Aging microenvironment in osteoarthritis focusing on early-stage alterations and targeted therapies

Abstract

Osteoarthritis (OA) is one of the most common degenerative and age-related diseases in joints, which affects 654 million people worldwide. Current therapies could not fundamentally reverse the pathologic process of OA due to the complex pathogenesis. Although OA mechanisms have been investigated on a large scale over the past decade, the OA pathology correlated with aging-associated changes is still largely unrevealed. Therefore, in-depth analysis of the aging microenvironment and aging-related molecular mechanisms in OA may offer additional strategies for clinical prevention and treatment. In this review, we discuss the potential pathogenesis of OA in light of aging-associated changes and summarize three main components of the aging microenvironment of the OA joint: immune homeostatic imbalance, cellular senescence, and stem cell exhaustion, which could be induced by aging and further exacerbate OA progression. Additionally, it is emphasized that immune homeostatic imbalance appears before established OA, which occurs in the early stage and is the therapeutic window of opportunity for better clinical outcomes. Importantly, we evaluate recent therapeutic targets and promising interventions against these components, as well as the challenges and prospects for precise and individualized therapies of OA patients, which we believe would guide the construction of novel combined strategies targeting aging-related factors against OA for better treatments in the future.

References

[1] Martel-Pelletier J. et al.. Osteoarthritis. Nat. Rev. Dis. Prim., 2016, 2. 16072

[2] Heinegård D, Saxne T. The role of the cartilage matrix in osteoarthritis. Nat. Rev. Rheumatol., 2011, 7: 50-56.

[3] Robinson WH. et al.. Low-grade inflammation as a key mediator of the pathogenesis of osteoarthritis. Nat. Rev. Rheumatol., 2016, 12: 580-592.

[4] Sellam J, Berenbaum F. The role of synovitis in pathophysiology and clinical symptoms of osteoarthritis. Nat. Rev. Rheumatol., 2010, 6: 625-635.

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

[6] Yu H, Huang Y, Yang L. Research progress in the use of mesenchymal stem cells and their derived exosomes in the treatment of osteoarthritis. Ageing Res Rev., 2022, 80. 101684

[7] Coryell PR, Diekman BO, Loeser RF. Mechanisms and therapeutic implications of cellular senescence in osteoarthritis. Nat. Rev. Rheumatol., 2021, 17: 47-57.

[8] Tao W, Yu Z, Han JJ. Single-cell senescence identification reveals senescence heterogeneity, trajectory, and modulators. Cell Metab., 2024, 36: 1126-1143.e1125.

[9] Swahn H. et al.. Senescent cell population with ZEB1 transcription factor as its main regulator promotes osteoarthritis in cartilage and meniscus. Ann. Rheum. Dis., 2023, 82: 403-415.

[10] Ji ML. et al.. Sirt6 attenuates chondrocyte senescence and osteoarthritis progression. Nat. Commun., 2022, 13. 7658

[11] Hou J. et al.. Aged bone marrow macrophages drive systemic aging and age-related dysfunction via extracellular vesicle-mediated induction of paracrine senescence. Nat. Aging, 2024, 4: 1562-1581.

[12] Yousefzadeh MJ. et al.. An aged immune system drives senescence and ageing of solid organs. Nature, 2021, 594: 100-105.

[13] Griffin TM, Scanzello CR. Innate inflammation and synovial macrophages in osteoarthritis pathophysiology. Clin. Exp. Rheumatol., 2019, 37: 57-63

[14] Woodell-May JE, Sommerfeld SD. Role of inflammation and the immune system in the progression of osteoarthritis. J. Orthop. Res., 2020, 38: 253-257.

[15] Miller RJ, Malfait AM, Miller RE. The innate immune response as a mediator of osteoarthritis pain. Osteoarthr. Cartil., 2020, 28: 562-571.

[16] Zhang H, Cai D, Bai X. Macrophages regulate the progression of osteoarthritis. Osteoarthr. Cartil., 2020, 28: 555-561.

[17] Zhang H. et al.. Synovial macrophage M1 polarisation exacerbates experimental osteoarthritis partially through R-spondin-2. Ann. Rheum. Dis., 2018, 77: 1524-1534.

[18] Culemann S. et al.. Locally renewing resident synovial macrophages provide a protective barrier for the joint. Nature, 2019, 572: 670-675.

[19] Knights AJ. et al.. Synovial fibroblasts assume distinct functional identities and secrete R-spondin 2 in osteoarthritis. Ann. Rheum. Dis., 2023, 82: 272-282.

[20] Wang B. et al.. An inducible p21-Cre mouse model to monitor and manipulate p21-highly-expressing senescent cells in vivo. Nat. Aging, 2021, 1: 962-973.

[21] Haston S. et al.. Clearance of senescent macrophages ameliorates tumorigenesis in KRAS-driven lung cancer. Cancer Cell, 2023, 41: 1242-1260.e1246.

[22] Covarrubias AJ. et al.. Senescent cells promote tissue NAD(+) decline during ageing via the activation of CD38⁺ macrophages. Nat. Metab., 2020, 2: 1265-1283.

[23] Hu H. et al.. Defective efferocytosis by aged macrophages promotes STING signaling mediated inflammatory liver injury. Cell Death Discov., 2023, 9: 236.

[24] Mehrotra P, Ravichandran KS. Drugging the efferocytosis process: concepts and opportunities. Nat. Rev. Drug Discov., 2022, 21: 601-620.

[25] Boada-Romero E, Martinez J, Heckmann BL, Green DR. The clearance of dead cells by efferocytosis. Nat. Rev. Mol. Cell Biol., 2020, 21: 398-414.

[26] Li B. et al.. SIRT6-regulated macrophage efferocytosis epigenetically controls inflammation resolution of diabetic periodontitis. Theranostics, 2023, 13: 231-249.

[27] Wang Y. et al.. Stiffness sensing via Piezo1 enhances macrophage efferocytosis and promotes the resolution of liver fibrosis. Sci. Adv., 2024, 10. eadj3289

[28] Wang X. et al.. Prolonged hypernutrition impairs TREM2-dependent efferocytosis to license chronic liver inflammation and NASH development. Immunity, 2023, 56: 58-77.e11.

[29] Del Sordo L. et al.. Impaired efferocytosis by synovial macrophages in patients with knee osteoarthritis. Arthritis Rheumatol., 2023, 75: 685-696.

[30] Yao, Z. et al. Down-regulated GAS6 impairs synovial macrophage efferocytosis and promotes obesity-associated osteoarthritis. Elife12 (2023).

[31] Li L, Zhang T, Xiao M, Lu Y, Gao L. Brain macrophage senescence in glioma. Semin Cancer Biol., 2024, 104: 46-60.

[32] Lee, M. Y., Jeon, J. W., Sievers, C. & Allen, C. T. Antigen processing and presentation in cancer immunotherapy. J. Immunother. Cancer8, e001111 (2020).

[33] Pishesha N, Harmand TJ, Ploegh HL. A guide to antigen processing and presentation. Nat. Rev. Immunol., 2022, 22: 751-764.

[34] Rosshirt N. et al.. Proinflammatory T cell polarization is already present in patients with early knee osteoarthritis. Arthritis Res. Ther., 2021, 23: 37.

[35] Shen PC. et al.. T helper cells promote disease progression of osteoarthritis by inducing macrophage inflammatory protein-1γ. Osteoarthr. Cartil., 2011, 19: 728-736.

[36] Hsieh JL. et al.. CD8⁺ T cell-induced expression of tissue inhibitor of metalloproteinses-1 exacerbated osteoarthritis. Int. J. Mol. Sci., 2013, 14: 19951-19970.

[37] Penatti A. et al.. Differences in serum and synovial CD4⁺ T cells and cytokine profiles to stratify patients with inflammatory osteoarthritis and rheumatoid arthritis. Arthritis Res. Ther., 2017, 19: 103.

[38] Zhang F. et al.. Defining inflammatory cell states in rheumatoid arthritis joint synovial tissues by integrating single-cell transcriptomics and mass cytometry. Nat. Immunol., 2019, 20: 928-942.

[39] McHugh J. T(reg) cell-inducing nanoparticles show promise for treating OA. Nat. Rev. Rheumatol., 2023, 19: 62.

[40] Li S. et al.. Downregulation of IL-10 secretion by Treg cells in osteoarthritis is associated with a reduction in Tim-3 expression. Biomed. Pharmacother., 2016, 79: 159-165.

[41] Kundu-Raychaudhuri S, Abria C, Raychaudhuri SP. IL-9, a local growth factor for synovial T cells in inflammatory arthritis. Cytokine, 2016, 79: 45-51.

[42] Murray PJ. Macrophage polarization. Annu. Rev. Physiol., 2017, 79: 541-566.

[43] Sakkas LI, Platsoucas CD. The role of T cells in the pathogenesis of osteoarthritis. Arthritis Rheum., 2007, 56: 409-424.

[44] Haghikia A. et al.. Clinical efficacy and autoantibody seroconversion with CD19^-CAR T cell therapy in a patient with rheumatoid arthritis and coexisting myasthenia gravis. Ann. Rheum. Dis., 2024, 83: 1597-1598.

[45] Sohn HS. et al.. Tolerogenic nanoparticles induce type II collagen-specific regulatory T cells and ameliorate osteoarthritis. Sci. Adv., 2022, 8. eabo5284

[46] Shiokawa S, Matsumoto N, Nishimura J. Clonal analysis of B cells in the osteoarthritis synovium. Ann. Rheum. Dis., 2001, 60: 802-805.

[47] Pringle JA, Byers PD, Brown ME. Immunofluorescence in osteoarthritis. Nature, 1978, 274: 94.

[48] Da RR, Qin Y, Baeten D, Zhang Y. B cell clonal expansion and somatic hypermutation of Ig variable heavy chain genes in the synovial membrane of patients with osteoarthritis. J. Immunol., 2007, 178: 557-565.

[49] Krenn V. et al.. Molecular IgV(H) analysis demonstrates highly somatic mutated B cells in synovialitis of osteoarthritis: a degenerative disease is associated with a specific, not locally generated immune response. Lab. Investig. J. Tech. Methods Pathol., 1999, 79: 1377-1384

[50] Revell PA, Mayston V, Lalor P, Mapp P. The synovial membrane in osteoarthritis: a histological study including the characterisation of the cellular infiltrate present in inflammatory osteoarthritis using monoclonal antibodies. Ann. Rheum. Dis., 1988, 47: 300-307.

[51] Magalhães R, Gehrke T, Souto-Carneiro MM, Kriegsmann J, Krenn V. Extensive plasma cell infiltration with crystal IgG inclusions and mutated IgV(H) gene in an osteoarthritis patient with lymphoplasmacellular synovitis. A case report. Pathol. Res. Pract., 2002, 198: 45-50.

[52] Qi T. et al.. Ascorbic acid promotes plasma cell differentiation through enhancing TET2/3-mediated DNA demethylation. Cell Rep., 2020, 33. 108452

[53] Chen, X., Schneewind, O. & Missiakas, D. Engineered human antibodies for the opsonization and killing of Staphylococcus aureus. Proc. Natl Acad. Sci. USA119, e2114478119 (2022).

[54] Ma S. et al.. Spatial transcriptomic landscape unveils immunoglobin-associated senescence as a hallmark of aging. Cell, 2024, 187: 7025-7044.e7034.

[55] Lin XC. et al.. B-cell-specific mammalian target of rapamycin complex 1 activation results in severe osteoarthritis in mice. Int. Immunopharmacol., 2018, 65: 522-530.

[56] Farr JN, Khosla S. Cellular senescence in bone. Bone, 2019, 121: 121-133.

[57] Sun H. et al.. IgM⁺CD27⁺ B cells possessed regulatory function and represented the main source of B cell-derived IL-10 in the synovial fluid of osteoarthritis patients. Hum. Immunol., 2019, 80: 263-269.

[58] Zheng, L. et al. ITGA5(+) synovial fibroblasts orchestrate proinflammatory niche formation by remodelling the local immune microenvironment in rheumatoid arthritis. Ann. Rheum. Dis.84, 232–252 (2024).

[59] Pereira B, Xu XN, Akbar AN. Targeting inflammation and immunosenescence to improve vaccine responses in the elderly. Front. Immunol., 2020, 11. 583019

[60] Yao Q. et al.. Osteoarthritis: pathogenic signaling pathways and therapeutic targets. Sig. Transduct. Target Ther., 2023, 8: 56.

[61] Guan YJ. et al.. Evidence that miR-146a attenuates aging- and trauma-induced osteoarthritis by inhibiting Notch1, IL-6, and IL-1 mediated catabolism. Aging Cell, 2018, 17. e12752

[62] Li H. et al.. Astragaloside inhibits IL-1β-induced inflammatory response in human osteoarthritis chondrocytes and ameliorates the progression of osteoarthritis in mice. Immunopharmacol. Immunotoxicol., 2019, 41: 497-503.

[63] Park, C. et al. Sargassum serratifolium extract attenuates interleukin-1β-induced oxidative stress and inflammatory response in chondrocytes by suppressing the activation of NF-κB, p38 MAPK, and PI3K/Akt. Int. J. Mol. Sci.19, 2308 (2018).

[64] Wei K. et al.. Notch signalling drives synovial fibroblast identity and arthritis pathology. Nature, 2020, 582: 259-264.

[65] Raghu H. et al.. CCL2/CCR2, but not CCL5/CCR5, mediates monocyte recruitment, inflammation and cartilage destruction in osteoarthritis. Ann. Rheum. Dis., 2017, 76: 914-922.

[66] Ogrodnik M. et al.. Guidelines for minimal information on cellular senescence experimentation in vivo. Cell, 2024, 187: 4150-4175.

[67] Suryadevara V. et al.. SenNet recommendations for detecting senescent cells in different tissues. Nat. Rev. Mol. Cell Biol., 2024, 25: 1001-1023.

[68] McCulloch K, Litherland GJ, Rai TS. Cellular senescence in osteoarthritis pathology. Aging Cell, 2017, 16: 210-218.

[69] Varela-Eirín M. et al.. Targeting of chondrocyte plasticity via connexin43 modulation attenuates cellular senescence and fosters a pro-regenerative environment in osteoarthritis. Cell Death Dis., 2018, 9: 1166.

[70] Zhang M, Theleman JL, Lygrisse KA, Wang J. Epigenetic mechanisms underlying the aging of articular cartilage and osteoarthritis. Gerontology, 2019, 65: 387-396.

[71] Diekman BO. et al.. Expression of p16(INK) (4a) is a biomarker of chondrocyte aging but does not cause osteoarthritis. Aging Cell, 2018, 17. e12771

[72] Toh WS. et al.. Cellular senescence in aging and osteoarthritis. Acta Orthopaedica, 2016, 87: 6-14.

[73] Del Rey MJ. et al.. Senescent synovial fibroblasts accumulate prematurely in rheumatoid arthritis tissues and display an enhanced inflammatory phenotype. Immun. Ageing I A, 2019, 16: 29.

[74] Pfeifer CG. et al.. Age-dependent subchondral bone remodeling and cartilage repair in a minipig defect model. Tissue Eng. Part C. Methods, 2017, 23: 745-753.

[75] Price JS. et al.. The role of chondrocyte senescence in osteoarthritis. Aging cell, 2002, 1: 57-65.

[76] Zhou HW, Lou SQ, Zhang K. Recovery of function in osteoarthritic chondrocytes induced by p16INK4a-specific siRNA in vitro. Rheumatology, 2004, 43: 555-568.

[77] Yudoh K. et al.. Potential involvement of oxidative stress in cartilage senescence and development of osteoarthritis: oxidative stress induces chondrocyte telomere instability and downregulation of chondrocyte function. Arthritis Res. Ther., 2005, 7: R380-R391.

[78] Rose J. et al.. DNA damage, discoordinated gene expression and cellular senescence in osteoarthritic chondrocytes. Osteoarthr. Cartil., 2012, 20: 1020-1028.

[79] Cox LG, van Donkelaar CC, van Rietbergen B, Emans PJ, Ito K. Alterations to the subchondral bone architecture during osteoarthritis: bone adaptation vs endochondral bone formation. Osteoarthr. Cartil., 2013, 21: 331-338.

[80] Jiang Y, Tuan RS. Origin and function of cartilage stem/progenitor cells in osteoarthritis. Nat. Rev. Rheumatol., 2015, 11: 206-212.

[81] Li J, Pei M. Cell senescence: a challenge in cartilage engineering and regeneration. Tissue Eng. Part B Rev., 2012, 18: 270-287.

[82] Rim, Y. A., Nam, Y. & Ju, J. H. The role of chondrocyte hypertrophy and senescence in osteoarthritis initiation and progression. Int. J. Mol. Sci.21, 2358 (2020).

[83] Xie J. et al.. Cellular senescence in knee osteoarthritis: molecular mechanisms and therapeutic implications. Ageing Res. Rev., 2021, 70. 101413

[84] Lietman, C. et al. Inhibition of Wnt/β-catenin signaling ameliorates osteoarthritis in a murine model of experimental osteoarthritis. JCI insight3, e96308 (2018).

[85] Xu M. et al.. Transplanted senescent cells induce an osteoarthritis-like condition in mice. J. Gerontol. Ser. A Biol. Sci. Med. Sci., 2017, 72: 780-785

[86] Faust HJ. et al.. IL-17 and immunologically induced senescence regulate response to injury in osteoarthritis. J. Clin. Invest, 2020, 130: 5493-5507.

[87] Rahmati M, Nalesso G, Mobasheri A, Mozafari M. Aging and osteoarthritis: central role of the extracellular matrix. Ageing Res. Rev., 2017, 40: 20-30.

[88] Greene MA, Loeser RF. Aging-related inflammation in osteoarthritis. Osteoarthr. Cartil., 2015, 23: 1966-1971.

[89] Zhang XX. et al.. Aging, cell senescence, the pathogenesis and targeted therapies of osteoarthritis. Front. Pharmacol., 2021, 12. 728100

[90] McGonagle D, Baboolal TG, Jones E. Native joint-resident mesenchymal stem cells for cartilage repair in osteoarthritis. Nat. Rev. Rheumatol., 2017, 13: 719-730.

[91] Barry F, Murphy M. Mesenchymal stem cells in joint disease and repair. Nat. Rev. Rheumatol., 2013, 9: 584-594.

[92] Seol D. et al.. Chondrogenic progenitor cells respond to cartilage injury. Arthritis Rheum., 2012, 64: 3626-3637.

[93] Doyle EC, Wragg NM, Wilson SL. Intraarticular injection of bone marrow-derived mesenchymal stem cells enhances regeneration in knee osteoarthritis. Knee Surg. Sports Traumatol. Arthrosc., 2020, 28: 3827-3842.

[94] Zhang S. et al.. MSC exosomes alleviate temporomandibular joint osteoarthritis by attenuating inflammation and restoring matrix homeostasis. Biomaterials, 2019, 200: 35-47.

[95] Toh WS, Lai RC, Hui JHP, Lim SK. MSC exosome as a cell-free MSC therapy for cartilage regeneration: implications for osteoarthritis treatment. Semin. Cell Dev. Biol., 2017, 67: 56-64.

[96] Baboolal TG. et al.. Synovial fluid hyaluronan mediates MSC attachment to cartilage, a potential novel mechanism contributing to cartilage repair in osteoarthritis using knee joint distraction. Ann. Rheum. Dis., 2016, 75: 908-915.

[97] Jones E. et al.. Large-scale extraction and characterization of CD271⁺ multipotential stromal cells from trabecular bone in health and osteoarthritis: implications for bone regeneration strategies based on uncultured or minimally cultured multipotential stromal cells. Arthritis Rheum., 2010, 62: 1944-1954.

[98] Čamernik K. et al.. Increased exhaustion of the subchondral bone-derived mesenchymal stem/ stromal cells in primary versus dysplastic osteoarthritis. Stem Cell Rev. Rep., 2020, 16: 742-754.

[99] De Bari C, Dell’Accio F, Luyten FP. Human periosteum-derived cells maintain phenotypic stability and chondrogenic potential throughout expansion regardless of donor age. Arthritis Rheum., 2001, 44: 85-95.

[100] Čamernik K. et al.. Comprehensive analysis of skeletal muscle- and bone-derived mesenchymal stem/stromal cells in patients with osteoarthritis and femoral neck fracture. Stem Cell Res. Ther., 2020, 11: 146.

[101] Hong X. et al.. Stem cell aging in the skeletal muscle: the importance of communication. Ageing Res. Rev., 2022, 73. 101528

[102] Malaise O. et al.. Mesenchymal stem cell senescence alleviates their intrinsic and seno-suppressive paracrine properties contributing to osteoarthritis development. Aging, 2019, 11: 9128-9146.

[103] Fu L. et al.. Up-regulation of FOXD1 by YAP alleviates senescence and osteoarthritis. PLoS Biol., 2019, 17: e3000201.

[104] Murphy MP. et al.. Articular cartilage regeneration by activated skeletal stem cells. Nat. Med., 2020, 26: 1583-1592.

[105] Deng S, Xie H, Xie B. Cell-based regenerative and rejuvenation strategies for treating neurodegenerative diseases. Stem Cell Res. Ther., 2025, 16: 167.

[106] Yu, P., Liu, B., Dong, C. & Chang, Y. Induced pluripotent stem cells-based regenerative therapies in treating human aging-related functional decline and diseases. Cells14, 619 (2025).

[107] Najar M, Fahmi H. Of mesenchymal stem/stromal cells and osteoarthritis: time to merge the latest breakthroughs. Stem Cell Rev. Rep., 2020, 16: 1016-1018.

[108] Li N. et al.. Synovial membrane mesenchymal stem cells: past life, current situation, and application in bone and joint diseases. Stem Cell Res. Ther., 2020, 11: 381.

[109] Tong W. et al.. In vivo identification and induction of articular cartilage stem cells by inhibiting NF-κB signaling in osteoarthritis. Stem Cells, 2015, 33: 3125-3137.

[110] Liu Y. et al.. Targeted knockdown of PGAM5 in synovial macrophages efficiently alleviates osteoarthritis. Bone Res., 2024, 12: 15.

[111] Bogeska R. et al.. Inflammatory exposure drives long-lived impairment of hematopoietic stem cell self-renewal activity and accelerated aging. Cell Stem Cell, 2022, 29: 1273-1284.e1278.

[112] Takayama K. et al.. mTOR signaling plays a critical role in the defects observed in muscle-derived stem/progenitor cells isolated from a murine model of accelerated aging. J. Orthop. Res., 2017, 35: 1375-1382.

[113] Jacob J. et al.. Senescent chondrogenic progenitor cells derived from articular cartilage of knee osteoarthritis patients contributes to senescence-associated secretory phenotype via release of IL-6 and IL-8. Acta Histochem., 2022, 124. 151867

[114] Gnani D. et al.. An early-senescence state in aged mesenchymal stromal cells contributes to hematopoietic stem and progenitor cell clonogenic impairment through the activation of a pro-inflammatory program. Aging Cell, 2019, 18. e12933

[115] Deng Y. et al.. Tumor cell senescence-induced macrophage CD73 expression is a critical metabolic immune checkpoint in the aging tumor microenvironment. Theranostics, 2024, 14: 1224-1240.

[116] Latourte A. et al.. SerpinA3N limits cartilage destruction in osteoarthritis by inhibiting macrophage-derived leucocyte elastase. Ann. Rheum. Dis., 2024, 83: 1781-1790.

[117] Xu M. et al.. Senolytics improve physical function and increase lifespan in old age. Nat. Med., 2018, 24: 1246-1256.

[118] Brunet A, Goodell MA, Rando TA. Ageing and rejuvenation of tissue stem cells and their niches. Nat. Rev. Mol. Cell Biol., 2023, 24: 45-62.

[119] Dulken BW. et al.. Single-cell analysis reveals T cell infiltration in old neurogenic niches. Nature, 2019, 571: 205-210.

[120] Yousef H. et al.. Aged blood impairs hippocampal neural precursor activity and activates microglia via brain endothelial cell VCAM1. Nat. Med., 2019, 25: 988-1000.

[121] Schett G. et al.. Vascular cell adhesion molecule 1 as a predictor of severe osteoarthritis of the hip and knee joints. Arthritis Rheum., 2009, 60: 2381-2389.

[122] Timmers P. et al.. Mendelian randomization of genetically independent aging phenotypes identifies LPA and VCAM1 as biological targets for human aging. Nat. Aging, 2022, 2: 19-30.

[123] Boer CG. et al.. Deciphering osteoarthritis genetics across 826,690 individuals from 9 populations. Cell, 2021, 184: 4784-4818.e4717.

[124] Nanus DE. et al.. Synovial tissue from sites of joint pain in knee osteoarthritis patients exhibits a differential phenotype with distinct fibroblast subsets. EBioMedicine, 2021, 72. 103618

[125] Komaravolu RK. et al.. Sex-specific effects of injury and beta-adrenergic activation on metabolic and inflammatory mediators in a murine model of post-traumatic osteoarthritis. Osteoarthr. Cartil., 2024, 32: 1097-1112.

[126] Fan Y. et al.. Unveiling inflammatory and prehypertrophic cell populations as key contributors to knee cartilage degeneration in osteoarthritis using multi-omics data integration. Ann. Rheum. Dis., 2024, 83: 926-944.

[127] Kolasinski SL. et al.. 2019 American College of Rheumatology/Arthritis Foundation Guideline for the Management of Osteoarthritis of the Hand, Hip, and Knee. Arthritis Care Res., 2020, 72: 149-162.

[128] Altman RD. Structure-/disease-modifying agents for osteoarthritis. Semin. Arthritis Rheumatism, 2005, 34: 3-5.

[129] Wu CL. et al.. Conditional macrophage depletion increases inflammation and does not inhibit the development of osteoarthritis in obese macrophage fas-induced apoptosis-transgenic mice. Arthritis Rheumatol., 2017, 69: 1772-1783.

[130] Zhou F. et al.. Kinsenoside attenuates osteoarthritis by repolarizing macrophages through inactivating NF-κB/MAPK signaling and protecting chondrocytes. Acta Pharmaceutica Sin. B, 2019, 9: 973-985.

[131] Hu Y. et al.. Quercetin alleviates rat osteoarthritis by inhibiting inflammation and apoptosis of chondrocytes, modulating synovial macrophages polarization to M2 macrophages. Free Radic. Biol. Med., 2019, 145: 146-160.

[132] Lv Z. et al.. TRPV1 alleviates osteoarthritis by inhibiting M1 macrophage polarization via Ca(2+)/CaMKII/Nrf2 signaling pathway. Cell Death Dis., 2021, 12: 504.

[133] Lu, J. et al. Fargesin ameliorates osteoarthritis via macrophage reprogramming by downregulating MAPK and NF-κB pathways. Arthritis Res. Ther.23, 142 (2021).

[134] Sun Y. et al.. Eucommia ulmoides polysaccharides attenuate rabbit osteoarthritis by regulating the function of macrophages. Front. Pharmacol., 2021, 12. 730557

[135] Zhou F. et al.. Modified ZIF-8 nanoparticles attenuate osteoarthritis by reprogramming the metabolic pathway of synovial macrophages. ACS Appl. Mater. interfaces, 2020, 12: 2009-2022.

[136] Kamada, K. et al. Attenuation of knee osteoarthritis progression in mice through polarization of M2 macrophages by intra-articular transplantation of non-cultured human adipose-derived regenerative cells. J. Clin. Med.10, 4309 (2021).

[137] Zhang J, Rong Y, Luo C, Cui W. Bone marrow mesenchymal stem cell-derived exosomes prevent osteoarthritis by regulating synovial macrophage polarization. Aging, 2020, 12: 25138-25152.

[138] Laberge RM. et al.. MTOR regulates the pro-tumorigenic senescence-associated secretory phenotype by promoting IL1A translation. Nat. cell Biol., 2015, 17: 1049-1061.

[139] Caramés B. et al.. Autophagy activation by rapamycin reduces severity of experimental osteoarthritis. Ann. Rheum. Dis., 2012, 71: 575-581.

[140] Philp AM, Davis ET, Jones SW. Developing anti-inflammatory therapeutics for patients with osteoarthritis. Rheumatology, 2017, 56: 869-881

[141] Platas J. et al.. Anti-senescence and anti-inflammatory effects of the C-terminal moiety of PTHrP peptides in OA osteoblasts. J. Gerontol. Ser. A Biol. Sci. Med. Sci., 2017, 72: 624-631

[142] Ross EA. et al.. Treatment of inflammatory arthritis via targeting of tristetraprolin, a master regulator of pro-inflammatory gene expression. Ann. Rheum. Dis., 2017, 76: 612-619.

[143] Jeon OH. et al.. Local clearance of senescent cells attenuates the development of post-traumatic osteoarthritis and creates a pro-regenerative environment. Nat. Med., 2017, 23: 775-781.

[144] Partridge L, Fuentealba M, Kennedy BK. The quest to slow ageing through drug discovery. Nat. Rev. Drug Discov., 2020, 19: 513-532.

[145] Peilin W. et al.. Directed elimination of senescent cells attenuates development of osteoarthritis by inhibition of c-IAP and XIAP. Biochim. Biophys. Acta Mol. Basis Dis., 2019, 1865: 2618-2632.

[146] Yang H. et al.. Navitoclax (ABT263) reduces inflammation and promotes chondrogenic phenotype by clearing senescent osteoarthritic chondrocytes in osteoarthritis. Aging, 2020, 12: 12750-12770.

[147] Sacitharan PK, Lwin S, Gharios GB, Edwards JR. Spermidine restores dysregulated autophagy and polyamine synthesis in aged and osteoarthritic chondrocytes via EP300. Exp. Mol. Med., 2018, 50: 123.

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

[149] Dai H. et al.. Eliminating senescent chondrogenic progenitor cells enhances chondrogenesis under intermittent hydrostatic pressure for the treatment of OA. Stem Cell Res. Ther., 2020, 11: 199.

[150] Montero-Melendez T. et al.. Therapeutic senescence via GPCR activation in synovial fibroblasts facilitates resolution of arthritis. Nat. Commun., 2020, 11. 745

[151] Si HB. et al.. miR-140 Attenuates the Progression of Early-Stage Osteoarthritis by Retarding Chondrocyte Senescence. Mol. Ther. Nucleic Acids, 2020, 19: 15-30.

[152] Cui C. et al.. Parathyroid hormone ameliorates temporomandibular joint osteoarthritic-like changes related to age. Cell Prolif., 2020, 53. e12755

[153] Antebi B, Pelled G, Gazit D. Stem cell therapy for osteoporosis. Curr. Osteoporos. Rep., 2014, 12: 41-47.

[154] Pas HI. et al.. Stem cell injections in knee osteoarthritis: a systematic review of the literature. Br. J. Sports Med., 2017, 51: 1125-1133.

[155] Mianehsaz E. et al.. Mesenchymal stem cell-derived exosomes: a new therapeutic approach to osteoarthritis?. Stem Cell Res. Ther., 2019, 10: 340.

[156] Trounson A, McDonald C. Stem cell therapies in clinical trials: progress and challenges. Cell Stem Cell, 2015, 17: 11-22.

[157] Dubey NK. et al.. Combating osteoarthritis through stem cell therapies by rejuvenating cartilage: a review. Stem Cells Int., 2018, 2018. 5421019

[158] Hwang JJ, Rim YA, Nam Y, Ju JH. Recent developments in clinical applications of mesenchymal stem cells in the treatment of rheumatoid arthritis and osteoarthritis. Front. Immunol., 2021, 12. 631291

[159] Copp G, Robb KP, Viswanathan S. Culture-expanded mesenchymal stromal cell therapy: does it work in knee osteoarthritis? A pathway to clinical success. Cell Mol. Immunol., 2023, 20: 626-650.

[160] Lei J. et al.. Exosomes from antler stem cells alleviate mesenchymal stem cell senescence and osteoarthritis. Protein cell., 2021, 13: 220-226.

[161] Hu, L. et al. Mesenchymal stem cells: cell fate decision to osteoblast or adipocyte and application in osteoporosis treatment. Int. J. Mol. Sci.19, 360 (2018).

[162] Johnson K. et al.. A stem cell-based approach to cartilage repair. Science, 2012, 336: 717-721.

[163] Wang P. et al.. Attenuation of osteoarthritis progression via locoregional delivery of Klotho-expressing plasmid DNA and Tanshinon IIA through a stem cell-homing hydrogel. J. Nanobiotechnol., 2024, 22. 325

[164] Shang Z, Wanyan P, Zhang B, Wang M, Wang X. A systematic review, umbrella review, and quality assessment on clinical translation of stem cell therapy for knee osteoarthritis: are we there yet?. Stem Cell Res. Ther., 2023, 14: 91.

[165] Wiggers TG, Winters M, Van den Boom NA, Haisma HJ, Moen MH. Autologous stem cell therapy in knee osteoarthritis: a systematic review of randomised controlled trials. Br. J. Sports Med., 2021, 55: 1161-1169.

[166] Shariatzadeh M, Song J, Wilson SL. The efficacy of different sources of mesenchymal stem cells for the treatment of knee osteoarthritis. Cell Tissue Res., 2019, 378: 399-410.

[167] Zupan, J. & Stražar, K. Synovium-derived and bone-derived mesenchymal stem/stromal cells from early OA patients show comparable in vitro properties to those of non-OA patients. Cells13, 1238 (2024).

[168] Shirasawa S. et al.. In vitro chondrogenesis of human synovium-derived mesenchymal stem cells: optimal condition and comparison with bone marrow-derived cells. J. Cell Biochem., 2006, 97: 84-97.

[169] Li J. et al.. Cartilage regeneration using arthroscopic flushing fluid-derived mesenchymal stem cells encapsulated in a one-step rapid cross-linked hydrogel. Acta Biomater., 2018, 79: 202-215.

[170] An, X. et al. Enhanced chondrogenic potential and osteoarthritis treatment using cyaonoside A-induced MSC delivered via a hyaluronic acid-based hydrogel system. Aging Dis.https://doi.org/10.14336/ad.2024.10016 (2025).

[171] Wang, X. et al. Recent advances in hydrogel technology in delivering mesenchymal stem cell for osteoarthritis therapy. Biomolecules14, 858 (2024).

[172] Luo D, Zhu H, Li S, Wang Z, Xiao J. Mesenchymal stem cell-derived exosomes as a promising cell-free therapy for knee osteoarthritis. Front. Bioeng. Biotechnol., 2024, 12. 1309946

[173] Lei J. et al.. Exosomes from antler stem cells alleviate mesenchymal stem cell senescence and osteoarthritis. Protein Cell, 2022, 13: 220-226.

[174] Iturriaga L, Hernáez-Moya R, Erezuma I, Dolatshahi-Pirouz A, Orive G. Advances in stem cell therapy for cartilage regeneration in osteoarthritis. Expert Opin. Biol. Ther., 2018, 18: 883-896.

[175] Segel M. et al.. Niche stiffness underlies the ageing of central nervous system progenitor cells. Nature, 2019, 573: 130-134.

[176] Stearns-Reider KM. et al.. Aging of the skeletal muscle extracellular matrix drives a stem cell fibrogenic conversion. Aging Cell, 2017, 16: 518-528.

[177] Zhu Y. et al.. Deciphering mechanical cues in the microenvironment: from non-malignant settings to tumor progression. Biomark. Res., 2025, 13. 11

[178] Childs BG, Baker DJ, Kirkland JL, Campisi J, van Deursen JM. Senescence and apoptosis: dueling or complementary cell fates?. EMBO Rep., 2014, 15: 1139-1153.

[179] Soto-Gamez A, Demaria M. Therapeutic interventions for aging: the case of cellular senescence. Drug Discov. Today, 2017, 22: 786-795.

[180] Zhu Y. et al.. The Achilles’ heel of senescent cells: from transcriptome to senolytic drugs. Aging Cell, 2015, 14: 644-658.

[181] Jeon OH. et al.. Systemic induction of senescence in young mice after single heterochronic blood exchange. Nat. Metab., 2022, 4: 995-1006.

[182] Guccini I. et al.. Senescence reprogramming by TIMP1 deficiency promotes prostate cancer metastasis. Cancer Cell, 2021, 39: 68-82.e69.

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

[184] von Loga IS. et al.. Active immunisation targeting nerve growth factor attenuates chronic pain behaviour in murine osteoarthritis. Ann. Rheum. Dis., 2019, 78: 672-675.

Funding

Science and Technology Commission of Shanghai Municipality (Shanghai Municipal Science and Technology Commission)(23141901200)

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The Author(s)