Risk of metabolic abnormalities in osteoarthritis: a new perspective to understand its pathological mechanisms

Abstract

Although aging has traditionally been viewed as the most important risk factor for osteoarthritis (OA), an increasing amount of epidemiological evidence has highlighted the association between metabolic abnormalities and OA, particularly in younger individuals. Metabolic abnormalities, such as obesity and type II diabetes, are strongly linked to OA, and they affect both weight-bearing and non-weight-bearing joints, thus suggesting that the pathogenesis of OA is more complicated than the mechanical stress induced by overweight. This review aims to explore the recent advances in research on the relationship between metabolic abnormalities and OA risk, including the impact of abnormal glucose and lipid metabolism, the potential pathogenesis and targeted therapeutic strategies.

References

[1] Hu Y et al. Subchondral bone microenvironment in osteoarthritis and pain. Bone Res., 2021, 9: 20

[2] Hunter DJ, Bierma-Zeinstra S. Osteoarthritis. Lancet, 2019, 393: 1745-1759

[3] Loeser RF et al. Osteoarthritis: a disease of the joint as an organ. Arthritis Rheum., 2012, 64: 1697-1707

[4] Chen D et al. Osteoarthritis: toward a comprehensive understanding of pathological mechanism. Bone Res., 2017, 5: 16044

[5] Tong L et al. Current understanding of osteoarthritis pathogenesis and relevant new approaches. Bone Res., 2022, 10: 60

[6] Scuderi GR. Complications after total knee arthroplasty: how to manage patients with osteolysis. J. Bone Jt. Surg. Am., 2011, 93: 2127-2135

[7] Grayson CW, Decker RC. Total joint arthroplasty for persons with osteoarthritis. Phys. Med. Rehabil., 2012, 4: S97-S103

[8] Deveza LA, Loeser RF. Is osteoarthritis one disease or a collection of many? Rheumatology., 2018, 57: iv34-iv42

[9] Bruyère O et al. Can we identify patients with high risk of osteoarthritis progression who will respond to treatment? A focus on epidemiology and phenotype of osteoarthritis. Drugs Aging, 2015, 32: 179-187

[10] Altman R et al. Development of criteria for the classification and reporting of osteoarthritis. Classification of osteoarthritis of the knee. Diagnostic and Therapeutic Criteria Committee of the American Rheumatism Association. Arthritis Rheum., 1986, 29: 1039-1049

[11] Courties A, Sellam J, Berenbaum F. Metabolic syndrome-associated osteoarthritis. Curr. Rheumatol. Rep., 2017, 29: 214-222

[12] Issa R. I. & Griffin T. M. Pathobiology of obesity and osteoarthritis: integrating biomechanics and inflammation. Pathobiol. Aging Age Relat. Dis. 2, (2012).

[13] Reyes C et al. Association between overweight and obesity and risk of clinically diagnosed knee, hip, and hand osteoarthritis: a population-based cohort study. Arthritis Rheumatol., 2016, 68: 1869-1875

[14] Chang J et al. Systemic and local adipose tissue in knee osteoarthritis. Osteoarthr. Cartil., 2018, 26: 864-871

[15] Urban H, Little CB. The role of fat and inflammation in the pathogenesis and management of osteoarthritis. Rheumatology, 2018, 57: iv10-iv21

[16] Thijssen E, van Caam A, van der Kraan PM. Obesity and osteoarthritis, more than just wear and tear: pivotal roles for inflamed adipose tissue and dyslipidaemia in obesity-induced osteoarthritis. Rheumatology, 2015, 54: 588-600

[17] Wang T, He C. Pro-inflammatory cytokines: the link between obesity and osteoarthritis. Cytokine Growth Factor Rev., 2018, 44: 38-50

[18] Voinier D et al. Using cumulative load to explain how body mass index and daily walking relate to worsening knee cartilage damage over two years: the MOST study. Arthritis Rheumatol., 2020, 72: 957-965

[19] Lohmander LS et al. Incidence of severe knee and hip osteoarthritis in relation to different measures of body mass: a population-based prospective cohort study. Ann. Rheum. Dis., 2009, 68: 490-496

[20] Plotz B et al. Current epidemiology and risk factors for the development of hand osteoarthritis. Curr. Rheumatol. Rep., 2021, 23: 61

[21] Giri B et al. Chronic hyperglycemia mediated physiological alteration and metabolic distortion leads to organ dysfunction, infection, cancer progression and other pathophysiological consequences: an update on glucose toxicity. Biomed. Pharmacother., 2018, 107: 306-328

[22] Veronese N et al. Type 2 diabetes mellitus and osteoarthritis. Semin. Arthritis Rheu, 2019, 49: 9-19

[23] Zhuo Q et al. Metabolic syndrome meets osteoarthritis. Nat. Rev. Rheumatol., 2012, 8: 729-737

[24] So MW, Lee S, Kim SH. Association between dietary glycemic index and knee osteoarthritis: the Korean national health and nutrition examination survey 2010-2012. J. Acad. Nutr. Diet., 2018, 118: 1673-1686.e1672

[25] Veronese N et al. Adherence to a Mediterranean diet is associated with lower prevalence of osteoarthritis: data from the osteoarthritis initiative. Clin. Nutr., 2017, 36: 1609-1614

[26] Gandhi R et al. Metabolic syndrome and the functional outcomes of hip and knee arthroplasty. J. Rheumatol., 2010, 37: 1917-1922

[27] Yasuda E et al. Association between the severity of symptomatic knee osteoarthritis and cumulative metabolic factors. Aging Clin. Exp. Res, 2018, 30: 481-488

[28] Centers for Disease Control and Prevention (CDC). Prevalence of doctor-diagnosed arthritis and arthritis-attributable activity limitation-United States, 2010-2012. MMWR Morb Mortal Wkly Rep. 62, 869–873 (2013).

[29] Jorgensen AE, Kjaer M, Heinemeier KM. The Effect of aging and mechanical loading on the metabolism of articular cartilage. J. Rheumatol., 2017, 44: 410-417

[30] Mobasheri A et al. The role of metabolism in the pathogenesis of osteoarthritis. Nat. Rev. Rheumatol., 2017, 13: 302-311

[31] Rasheed Z, Akhtar N, Haqqi TM. Advanced glycation end products induce the expression of interleukin-6 and interleukin-8 by receptor for advanced glycation end product-mediated activation of mitogen-activated protein kinases and nuclear factor-κB in human osteoarthritis chondrocytes. Rheumatology, 2011, 50: 838-851

[32] Steenvoorden MM et al. Activation of receptor for advanced glycation end products in osteoarthritis leads to increased stimulation of chondrocytes and synoviocytes. Arthritis Rheum., 2006, 54: 253-263

[33] DeGroot J et al. Accumulation of advanced glycation endproducts reduces chondrocyte-mediated extracellular matrix turnover in human articular cartilage. Osteoarthr. Cartil., 2001, 9: 720-726

[34] Huang CY et al. Advanced glycation end products cause collagen II reduction by activating Janus kinase/signal transducer and activator of transcription 3 pathway in porcine chondrocytes. Rheumatology, 2011, 50: 1379-1389

[35] Yang Q et al. Advanced glycation end products-induced chondrocyte apoptosis through mitochondrial dysfunction in cultured rabbit chondrocyte. Fundam. Clin. Pharm., 2015, 29: 54-61

[36] Suzuki A, Yabu A, Nakamura H. Advanced glycation end products in musculoskeletal system and disorders. Methods, 2022, 203: 179-186

[37] Gallo J et al. Inflammation and its resolution and the musculoskeletal system. J. Orthop. Transl., 2017, 10: 52-67

[38] Jrad AIS et al. Role of pro-inflammatory interleukins in osteoarthritis: a narrative review. Connect. Tissue Res., 2023, 64: 238-247

[39] Anderson JJ, Felson DT. Factors associated with osteoarthritis of the knee in the first national health and nutrition examination survey (HANES I). Evidence for an association with overweight, race, and physical demands of work. Am. J. Epidemiol., 1988, 128: 179-189

[40] Rogero MM, Calder PC. Obesity, inflammation, toll-Like receptor 4 and fatty acids. Nutrients, 2018, 10: 432

[41] Conde J et al. Adipokines and osteoarthritis: novel molecules involved in the pathogenesis and progression of disease. Arthritis, 2011, 2011: 203901

[42] Fain JN. Release of inflammatory mediators by human adipose tissue is enhanced in obesity and primarily by the nonfat cells: a review. Mediat. Inflamm., 2010, 2010: 513948

[43] Guss JD et al. The effects of metabolic syndrome, obesity, and the gut microbiome on load-induced osteoarthritis. Osteoarthr. Cartil., 2019, 27: 129-139

[44] Jiang M et al. Oral Administration of resveratrol alleviates osteoarthritis pathology in C57BL/6J mice model induced by a high-fat diet. Mediat. Inflamm., 2017, 2017: 7659023

[45] Liu L et al. Protective effect of resveratrol against IL-1β-induced inflammatory response on human osteoarthritic chondrocytes partly via the TLR4/MyD88/NF-κB signaling pathway: an “in vitro study”. Int. J. Mol. Sci., 2014, 15: 6925-6940

[46] de Silva VA et al. Metformin in prevention and treatment of antipsychotic induced weight gain: a systematic review and meta-analysis. BMC Psychiatry, 2016, 16

[47] Yerevanian A, Soukas AA. Metformin: mechanisms in human obesity and weight loss. Curr. Obes. Rep., 2019, 8: 156-164

[48] Lu CH et al. Combination COX-2 inhibitor and metformin attenuate rate of joint replacement in osteoarthritis with diabetes: A nationwide, retrospective, matched-cohort study in Taiwan. PLoS One, 2018, 13: e0191242

[49] Li J et al. Metformin limits osteoarthritis development and progression through activation of AMPK signalling. Ann. Rheum. Dis., 2020, 79: 635-645

[50] Conrozier T. How to treat osteoarthritis in obese patients? Curr. Rheumatol. Rev., 2020, 16: 99-104

[51] Matsuda M, Shimomura I. Increased oxidative stress in obesity: Implications for metabolic syndrome, diabetes, hypertension, dyslipidemia, atherosclerosis, and cancer. Obes. Res. Clin. Pr., 2013, 7: E330-E341

[52] Niemann B et al. Oxidative stress and cardiovascular risk: obesity, diabetes, smoking, and pollution part 3 of a 3-part series. J. Am. Coll. Cardiol., 2017, 70: 230-251

[53] Ahmed B, Sultana R, Greene MW. Adipose tissue and insulin resistance in obese. Biomed. Pharmacother., 2021, 137: 111315

[54] Paneni F et al. Diabetes and vascular disease: pathophysiology, clinical consequences, and medical therapy: part I. Eur. Heart J., 2013, 34: 2436-U2434

[55] de Mello AH et al. Mitochondrial dysfunction in obesity. Life Sci., 2018, 192: 26-32

[56] Rendra E et al. Reactive oxygen species (ROS) in macrophage activation and function in diabetes. Immunobiology, 2019, 224: 242-253

[57] Ansari MY, Ahmad N, Haqqi TM. Oxidative stress and inflammation in osteoarthritis pathogenesis: Role of polyphenols. Biomed. Pharmacother., 2020, 129: 110452

[58] Lepetsos P, Papavassiliou KA, Papavassiliou AG. Redox and NF-κB signaling in osteoarthritis. Free Radic. Bio. Med., 2019, 132: 90-100

[59] Zhou F et al. Isorhamnetin attenuates osteoarthritis by inhibiting osteoclastogenesis and protecting chondrocytes through modulating reactive oxygen species homeostasis. J. Cell Mol. Med., 2019, 23: 4395-4407

[60] Bolduc JA, Collins JA, Loeser RF. Reactive oxygen species, aging and articular cartilage homeostasis. Free Radic. Biol. Med., 2019, 132: 73-82

[61] Li J, Dong S. The signaling pathways involved in chondrocyte differentiation and hypertrophic differentiation. Stem Cells Int, 2016, 2016: 2470351

[62] Han J et al. Inhibition of NADPH oxidases prevents the development of osteoarthritis. Antioxidants, 2022, 11: 2346

[63] Gui T et al. Superoxide dismutase-loaded porous polymersomes as highly efficient antioxidant nanoparticles targeting synovium for osteoarthritis therapy. Biomaterials, 2022, 283: 121437

[64] Lu HL et al. Radical-scavenging and subchondral bone-regenerating nanomedicine for osteoarthritis treatment. ACS Nano, 2023, 17: 6131-6146

[65] Reed KN et al. The role of mitochondrial reactive oxygen species in cartilage matrix destruction. Mol. Cell Biochem., 2014, 397: 195-201

[66] Kang D et al. Selenophosphate synthetase 1 deficiency exacerbates osteoarthritis by dysregulating redox homeostasis. Nat. Commun., 2022, 13

[67] Lee SH, Park SY, Choi CS. Insulin resistance: from mechanisms to therapeutic strategies. Diabetes Metab. J., 2022, 46: 15-37

[68] Eymard F et al. Diabetes is a risk factor for knee osteoarthritis progression. Osteoarthr. Cartil., 2015, 23: 851-859

[69] Hamada D et al. Suppressive effects of insulin on tumor necrosis factor-dependent early osteoarthritic changes associated with obesity and type 2 diabetes mellitus. Arthritis Rheumatol., 2016, 68: 1392-1402

[70] Ribeiro M et al. Diabetes-accelerated experimental osteoarthritis is prevented by autophagy activation. Osteoarthr. Cartil., 2016, 24: 2116-2125

[71] Schett G et al. Diabetes is an independent predictor for severe osteoarthritis: results from a longitudinal cohort study. Diabetes Care, 2013, 36: 403-409

[72] Qiao L, Li Y, Sun S. Insulin exacerbates inflammation in fibroblast-like synoviocytes. Inflammation, 2020, 43: 916-936

[73] Blaney Davidson EN et al. Inducible chondrocyte-specific overexpression of BMP2 in young mice results in severe aggravation of osteophyte formation in experimental OA without altering cartilage damage. Ann. Rheum. Dis., 2015, 74: 1257-1264

[74] Courties A, Sellam J. Osteoarthritis and type 2 diabetes mellitus: what are the links? Diabetes Res. Clin. Pr., 2016, 122: 198-206

[75] Chen YJ et al. Advanced glycation end-products induced VEGF production and inflammatory responses in human synoviocytes via RAGE-NF-κB pathway activation. J. Orthop. Res., 2016, 34: 791-800

[76] Zhu S et al. The molecular structure and role of LECT2 or CHM-II in arthritis, cancer, and other diseases. J. Cell Physiol., 2022, 237: 480-488

[77] Willis SA et al. Acute hyperenergetic, high-fat feeding increases circulating FGF21, LECT2, and Fetuin-A in healthy men. J. Nutr., 2020, 150: 1076-1085

[78] Ikeda D et al. iTRAQ-based proteomics reveals novel biomarkers of osteoarthritis. Biomarkers, 2013, 18: 565-572

[79] Yang Y et al. Lipid metabolism in cartilage and its diseases: a concise review of the research progress. Acta Biochim. Biophys. Sin., 2021, 53: 517-527

[80] Dahaghin S et al. Do metabolic factors add to the effect of overweight on hand osteoarthritis? The rotterdam study. Ann. Rheum. Dis., 2007, 66: 916-920

[81] Gkretsi V, Simopoulou T, Tsezou A. Lipid metabolism and osteoarthritis: lessons from atherosclerosis. Prog. Lipid Res., 2011, 50: 133-140

[82] Puenpatom RA, Victor TW. Increased prevalence of metabolic syndrome in individuals with osteoarthritis: an analysis of NHANES III data. Postgrad. Med., 2009, 121: 9-20

[83] Chang HW et al. Blue mussel (Mytilus edulis) water extract ameliorates inflammatory responses and oxidative stress on osteoarthritis in obese rats. J. Pain. Res., 2020, 13: 1109-1119

[84] Sekar S et al. Saturated fatty acids induce development of both metabolic syndrome and osteoarthritis in rats. Sci. Rep., 2017, 7

[85] Alvarez-Garcia O et al. Palmitate has proapoptotic and proinflammatory effects on articular cartilage and synergizes with interleukin-1. Arthritis Rheumatol., 2014, 66: 1779-1788

[86] Sekar S et al. Saturated fatty acids promote chondrocyte matrix remodeling through reprogramming of autophagy pathways. Nutrition, 2018, 54: 144-152

[87] Ma H et al. Myriocin alleviates Oleic/Palmitate induced chondrocyte degeneration via the suppression of ceramide. Eur. Rev. Med. Pharm. Sci., 2020, 24: 12938-12947

[88] Lu B et al. Dietary fat intake and radiographic progression of knee osteoarthritis: data from the osteoarthritis initiative. Arthritis Care Res., 2017, 69: 368-375

[89] Mustonen AM et al. Anterior cruciate ligament transection alters the n-3/n-6 fatty acid balance in the lapine infrapatellar fat pad. Lipids Health Dis., 2019, 18: 67

[90] Bastiaansen-Jenniskens YM et al. Monounsaturated and saturated, but not n-6 polyunsaturated fatty acids decrease cartilage destruction under inflammatory conditions: a preliminary study. Cartilage, 2013, 4: 321-328

[91] Van de Vyver A et al. Synovial fluid fatty acid profiles differ between osteoarthritis and healthy patients. Cartilage, 2020, 11: 473-478

[92] Jiang H et al. Adiponectin, may be a potential protective factor for obesity-related osteoarthritis. Diabetes Metab. Syndr. Obes., 2022, 15: 1305-1319

[93] Loef M et al. Fatty acids and osteoarthritis: different types, different effects. Jt. Bone Spine, 2019, 86: 451-458

[94] Frommer KW et al. Free fatty acids: potential proinflammatory mediators in rheumatic diseases. Ann. Rheum. Dis., 2015, 74: 303-310

[95] Adler N, Schoeniger A, Fuhrmann H. Polyunsaturated fatty acids influence inflammatory markers in a cellular model for canine osteoarthritis. J. Anim. Physiol. N., 2018, 102: E623-E632

[96] Wu CL et al. Serum and synovial fluid lipidomic profiles predict obesity-associated osteoarthritis, synovitis, and wound repair. Sci. Rep., 2017, 7

[97] Loef M et al. The association of plasma fatty acids with hand and knee osteoarthritis: the NEO study. Osteoarthr. Cartil., 2020, 28: 223-230

[98] Huang M-J et al. Enhancement of the synthesis of n-3 PUFAs in fat-1 transgenic mice inhibits mTORC1 signalling and delays surgically induced osteoarthritis in comparison with wild-type mice. Ann. Rheum. Dis., 2014, 73: 1719

[99] Zainal Z et al. Relative efficacies of omega-3 polyunsaturated fatty acids in reducing expression of key proteins in a model system for studying osteoarthritis. Osteoarthr. Cartil., 2009, 17: 896-905

[100] Sibille KT et al. Omega-6: Omega-3 PUFA ratio, pain, functioning, and distress in adults with knee pain. Clin. J. Pain., 2018, 34: 182-189

[101] Hill CL et al. Fish oil in knee osteoarthritis: a randomised clinical trial of low dose versus high dose. Ann. Rheum. Dis., 2016, 75: 23-29

[102] Pousinis P et al. Lipidomic identification of plasma lipids associated with pain behaviour and pathology in a mouse model of osteoarthritis. Metabolomics, 2020, 16

[103] Zhao W et al. Label-free and continuous-flow ferrohydrodynamic separation of HeLa cells and blood cells in biocompatible ferrofluids. Adv. Funct. Mater., 2016, 26: 3990-3998

[104] Siodmiak J et al. Molecular dynamic analysis of hyaluronic acid and phospholipid interaction in tribological surgical adjuvant design for osteoarthritis. Molecules, 2017, 22: 1436

[105] Rocha B et al. Identification of a distinct lipidomic profile in the osteoarthritic synovial membrane by mass spectrometry imaging. Osteoarthr. Cartil., 2021, 29: 750-761

[106] Kosinska MK et al. A lipidomic study of phospholipid classes and species in human synovial fluid. Arthritis Rheum., 2013, 65: 2323-2333

[107] Zhai G et al. Activation of the phosphatidylcholine to lysophosphatidylcholine pathway is associated with osteoarthritis knee cartilage volume loss over time. Sci. Rep., 2019, 9

[108] Rocha B et al. Targeted phospholipidomic analysis of synovial fluid as a tool for osteoarthritis deep phenotyping. Osteoarthr. Cartil. Open, 2021, 3: 100219

[109] Zhang W et al. Lysophosphatidylcholines to phosphatidylcholines ratio predicts advanced knee osteoarthritis. Rheumatology, 2016, 55: 1566-1574

[110] Zhai G. Chapter Three - Clinical relevance of biochemical and metabolic changes in osteoarthritis. In: Makowski G. S. (ed). Advances in Clinical Chemistry, vol. 101. Elsevier, (2021), pp 95-120.

[111] Zhai GJ, Randell EW, Rahman P. Metabolomics of osteoarthritis: emerging novel markers and their potential clinical utility. Rheumatology, 2018, 57: 2087-2095

[112] Pruzanski W et al. Enzymatic activity and distribution of phospholipase A2 in human cartilage. Life Sci., 1991, 48: 2457-2462

[113] Bomalaski JS, Clark MA. Phospholipase A2 and arthritis. Arthritis Rheum., 1993, 36: 190-198

[114] Soccio RE, Breslow JL. Intracellular cholesterol transport. Arterioscler Thromb. Vasc. Biol., 2004, 24: 1150-1160

[115] Wu S, De Luca F. Role of cholesterol in the regulation of growth plate chondrogenesis and longitudinal bone growth. J. Biol. Chem., 2004, 279: 4642-4647

[116] Tsezou A et al. Impaired expression of genes regulating cholesterol efflux in human osteoarthritic chondrocytes. J. Orthop. Res., 2010, 28: 1033-1039

[117] Wang Q et al. Fermentation supernatant of Staphylococcus aureus drives catabolism in chondrocytes via NF-κB signaling mediated increase of cholesterol metabolism. Exp. Cell Res., 2022, 410: 112952

[118] Wang X et al. Ultrasound-targeted simvastatin-loaded microbubble destruction promotes OA cartilage repair by modulating the cholesterol efflux pathway mediated by PPARγ in rabbits. Bone Jt. Res., 2021, 10: 693-703

[119] Kim K et al. RORα controls hepatic lipid homeostasis via negative regulation of PPARγ transcriptional network. Nat. Commun., 2017, 8

[120] Sun MM, Beier F. Liver X receptor activation regulates genes involved in lipid homeostasis in developing chondrocytes. Osteoarthr. Cartil. Open, 2020, 2: 100030

[121] Bougarne N et al. Molecular actions of PPARα in lipid metabolism and inflammation. Endocr. Rev., 2018, 39: 760-802

[122] Ratneswaran A et al. Nuclear receptors regulate lipid metabolism and oxidative stress markers in chondrocytes. J. Mol. Med., 2017, 95: 431-444

[123] Xiao J et al. Activation of liver X receptors promotes inflammatory cytokine mRNA degradation by upregulation of tristetraprolin. Acta Biochim. Biophys. Sin., 2017, 49: 277-283

[124] Joseph SB et al. Direct and indirect mechanisms for regulation of fatty acid synthase gene expression by liver X receptors. J. Biol. Chem., 2002, 277: 11019-11025

[125] Kostopoulou F et al. MicroRNA-33a regulates cholesterol synthesis and cholesterol efflux-related genes in osteoarthritic chondrocytes. Arthritis Res. Ther., 2015, 17: 42

[126] Collins-Racie LA et al. Global analysis of nuclear receptor expression and dysregulation in human osteoarthritic articular cartilage: reduced LXR signaling contributes to catabolic metabolism typical of osteoarthritis. Osteoarthr. Cartil., 2009, 17: 832-842

[127] Joseph SB et al. Reciprocal regulation of inflammation and lipid metabolism by liver X receptors. Nat. Med., 2003, 9: 213-219

[128] Tall AR, Yvan-Charvet L. Cholesterol, inflammation and innate immunity. Nat. Rev. Immunol., 2015, 15: 104-116

[129] He H et al. Vaspin regulated cartilage cholesterol metabolism through miR155/LXRα and participated in the occurrence of osteoarthritis in rats. Life Sci., 2021, 269: 119096

[130] Xing H et al. Metformin mitigates cholesterol accumulation via the AMPK/SIRT1 pathway to protect osteoarthritis chondrocytes. Biochem. Biophys. Res. Commun., 2022, 632: 113-121

[131] Lin XL et al. Curcumin enhanced cholesterol efflux by upregulating ABCA1 expression through AMPK-SIRT1-LXRα signaling in THP-1 macrophage-derived foam cells. DNA Cell Biol., 2015, 34: 561-572

[132] Zhu Z et al. AMPK activator decelerates osteoarthritis development by inhibition of β-catenin signaling in chondrocytes. J. Orthop. Transl., 2023, 38: 158-166

[133] Li J et al. Oral administration of berberine limits post-traumatic osteoarthritis development and associated pain via AMP-activated protein kinase (AMPK) in mice. Osteoarthr. Cartil., 2022, 30: 160-171

[134] Yi D et al. AMPK signaling in energy control, cartilage biology, and osteoarthritis. Front. Cell Dev. Biol., 2021, 9: 696602

[135] Liang C et al. Resveratrol improves the progression of osteoarthritis by regulating the SIRT1-FoxO1 pathway-mediated cholesterol metabolism. Mediat. Inflamm., 2023, 2023: 2936236

[136] Su Z et al. Lipid metabolism in cartilage development, degeneration, and regeneration. Nutrients, 2022, 14: 3984

[137] Chambers KF et al. Polyphenol effects on cholesterol metabolism via bile acid biosynthesis, CYP7A1: a review. Nutrients, 2019, 11: 2588

[138] Chen L et al. Molecular mechanisms for ABCA1-mediated cholesterol efflux. Cell Cycle, 2022, 21: 1121-1139

[139] Triantaphyllidou IE et al. Perturbations in the HDL metabolic pathway predispose to the development of osteoarthritis in mice following long-term exposure to western-type diet. Osteoarthr. Cartil., 2013, 21: 322-330

[140] Garcia-Gil M et al. Serum lipid levels and risk of hand osteoarthritis: the chingford prospective cohort study. Sci. Rep., 2017, 7

[141] Lu K et al. Defects in a liver-bone axis contribute to hepatic osteodystrophy disease progression. Cell Metab., 2022, 34: 441-457.e447

[142] Liu Y et al. The role of PPAR-δ in metabolism, inflammation, and cancer: many characters of a critical transcription factor. Int. J. Mol. Sci., 2018, 19: 3339

[143] Zhang H et al. Glucagon-like peptide-1 attenuated carboxymethyl lysine induced neuronal apoptosis via peroxisome proliferation activated receptor-γ. Aging, 2021, 13: 19013-19027

[144] Nogueira-Recalde U et al. Fibrates as drugs with senolytic and autophagic activity for osteoarthritis therapy. Ebiomedicine, 2019, 45: 588-605

[145] Park S et al. PPARα-ACOT12 axis is responsible for maintaining cartilage homeostasis through modulating de novo lipogenesis. Nat. Commun., 2022, 13

[146] Zhou Y et al. Chondroprotection of PPARα activation by WY14643 via autophagy involving Akt and ERK in LPS-treated mouse chondrocytes and osteoarthritis model. J. Cell Mol. Med., 2019, 23: 2782-2793

[147] Sabatini M et al. Effects of agonists of peroxisome proliferator-activated receptor gamma on proteoglycan degradation and matrix metalloproteinase production in rat cartilage in vitro. Osteoarthr. Cartil., 2002, 10: 673-679

[148] Vasheghani F et al. PPARγ deficiency results in severe, accelerated osteoarthritis associated with aberrant mTOR signalling in the articular cartilage. Ann. Rheum. Dis., 2015, 74: 569-578

[149] Watters JW et al. Inverse relationship between matrix remodeling and lipid metabolism during osteoarthritis progression in the STR/Ort mouse. Arthritis Rheum., 2007, 56: 2999-3009

[150] Wang H et al. GDF11 inhibits abnormal adipogenesis of condylar chondrocytes in temporomandibular joint osteoarthritis. Bone Jt. Res., 2022, 11: 453-464

[151] Huang G et al. Role of peroxisome proliferator-activated receptors in osteoarthritis (Review). Mol. Med. Rep., 2021, 23: 159

[152] Ratneswaran A et al. Peroxisome proliferator-activated receptor δ promotes the progression of posttraumatic osteoarthritis in a mouse model. Arthritis Rheumatol., 2015, 67: 454-464

[153] Choi WS et al. The CH25H-CYP7B1-RORα axis of cholesterol metabolism regulates osteoarthritis. Nature, 2019, 566: 254-258

[154] Gentili C et al. Cholesterol secretion and homeostasis in chondrocytes: a liver X receptor and retinoid X receptor heterodimer mediates apolipoprotein A1 expression. Matrix Biol., 2005, 24: 35-44

[155] Liang T et al. Inhibition of nuclear receptor RORα attenuates cartilage damage in osteoarthritis by modulating IL-6/STAT3 pathway. Cell Death Dis., 2021, 12

[156] Li XC et al. MicroRNA-10a-3p improves cartilage degeneration by regulating CH25H-CYP7B1-ROR alpha mediated cholesterol metabolism in knee osteoarthritis rats. Front. Pharm., 2021, 12: 690181

[157] Cao C et al. Cholesterol-induced LRP3 downregulation promotes cartilage degeneration in osteoarthritis by targeting Syndecan-4. Nat. Commun., 2022, 13

[158] Farnaghi S et al. Cholesterol metabolism in pathogenesis of osteoarthritis disease. Int. J. Rheum. Dis., 2017, 20: 131-140

[159] Pan F et al. Association between metabolic syndrome and knee structural change on MRI. Rheumatology, 2020, 59: 185-193

[160] Meng T et al. Association of glucose homeostasis and metabolic syndrome with knee cartilage defects and cartilage volume in young adults. Semin. Arthritis Rheum., 2020, 50: 192-197

[161] Schwager JL et al. Association of serum low-density lipoprotein, high-density lipoprotein, and total cholesterol with development of knee osteoarthritis. Arthrit Care Res., 2022, 74: 274-280

[162] Zhang KB et al. High-density lipoprotein cholesterol and apolipoprotein A1 in synovial fluid: potential predictors of disease severity of primary knee osteoarthritis. Cartilage, 2021, 13: 1465S-1473S

[163] Luo QL et al. Effects of ultrasound therapy on the synovial fluid proteome in a rabbit surgery-induced model of knee osteoarthritis. Biomed. Eng. Online, 2019, 18

[164] Sánchez-Enríquez S et al. Increase levels of apo-A1 and apo B are associated in knee osteoarthritis: lack of association with VEGF-460 T/C and +405 C/G polymorphisms. Rheumatol. Int., 2008, 29: 63-68

[165] Meng H et al. Causal associations of circulating lipids with osteoarthritis: a bidirectional mendelian randomization study. Nutrients, 2022, 14: 1327

[166] Kurano M et al. Apolipoprotein D modulates lipid mediators and osteopontin in an anti-inflammatory direction. Inflamm. Res., 2023, 72: 263-280

[167] Bhatia S et al. Selective reduction of hydroperoxyeicosatetraenoic acids to their hydroxy derivatives by apolipoprotein D: implications for lipid antioxidant activity and Alzheimer’s disease. Biochem. J., 2012, 442: 713-721

[168] Zhang Y et al. Antioxidant activities of recombinant amphioxus (Branchiostoma belcheri) apolipoprotein D. Mol. Biol. Rep., 2011, 38: 1847-1851

[169] Qin Y et al. Apolipoprotein D as a potential biomarker and construction of a transcriptional regulatory-immune network associated with osteoarthritis by weighted gene coexpression network analysis. Cartilage, 2021, 13: 1702s-1717s

[170] Li B et al. A novel serological biomarker are associated with disease severity in patients with osteoarthritis. J. Bone Min. Metab., 2022, 40: 1007-1013

[171] Farnaghi S et al. Protective effects of mitochondria-targeted antioxidants and statins on cholesterol-induced osteoarthritis. Faseb J., 2017, 31: 356-367

[172] de Munter W et al. High LDL levels lead to increased synovial inflammation and accelerated ectopic bone formation during experimental osteoarthritis. Osteoarthr. Cartil., 2016, 24: 844-855

[173] Friedman JM. Leptin and the endocrine control of energy balance. Nat. Metab., 2019, 1: 754-764

[174] Hui W et al. Leptin produced by joint white adipose tissue induces cartilage degradation via upregulation and activation of matrix metalloproteinases. Ann. Rheum. Dis., 2012, 71: 455-462

[175] Bao JP et al. Leptin plays a catabolic role on articular cartilage. Mol. Biol. Rep., 2010, 37: 3265-3272

[176] Abella V et al. Leptin in the interplay of inflammation, metabolism and immune system disorders. Nat. Rev. Rheumatol., 2017, 13: 100-109

[177] Stannus OP et al. Cross-sectional and longitudinal associations between circulating leptin and knee cartilage thickness in older adults. Ann. Rheum. Dis., 2015, 74: 82-88

[178] Dumond H et al. Evidence for a key role of leptin in osteoarthritis. Arthritis Rheum., 2003, 48: 3118-3129

[179] Chen TH et al. Evidence for a protective role for adiponectin in osteoarthritis. Biochim. Biophys. Acta, 2006, 1762: 711-718

[180] Kang EH et al. Adiponectin is a potential catabolic mediator in osteoarthritis cartilage. Arthritis Res. Ther., 2010, 12: R231

[181] Yamauchi T et al. Cloning of adiponectin receptors that mediate antidiabetic metabolic effects. Nature, 2003, 423: 762-769

[182] Yamauchi T et al. Targeted disruption of AdipoR1 and AdipoR2 causes abrogation of adiponectin binding and metabolic actions. Nat. Med., 2007, 13: 332-339

[183] Koskinen A et al. Adiponectin associates with markers of cartilage degradation in osteoarthritis and induces production of proinflammatory and catabolic factors through mitogen-activated protein kinase pathways. Arthritis Res. Ther., 2011, 13: R184

[184] Hao D et al. Synovial fluid level of adiponectin correlated with levels of aggrecan degradation markers in osteoarthritis. Rheumatol. Int., 2011, 31: 1433-1437

[185] Sharma L. Osteoarthritis of the knee. N. Engl. J. Med., 2021, 384: 51-59

[186] Bannuru RR et al. OARSI guidelines for the non-surgical management of knee, hip, and polyarticular osteoarthritis. Osteoarthr. Cartil., 2019, 27: 1578-1589

[187] Kolasinski SL et al. 2019 American college of rheumatology/arthritis foundation guideline for the management of osteoarthritis of the hand, hip, and knee. Arthritis Rheumatol., 2020, 72: 220-233

[188] Fransen M et al. Exercise for osteoarthritis of the knee. Cochrane Database Syst. Rev., 2015, 1: Cd004376

[189] Juhl C et al. Impact of exercise type and dose on pain and disability in knee osteoarthritis: a systematic review and meta-regression analysis of randomized controlled trials. Arthritis Rheumatol., 2014, 66: 622-636

[190] Messier SP et al. Intentional weight loss in overweight and obese patients with knee osteoarthritis: is more better? Arthritis Care Res., 2018, 70: 1569-1575

[191] Hall M et al. Diet-induced weight loss alone or combined with exercise in overweight or obese people with knee osteoarthritis: A systematic review and meta-analysis. Semin. Arthritis Rheum., 2019, 48: 765-777

[192] Heidari B. Knee osteoarthritis diagnosis, treatment and associated factors of progression: part II. Casp. J. Intern. Med., 2011, 2: 249-255

[193] Deyle GD et al. Physical therapy versus glucocorticoid injection for osteoarthritis of the knee. N. Engl. J. Med., 2020, 382: 1420-1429

[194] Rutjes AW et al. Viscosupplementation for osteoarthritis of the knee: a systematic review and meta-analysis. Ann. Intern. Med., 2012, 157: 180-191

[195] Shan L et al. Intermediate and long-term quality of life after total knee replacement: a systematic review and meta-analysis. J. Bone Jt. Surg. Am., 2015, 97: 156-168

[196] Gai Z et al. Lipid accumulation and chronic kidney disease. Nutrients, 2019, 11: 722

[197] Istvan ES, Deisenhofer J. Structural mechanism for statin inhibition of HMG-CoA reductase. Science, 2001, 292: 1160-1164

[198] Saberianpour S et al. Therapeutic effects of statins on osteoarthritis: a review. J. Cell Biochem., 2022, 123: 1285-1297

[199] Oesterle A, Laufs U, Liao JK. Pleiotropic effects of statins on the cardiovascular system. Circ. Res, 2017, 120: 229-243

[200] Juybari KB, Hosseinzadeh A, Sharifi AM. Protective effects of atorvastatin against high glucose-induced nuclear factor-κB activation in cultured C28I2 chondrocytes. J. Recept Signal Transduct. Res., 2019, 39: 1-8

[201] Terabe K et al. Simvastatin promotes restoration of chondrocyte morphology and phenotype. Arch. Biochem. Biophys., 2019, 665: 1-11

[202] Wu YP et al. Pravastatin reduces matrix metalloproteinases expression and promotes cholesterol efflux in osteoarthritis chondrocytes. Evid.-Based Compl. Alt., 2022, 2022: 9666963

[203] Du J et al. Effect of high fat diet and excessive compressive mechanical force on pathologic changes of temporomandibular joint. Sci. Rep.-Uk, 2020, 10: 17457

[204] Tanaka T et al. Attenuation of osteoarthritis progression in mice following intra-articular administration of simvastatin-conjugated gelatin hydrogel. J. Tissue Eng. Regen. Med, 2019, 13: 423-432

[205] Katole NT, Kale JS, Salankar HV. Evaluation of the antinociceptive action of simvastatin in mice. Cureus, 2022, 14: e26910-e26910

[206] Goto N et al. Single intra-articular injection of fluvastatin-PLGA microspheres reduces cartilage degradation in rabbits with experimental osteoarthritis. J. Orthop. Res, 2017, 35: 2465-2475

[207] Zhou B et al. Proliferation of rabbit chondrocyte and inhibition of IL-1β-induced apoptosis through MEK/ERK signaling by statins. Vitr. Cell Dev.-, 2017, 53: 124-131

[208] Clockaerts S et al. Statin use is associated with reduced incidence and progression of knee osteoarthritis in the Rotterdam study. Ann. Rheum. Dis., 2012, 71: 642-647

[209] Haj-Mirzaian A et al. Statin use and knee osteoarthritis outcome measures according to the presence of heberden nodes: results from the osteoarthritis initiative. Radiology, 2019, 293: 396-404

[210] Loomba R et al. Ezetimibe for the treatment of nonalcoholic steatohepatitis: assessment by novel magnetic resonance imaging and magnetic resonance elastography in a randomized trial (mozart trial). Hepatology, 2015, 61: 1239-1250

[211] Cannon CP et al. Ezetimibe added to statin therapy after acute coronary syndromes. N. Engl. J. Med., 2015, 372: 2387-2397

[212] Gierman LM et al. Osteoarthritis development is induced by increased dietary cholesterol and can be inhibited by atorvastatin in APOE*3Leiden.CETP mice-a translational model for atherosclerosis. Ann. Rheum. Dis., 2014, 73: 921-927

[213] Szychlinska MA, Ravalli S, Musumeci G. Pleiotropic effect of fibrates on senescence and autophagy in osteoarthritis. Ebiomedicine, 2019, 45: 11-12

[214] Lalloyer F, Staels B. Fibrates, glitazones, and peroxisome proliferator-activated receptors. Arterioscler Thromb. Vasc. Biol., 2010, 30: 894-899

[215] Clockaerts S et al. Cytokine production by infrapatellar fat pad can be stimulated by interleukin 1 beta and inhibited by peroxisome proliferator activated receptor alpha agonist. Ann. Rheum. Dis., 2012, 71: 1012-1018

[216] Clockaerts S et al. The infrapatellar fat pad should be considered as an active osteoarthritic joint tissue: a narrative review. Osteoarthr. Cartil., 2010, 18: 876-882

[217] Distel E et al. The infrapatellar fat pad in knee osteoarthritis: an important source of interleukin-6 and its soluble receptor. Arthritis Rheum., 2009, 60: 3374-3377

[218] Shirinsky IV, Shirinsky VS. Treatment of erosive osteoarthritis with peroxisome proliferator-activated receptor alpha agonist fenofibrate: a pilot study. Rheumatol. Int, 2014, 34: 613-616

[219] Wei W et al. Statins and fibrates do not affect development of spontaneous cartilage damage in STR/Ort mice. Osteoarthr. Cartil., 2014, 22: 293-301

[220] van Gemert Y et al. Novel high-intensive cholesterol-lowering therapies do not ameliorate knee OA development in humanized dyslipidemic mice. Osteoarthr. Cartil., 2021, 29: 1314-1323

[221] Wu CL et al. Dietary fatty acid content regulates wound repair and the pathogenesis of osteoarthritis following joint injury. Ann. Rheum. Dis., 2015, 74: 2076-2083

[222] Yu H et al. A low ratio of n-6/n-3 polyunsaturated fatty acids suppresses matrix metalloproteinase 13 expression and reduces adjuvant-induced arthritis in rats. Nutr. Res, 2015, 35: 1113-1121

[223] Shen CL et al. Decreased production of inflammatory mediators in human osteoarthritic chondrocytes by conjugated linoleic acids. Lipids, 2004, 39: 161-166

[224] Tsubosaka M et al. Gelatin hydrogels with eicosapentaenoic acid can prevent osteoarthritis progression in vivo in a mouse model. J. Orthop. Res, 2020, 38: 2157-2169

[225] Stonehouse W et al. Krill oil improved osteoarthritic knee pain in adults with mild to moderate knee osteoarthritis: a 6-month multicenter, randomized, double-blind, placebo-controlled trial. Am. J. Clin. Nutr., 2022, 116: 672-685

[226] MacFarlane LA et al. The effects of vitamin d and marine omega-3 fatty acid supplementation on chronic knee pain in older us adults: results from a randomized trial. Arthritis Rheumatol., 2020, 72: 1836-1844

Funding

National Natural Science Foundation of China (National Science Foundation of China)(82030067)

National Key Research and Development Program of China (2021YFB3800800) Hong Kong RGC grant HKU-17101821

SIAT Innovation Program for Excellent Young Researchers