:9 ratio with 0.45 g omega-3) 15 mL/d. Improvements were found in both groups;</p><p>however, no changes in cartilage volume were achieved, and interestingly, the low-dose</p><p>group had a greater reduction in pain and improved function at the 2-year follow-up.</p><p>These researchers noted that this could be due to a placebo effect; however, there was</p><p>no control group to compare baseline values, suggesting further research to determine</p><p>human responses. In more recent research, human subjects with mild to moderate knee OA</p><p>supplementing with krill oil demonstrated moderate improvements in knee pain, stiffness,</p><p>and physical function [80]. Over 6 months, participants were randomly assigned to either a</p><p>placebo group (mixed vegetable oil) or an intervention group (4 g krill oil/d—0.60 g EPA,</p><p>0.28 g DHA). Those with omega-3 supplementation demonstrated an increased omega-3</p><p>index (p < 0.001), improvements in knee stiffness and physical function (p < 0.05), and</p><p>improvements in pain in both groups.</p><p>New Zealand Green Lippped Musssel (GLP) has demonstrated a promising influence</p><p>on treatment for osteoarthritis due to its anti-inflammatory properties, attributed to its</p><p>make-up of long-chain omega-3 fatty acids [81]. When GLP is administered in supplemental</p><p>form (600 mg/d) in subjects with moderate to severe hip OA, there was a reduction in</p><p>joint stiffness (p = 0.046) and pain medication use (p = 0.001) after 12 weeks [82]. However,</p><p>despite these significant benefits, this did not achieve a clinical benefit, as there were</p><p>no significant differences in pain or quality of life when compared to individuals in the</p><p>control group.</p><p>The use of gelatin hydrogels has also been evaluated as they have demonstrated the</p><p>ability to contain a physiologically active substance with gradual release over 3 weeks [83].</p><p>Researchers assessed the effect of incorporating EPA into the gelatin hydrogels to determine</p><p>a potential beneficial response in a mouse model with OA. When compared against direct</p><p>injection of EPA, the hydrogels provided a significantly lower histological profile of MMP-3,</p><p>MMP-13, and IL-1β, as well as a significantly lower presence of macrophages (p = 0.004).</p><p>Additionally, this study demonstrated that the gelatin hydrogels containing EPA had more</p><p>potent effects than a single EPA injection and that the EPA in the hydrogels was fully</p><p>Nutrients 2024, 16, 1650 13 of 22</p><p>released within 4 weeks with effects maintained for approximately 8 weeks, suggesting a</p><p>potential approach for OA treatment.</p><p>6.5. Omega-3 Supplementation for OA with Comorbidities</p><p>Omega-3 PUFAs have also been shown to have cardioprotective effects, specifically in</p><p>those with coronary artery disease (CAD) [84]. Aerobic exercise and capacity are inversely</p><p>related to cardiovascular morbidity, which can be perpetuated by pain and limited physical</p><p>function from osteoarthritis. Taking into consideration omega-3’s cardioprotective and</p><p>symptom-mediating effects, researchers have assessed whether supplementation with EPA</p><p>and DHA could maintain physical function and improve tolerance to physical activity in</p><p>subjects with CAD and limited by osteoarthritis symptoms [85]. Participants were split into</p><p>the experimental group, supplementing with Lovaza (465 mg EPA, 375 mg DHA) 4× daily</p><p>(total of 3.36 g omega-3) or no supplementation for one year. The treatment group found</p><p>a significant reduction in triglyceride levels (p < 0.001), hs-CRP levels (p = 0.023), white</p><p>blood cell count (p = 0.029), and neutrophil count (p = 0.007). At the one-year follow-up, the</p><p>control group experienced a significant increase in pain and stiffness (p = 0.002 and p-0.001,</p><p>respectively) and worsening physical function (p < 0.001) compared to no change in the</p><p>intervention group. Following the study, those who partook in supplementation had a</p><p>47-minute increase in total minutes of physical activity (p = 0.044), which was significantly</p><p>higher when compared to the control group (p = 0.028). Furthermore, 4 subjects in the</p><p>control group underwent total hip or knee surgery due to the severity of OA symptoms,</p><p>whereas no subjects in the treatment group required surgery. This trend was similar at</p><p>the 30-month follow-up, resulting in surgical intervention for 11 members of the control</p><p>group and 1 member of the Lovaza group. This study concluded that high doses of omega-</p><p>3 supplementation were able to preserve physical function and reduce musculoskeletal</p><p>events without adverse effects.</p><p>6.6. Omega-3 Supplementation and Its Indirect Effects on OA</p><p>Despite the varying evidence for omega-3 supplementations’ direct effect on os-</p><p>teoarthritis progression and symptoms, researchers have demonstrated the indirect ef-</p><p>fects of omega-3 supplements on muscle recovery following exercise. A common non-</p><p>pharmacological treatment for osteoarthritis is exercised to improve or maintain joint</p><p>mobility flexibility and promote muscle power and function, thus reducing unnecessary</p><p>loads from the joint [86]. Studies have demonstrated a reduction in the isokinetic force of</p><p>the hip muscle in the setting of knee OA, with a direct correlation to pain and self-reported</p><p>functional ability [87,88]. When tested in community-dwelling adults between the ages of</p><p>60- and 85 years old, fish oil-derived omega-3 supplementation allowed for improvements</p><p>in quadriceps muscle volume, hand grip strength, and 1RM strength (all p < 0.05). This</p><p>reduction in age-related muscle mass decline is imperative to maintaining functional inde-</p><p>pendence and physical activity levels, thus reducing the risk of comorbidities. Similarly,</p><p>omega-3 supplementation has demonstrated a positive influence on the onset of delayed</p><p>onset muscle soreness</p><p>(DOMS) following excessive eccentric contractions (ECC). DOMS re-</p><p>sults in a reduction of muscle power, decreased joint range of motion, and muscle swelling,</p><p>peaking 1–3 days and lasting up to 7 days following ECC and/or increased exercise [89,90].</p><p>Supplementation with 600 mg EPA and 260 mg DHA, 8 weeks before initiating exercise and</p><p>continued 5 days following the intervention, demonstrated improvements in joint range</p><p>of motion (p < 0.05), increased maximal voluntary contraction (p < 0.05), and reduction</p><p>in reported muscle soreness (p < 0.05). This study was repeated with a 4-week duration,</p><p>finding similar results in maintained joint range of motion (p < 0.050), yet no differences</p><p>in the other outcome measures when compared to the control group [91]. However, re-</p><p>searchers found a significant reduction in creatine kinase levels 3 days following ECC,</p><p>demonstrating a reduction in muscle tissue damage. By enhancing recovery following exer-</p><p>cise, individuals in an OA or healthy state will be able to promote and maintain mobility</p><p>Nutrients 2024, 16, 1650 14 of 22</p><p>and physical activity that would further reduce the risk of the progression of comorbidities</p><p>related to osteoarthritis.</p><p>6.7. Omega-3 Supplementation in Combination with Other Nutraceuticals in OA</p><p>Multiple supplemental and nutritional products have been evaluated to reduce the</p><p>physical and psychological impact of OA [92]. Moreover, researchers have assessed the</p><p>positive response to such nutraceuticals in combination with omega-3 supplementation.</p><p>A food supplement, Phytaligic (fish oil, vitamin E, and Urtica doica), was created and</p><p>evaluated for its effectiveness in patients with hip or knee OA as compared to a control</p><p>with regular use of NSAIDs [93]. After 3 months of supplementation, there was a significant</p><p>decrease between groups in the use of NSAIDs (p < 0.001) and WOMAC scores for pain,</p><p>stiffness, and function (p < 0.001), concluding a positive response to osteoarthritis symptoms</p><p>and reduced need for analgesics.</p><p>Curcumin is a Neutraceutical agent that has been studied for the treatment of os-</p><p>teoarthritis due to its anti-inflammatory properties [94]. Research has evaluated if omega-3</p><p>and/or curcumin could be used as a substitute treatment method for OA, and fish oil</p><p>was found to be superior to curcumin both alone and in combination [95]. This study,</p><p>in particular, administered fish oil made up of 2000 mg/d DHA, 400 mg/d EPA, and</p><p>160 mg curcumin, or both for 16 weeks in obese individuals with OA-related chronic</p><p>pain. Researchers found that the fish oil supplement significantly reduced OA-specific</p><p>pain (p = 0.002) and burden (p = 0.015) associated with changes in microvascular elasticity,</p><p>CRP inflammatory markers, and wellbeing, compared to a control, and no change in the</p><p>curcumin group.</p><p>Supplementation with glucosamine sulfate has been established as a common treat-</p><p>ment for osteoarthritis despite its variable results in research [96]. Similar to omega-3</p><p>PUFAs, glucosamine functions as a substrate for the biosynthesis of chondroitin sulfate,</p><p>which is required for the development and maintenance of cartilage and extracellular</p><p>matrix [97]. Researchers have assessed if supplementation of glucosamine alone or in</p><p>combination with omega-3 influences symptoms of OA, finding a greater improvement in</p><p>combination supplementation (p = 0.004) in reducing morning stiffness of hips and knees.</p><p>These findings were allocated to the fact that the omega-3 content assisted in the reduction</p><p>of cartilage degradation by controlling the inflammatory response, resulting in a reduction</p><p>of swelling and, thus, the symptom of stiffness.</p><p>Recent research has highlighted the role of vitamin D influence on OA due to its role in</p><p>muscle strength and bone resorption, with similar anti-inflammatory properties as omega-3</p><p>PUFAs [98]. Studies have demonstrated a correlation between low vitamin D levels and</p><p>the progression of OA; however, results remain conflicted. A large double-blind, placebo-</p><p>controlled trial was conducted over 5 years to test the response of vitamin D (cholecalciferol</p><p>2000 IU/day) and omega-3 (1 g/day, 840 mg EPA and DHA 1.3:1 ratio) supplementation</p><p>on chronic knee pain secondary to OA. No significant differences were observed between</p><p>either vitamin D or omega-3 and their respective control groups on symptoms of OA. This</p><p>study, however, did not consider radiographic findings, which could have demonstrated</p><p>changes in the quality of joint space despite limited improvements in symptoms.</p><p>6.8. Diet Rich in Omega-3 and Osteoarthritis</p><p>Obesity is a modifiable risk factor for osteoarthritis symptoms [99]. Clinical guidelines</p><p>for knee OA recommend diet and exercise as a safe and effective approach to relieve pain</p><p>and improve function. However, weight loss can be difficult when attempting to utilize</p><p>exercise secondary to pain and disability related to OA progression. Simply administering</p><p>a calorie-restricted diet, no less than 1100 kcal/day for women and 1200 kcal/day for men,</p><p>with appropriate calorie distribution and gentle exercise, resulted in a significant, yet small,</p><p>reduction in knee pain over 18 months.</p><p>In addition to reduced biomechanical forces with weight loss, losing weight is also</p><p>associated with a reduction in pain-associated inflammation [100]. This is further sup-</p><p>Nutrients 2024, 16, 1650 15 of 22</p><p>ported when administering a diet rich in food sources containing anti-inflammatory com-</p><p>pounds, including food sources rich in omega-3 PUFAs. Research has evaluated an anti-</p><p>inflammatory diet in comparison to a calorie-restricted diet in women over the age of</p><p>40 referred to physical therapy for knee pain related to OA. The low-calorie diet requires</p><p>the consumption of 500 kcal/day less energy than the total energy expenditure of each</p><p>individual. This intervention was designed to consume fat less than 30% of calories, car-</p><p>bohydrates 55–60%, and protein 10–15%. The anti-inflammatory diet relied on fruit and</p><p>vegetables in large quantities, protein from plants (legumes, soy, nuts, seeds) and fish</p><p>sources (encouraged to supplement with omega-3 in addition to normal intake), and plant</p><p>sources of fat, including walnuts and flaxseed rich in alpha-linoleic acid. After 2 months of</p><p>intervention, there was a reduction in pain in both groups (p < 0.001), with a significant</p><p>reduction in the anti-inflammatory diet group when compared to the calorie-restricted</p><p>diet (p < 0.001). Only the anti-inflammatory group demonstrated significant increases in</p><p>quality-of-life subscales of general health (p < 0.001), pain (p = 0.002), emotional wellbeing</p><p>(p = 0.006), vitality (p = 0.031), physical function (p < 0.001), and a significant reduction</p><p>in depression and anxiety (p = 0.003 and p = 0.011, respectively). This study also found</p><p>that the weight loss was three times greater in the anti-inflammatory group, which was</p><p>attributed to the use of plant proteins and vegetables, reduction in trans fatty acids, and</p><p>use of omega-3-rich foods.</p><p>High-fat diets, consisting of greater concentrations of trans and saturated fats, have</p><p>demonstrated increased risk factors and pain in individuals with OA [101]. Conversely,</p><p>the Mediterranean diet emphasizes fruit and vegetables, whole grains, and healthy fats</p><p>(omega-3 sources of olive oil, nuts, fatty fish, and low-fat dairy) and has been shown to</p><p>reduce the prevalence of OA in some individuals [102]. A total of 129 patients with knee</p><p>OA between the ages of 45 and 70 were included in a study evaluating the effectiveness</p><p>of a Mediterranean diet versus a low-fat diet on biometrics, pain, physical function, and</p><p>stiffness over 12 weeks. The Mediterranean diet consisted of 35%, 50%, and 15% calories</p><p>from fats, carbohydrates, and proteins, 27–37 g of fiber per day, and at least one serving</p><p>of nuts and legumes per day. The low-fat diet contained 20%, 65%, and 15% of total</p><p>daily calories from fats, carbohydrates, and protein, with no additional dietary advice.</p><p>Both groups were compared against a control group, which was asked not to change its</p><p>dietary</p><p>patterns. This study found weight and waist circumference to be significantly</p><p>reduced in the two intervention groups (p < 0.001), as well as pain, stiffness, and physical</p><p>function. However, there was only a significant difference in pain in the Mediterranean diet</p><p>compared to the low-fat diet (p = 0.02). The onset of knee pain in standing improved by</p><p>100% in the Mediterranean diet group (p = 0.01), and morning stiffness decreased by 81%</p><p>after 12 weeks. The authors concluded that the dietary components of the Mediterranean</p><p>diet are effective in pain modulation of knee osteoarthritis.</p><p>As explained, diet and nutrition have the potential to play an important role in pain</p><p>control and functional activity tolerance in osteoarthritis. The high concentrations of</p><p>omega 3, an anti-inflammatory source, within the Mediterranean diet have demonstrated a</p><p>positive influence on symptom management in OA; however, there are limited studies on</p><p>its influence on serum biomarkers of inflammation [103]. Dyer, Davidson, Marcora, and</p><p>Mauger recruited 99 volunteers with a clinical diagnosis of OA to participate in a 16-week</p><p>dietary intervention to assess the systemic response of a Mediterranean diet. Subjects were</p><p>randomized into either a diet group, provided with nutritional information and dietary</p><p>advice consistent with a Mediterranean diet, or into a control group, provided without</p><p>additional information, and blood samples were taken pre- and post-intervention. This</p><p>study found all members were similar in baseline biomarker measurements, yet, at post-</p><p>treatment analysis, there was a significant reduction in pro-inflammatory IL-1α (p = 0.019)</p><p>and a non-significant reduction in serum cartilage oligomeric matrix protein (a marker for</p><p>cartilage degradation, p = 0.057) in the diet group, and no change seen in the control group.</p><p>However, this study did not find a significant change in additional biomarkers, including</p><p>the interleukin family, IFN-γ, TNF-α, and EGF. Despite the lack of significant response,</p><p>Nutrients 2024, 16, 1650 16 of 22</p><p>it has been explained that relatively small changes in biomarkers have been shown to</p><p>precede radiological evidence of changes in the joint [104]. In addition to biomarkers, these</p><p>researchers demonstrated significant improvements in hip and knee ROM (knee flexion</p><p>p = 0.072, and hip rotation p = 0.010) following the diet intervention when compared to</p><p>the control [103]. These results suggest potential benefits through dietary intervention,</p><p>yet they should be further studied in the long term to determine potential further or</p><p>prolonged benefits.</p><p>7. Dietary Sources of Omega-3</p><p>According to the National Institute of Health (NIH), adequate intakes of omega-3</p><p>PUFAs in those older than the age of 19 are 1.6 g/d in males and 1.1 g/d in females, with</p><p>increased requirements for females during pregnancy and lactation [105,106]. In addition</p><p>to food sources seen in Figure 1, omega-3s are available in dietary supplement form [105].</p><p>Doses have a wide variety; however, supplements typically provide about 1000 mg of fish</p><p>oil, which contains 180 mg of EPA and 120 mg of DHA. Some supplements are provided in</p><p>marine oil form, which is also a rich source of fat-soluble vitamins [107]. In particular, the</p><p>liver oil of cod, haddock, halibut, shark, whales, and tuna are typically used to produce</p><p>vitamins A and D, containing approximately 1000 and 10 IU/g, respectively. Omega-3s are</p><p>presented in many different forms in supplements, including natural triglycerides found in</p><p>marine oils, free fatty acids, ethyl esters, re-esterified triglycerides, and phospholipids. Sup-</p><p>plements in the form of re-esterified triglycerides, natural triglycerides, and free fatty acids</p><p>have been reported to have greater bioavailability than ethyl esters; however, consumption</p><p>of any form of the supplement will enhance plasma EPA and DHA levels [105].</p><p>Nutrients 2024, 16, x FOR PEER REVIEW  16  of  21</p><p>a positive influence on symptom management in OA; however, there are limited studies</p><p>on  its  influence on serum biomarkers of  inflammation [103]. Dyer, Davidson, Marcora,</p><p>and Mauger recruited 99 volunteers with a clinical diagnosis of OA to participate in a 16-</p><p>week dietary intervention to assess the systemic response of a Mediterranean diet. Sub-</p><p>jects were randomized into either a diet group, provided with nutritional information and</p><p>dietary advice consistent with a Mediterranean diet, or  into a control group, provided</p><p>without additional  information, and blood samples were  taken pre- and post-interven-</p><p>tion. This study found all members were similar in baseline biomarker measurements, yet,</p><p>at post-treatment analysis, there was a significant reduction in pro-inflammatory IL-1α (p</p><p>= 0.019) and a non-significant reduction in serum cartilage oligomeric matrix protein (a</p><p>marker for cartilage degradation, p = 0.057) in the diet group, and no change seen in the</p><p>control group. However,  this  study did not find a  significant  change  in additional bi-</p><p>omarkers, including the interleukin family, IFN-γ, TNF-α, and EGF. Despite the lack of</p><p>significant  response,  it has been explained  that  relatively small changes  in biomarkers</p><p>have been shown to precede radiological evidence of changes in the joint [104]. In addition</p><p>to biomarkers, these researchers demonstrated significant improvements in hip and knee</p><p>ROM (knee flexion p = 0.072, and hip rotation p = 0.010) following the diet intervention</p><p>when compared to the control [103]. These results suggest potential benefits through die-</p><p>tary intervention, yet they should be further studied in the long term to determine poten-</p><p>tial further or prolonged benefits.</p><p>7. Dietary Sources of Omega-3</p><p>According  to  the National  Institute of Health  (NIH), adequate  intakes of omega-3</p><p>PUFAs in those older than the age of 19 are 1.6 g/d in males and 1.1 g/d in females, with</p><p>increased requirements for females during pregnancy and lactation [105,106]. In addition</p><p>to food sources seen in Figure 1, omega-3s are available in dietary supplement form [105].</p><p>Doses have a wide variety; however, supplements typically provide about 1000 mg of fish</p><p>oil, which contains 180 mg of EPA and 120 mg of DHA. Some supplements are provided</p><p>in marine oil form, which is also a rich source of fat-soluble vitamins [107]. In particular,</p><p>the liver oil of cod, haddock, halibut, shark, whales, and tuna are typically used to produce</p><p>vitamins A and D, containing approximately 1000 and 10 IU/g, respectively. Omega-3s are</p><p>presented in many different forms in supplements, including natural triglycerides found</p><p>in marine oils, free fatty acids, ethyl esters, re-esterified triglycerides, and phospholipids.</p><p>Supplements in the form of re-esterified triglycerides, natural triglycerides, and free fatty</p><p>acids have been reported to have greater bioavailability than ethyl esters; however, con-</p><p>sumption of any form of the supplement will enhance plasma EPA and DHA levels [105].</p><p>0 0.2 0.4 0.6 0.8 1 1.2 1.4</p><p>Atlantic Salmon 3oz</p><p>Canned Sardines in tomato sauce</p><p>Mackerel 3oz</p><p>Rainbow trout 3oz</p><p>Oysters</p><p>Sea Bass 3oz</p><p>Cooked Shrimp 3oz</p><p>Light Canned Tuna 3oz</p><p>Egg, cooked, 1</p><p>Chicken Breast, roasted, 3oz</p><p>EPA g/Serving DHA g/serving</p><p>Figure 1. Dietary sources of Omega 3 PUFA.</p><p>The Institute of Medicine (IOM) developed the acceptable daily macronutrient range</p><p>(ADMR) based on potential adverse effects [105]. The AMDR for omega-3 as ALA is</p><p>established as 0.6–1.2% of energy for children and adults, with 10% of that intake safe</p><p>to be consumed as EPA and/or DHA. The IOM has not established the UL for omega-</p><p>3 but has explained that high dosages of EPA and/or DHA (900 mg/d and 600 mg/d,</p><p>respectively) for several weeks or years have the potential to reduce immune function due</p><p>to suppression of the inflammatory response, increase the bleeding time by a reduction in</p><p>platelet aggregation, and slightly increase the risk of atrial fibrillation in those with CVD or</p><p>at high risk of CVD. The FDA has concluded</p>