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Review

Emerging therapeutic targets for osteoarthritis

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Pages 111-120 | Received 11 Jun 2021, Accepted 23 Feb 2023, Published online: 27 Feb 2023

References

  • Safiri S, Kolahi AA, Smith E, et al. Global, regional and national burden of osteoarthritis 1990-2017: a systematic analysis of the Global Burden of Disease Study 2017. Ann Rheum Dis. 2020;79(6):819–828.
  • Standardization of osteoarthritis definitions. Osteoarthritis Cartilage. 2015. Available at https://oarsi.org/research/standardization-osteoarthritis-definitions.
  • Castaneda S, Roman-Blas JA, Largo R, et al. Osteoarthritis: a progressive disease with changing phenotypes. J Rheumatol. 2014;53(1):1–3.
  • Deveza LA, Melo L, Yamato TP, et al. Knee osteoarthritis phenotypes and their relevance for outcomes: a systematic review. Osteoarthritis Cartilage. 2017;25(12):1926–1941.
  • Dell’Isola A, Allan R, Smith SL, et al. Identification of clinical phenotypes in knee osteoarthritis: a systematic review of the literature. BMC Musculoskelet Discord. 2016;17(1):425–437.
  • Bannuru RR, Osani MC, Vaysbrot EE, et al. OARSI guidelines for the non-surgical management of knee, hip, and polyarticular osteoarthritis. Osteoarthritis Cartilage. 2019;27(11):1578–1589.
  • Higashi H, Barendregt JJ, van Baal PHM. Cost-effectiveness of total hip and knee replacement for the Australian population with osteoarthritis: discrete-event simulation model. PLoS One. 2011;6(9):e25403.
  • Fu K, Robbins SR, McDougall JJ. Osteoarthritis: the genesis of pain. Rheumatology. 2017;57(suppl_4):iv43–iv50.
  • McCoy AM. Animal models of osteoarthritis: comparisons and key considerations. Vet Pathol. 2015;52(5):803–818.
  • Sun MMG, Beier F, Pest MA. Recent developments in emerging therapeutic targets of osteoarthritis. Curr Opin Rheumatol. 2017;29(1):96–102.
  • Latourte A, Kloppenburg M, Richette P. Emerging pharmaceutical therapies for osteoarthritis. Nat Rev Rheumatol. 2020;16(12):673–688.
  • Vincent TL. Of mice and men: converging on a common molecular understanding of osteoarthritis. Lancet Rheumatol. 2020;2(10):e633–45.
  • Cuervo AM. Autophagy: many paths to the same end. Mol Cell Biochem. 2004;263(1/2):55–72.
  • Lotz MK, Carames B. Autophagy and cartilage homeostasis mechanisms in joint health, aging and OA. Nat Rev Rheumatol. 2011;7(10):579–587.
  • Terman A, Kurz T, Navratil M, et al. Mitochondrial turnover and aging of long-living postmitotic cells: the mitochondrial-lysosomal axis theory of aging. Antioxid Redox Signal. 2010;12(4):503–535.
  • Carmes B, Taniguchi N, Otsuki S, et al. Autophagy is a protective mechanism in normal cartilage, and its aging-related loss is linked with cell death and osteoarthritis. Arthritis Rheum. 2010;62(3):791–801.
  • Wang C, Yao Z, Zhang Y, et al. Metformin mitigates cartilage degradation by activating AMPK/SIRT1-mediated autophagy in a mouse osteoarthritis model. Font Pharmacol. 2020;11:1114.
  • Zhang X, Yang Y, Li X, et al. Alterations of autophagy in knee cartilage by treatment with treadmill exercise in a rat osteoarthritis model. Int J Mol Med. 2019;43(1):336–344.
  • Carames B, Hasegawa A, Taniguchi, et al. Autophagy activation by rapamycin reduces severity of experimental osteoarthritis. Ann Rheum Dis. 2012;71(4):575–581.
  • Takayama K, Kawakami Y, Kobayashi M, et al. Local intra-articular injection of rapamycin delays articular cartilage degeneration in a murine model of osteoarthritis. Arthritis Res Ther. 2014;16(6):482–492.
  • Ma L, Liu Y, Zhao X, et al. Rapamycin attenuates articular cartilage degeneration by inhibiting β-catenin in a murine model of osteoarthritis. Connect Tissue Res. 2019;60(5):452–462.
  • Liu Y, Li X, Jin A. Rapamycin inhibits NF-κB activation by autophagy to reduce catabolism in human chondrocytes. J Invest Surg. 2020;33(9):861–873.
  • Luna-Preitschopf AD, Zwickl H, Nehrer S, et al. Rapamycin maintains the chondrocytic phenotype and interferes with inflammatory cytokine induced processes. Int J Mol Sci. 2017;18(7):1494–1509.
  • Sun K, Luo J, Guo J, et al. The PI3K/AKT/mTOR signaling pathway in osteoarthritis: a narrative review. Osteoarthritis Cartilage. 2020;28(4):400–409.
  • Laragione T, Gulko PS. mTOR regulates the invasive properties of synovial fibroblasts in rheumatoid arthritis. Mol Med. 2010;16(9–10):352–358.
  • Guo SM, Wang JX, Li J, et al. Identification of gene expression profiles and key genes in subchondral bone of osteoarthritis using weighted gene coexpression network analysis. J Cell Biochem. 2018;119(9):7687–7695.
  • Lin C, Shao Y, Zeng C, et al. Blocking PI3K/AKT signalling inhibits bone sclerosis in subchondral bone and attenuates post-traumatic osteoarthritis. J Cell Physiol. 2018;223(8):6135–6147.
  • Lin C, Liu L, Zeng C, et al. Activation of mTORC1 in subchondral bone preosteoblasts promotes osteoarthritis by stimulating bone sclerosis and secretion of CXCL12. Bone Res. 2019;7:5.
  • Lu J, Ji M, Zhang X, et al. MicroRNA-218-5p as a potential target for the treatment of human osteoarthritis. Mol Ther. 2017;25(12):2676–2688.
  • Cai C, Min S, Yan B, et al. MiR-27a promotes the autophagy and apoptosis of IL-1β treated-articular chondrocytes in osteoarthritis through PI3K/AKT/mTOR signaling. Aging (Albany NY). 2019;11(16):6371–6384.
  • Martin JA, Buckwalter JA. The role of chondrocyte senescence in the pathogenesis of osteoarthritis and in limiting cartilage repair. J Bone Joint Surg. 2003;85:106–110.
  • McCulloch K, Litherland GJ, Rai TS. Cellular senescence in osteoarthritis pathology. Aging Cell. 2017;16(2):210–218.
  • Philipot D, Guerit D, Platano D, et al. p16INK4a and its regulator miR-24 link senescence and chondrocyte terminal differentiation-associated matrix remodeling in osteoarthritis. Arthritis Res Ther. 2014;16(1):58–70.
  • Vinatier C, Dominguez E, Guicheux J, et al. Role of inflammation-autophagy-senescence integrative network in osteoarthritis. Front Physiol. 2018;9. DOI:10.3389/fphys.2018.00706
  • Acosta JC, Banito A, Wuestefeld, et al. A complex secretory program orchestrated by the inflammasome controls paracrine senescence. Nat Cell Biol. 2013;15(8):978–990.
  • Greene MA, Loeser RF. Aging-related inflammation in osteoarthritis. Osteoarthritis Cartilage. 2015;23(11):1966–1971.
  • Dvir-Ginzberg M, Mobasheri A, Kumar A. The role of sirtuins in cartilage homeostasis and osteoarthritis. Curr Rheumatol Rep. 2016;18:42–51.
  • Zhao G, Wang H, Xu C, et al. SIRT6 delays cellular senescence by promoting p27Kip1 ubiquitin-proteasome degradation. Aging (Albany NY). 2016;8(10):2308–2323.
  • Collins JA, Japustina M, Bolduc JA, et al. Sirtuin 6 (SIRT6) regulates redox homeostasis and signaling events in human articular chondrocytes. Free Radic Biol Med. 2021;166:90–103.
  • Nagai K, Matsushita T, Matsuzaki T, et al. Depletion of SIRT6 causes cellular senescence, DNA damage, and telomere dysfunction in human chondrocytes. Osteoarthritis Cartilage. 2015;23(8):1412–1420.
  • Wu Y, Chen L, Wang Y, et al. Overexpression of sirtuin 6 suppresses cellular senescence and NF-κB mediated inflammatory responses in osteoarthritis development. Sci Rep. 2015;5(1):17602–17613.
  • Jeon OH, Kim C, Laberge RM, et al. Local clearance of senescent cells attenuates the development of post-traumatic osteoarthritis and creates a pro-regenerative environment. Nat Med. 2017;23(6):775–781.
  • Farr JN, Xu M, Weivoda MM, et al. Targeting cellular senescence prevents age-related bone loss in mice. Nat Med. 2017;23(9):1072–1079.
  • Lane N, Hsu B, Visich J, et al. A phase 2, randomized, double-blind, placebo-controlled study of senolytics molecule UBX0101 in the treatment of painful knee osteoarthritis. Osteoarthritis Cartilage. 2021;29:S10–S432.
  • Faust HJ, Zhang H, Han J, et al. IL-17 and immunologically induced senescence regulate response to injury in osteoarthritis. J Clin Invest. 2020;130(10):5493–5507.
  • Kapoor M, Martel-Pelletier J, Lajeunesse D, et al. Role of proinflammatory cytokines in the pathophysiology of osteoarthritis. Nat Rev Rheumatol. 2011;7(1):33–42.
  • Van der Kraan PM. The changing role of TGFβ in healthy, ageing and osteoarthritis joints. Nat Rev Rheumatol. 2017;13(3):155–163.
  • Maumus M, Noel D, Ea HK, et al. Identification of TGFβ signatures in six murine models mimicking different osteoarthritis clinical phenotypes. Osteoarthritis Cartilage. 2020;28(10):1373–1384.
  • Wang R, Xu B, Xu H. TGF-β1 promoted chondrocyte proliferation by regulating Sp1 through MSC-exosomes derived miR-135b. Cell Cycle. 2018;17(24):2756–2765.
  • Kim MK, Ha CW, In Y, et al. A multicenter, double-blind, phase III clinical trial to evaluate the efficacy and safety of a cell and gene therapy in knee osteoarthritis patients. Hum Gene Ther Clin Dev. 2018;29(1):48–59.
  • Guermazi A, Kalsi G, Niu J, et al. Structural effects of intra-articular TGF-β1 in moderate to advanced knee osteoarthritis: MRI-based assessment in a randomized control trial. BMC Musculoskelet Disord. 2017;18(1). DOI:10.1186/s12891-017-1830-8.
  • Chen R, Mian M, Fu M, et al. Attenuation of the progression of articular cartilage degeneration by inhibition of TGF-β1 signaling in a mouse model of osteoarthritis. Am J Pathol. 2015;185(11):2875–2885.
  • Thielen NGM, van der Kraan PM, van Caam APM. TGFβ/BMP signalling pathway in cartilage homeostasis. Cells. 2019;8(9):969.
  • Bush JR, Beier F. TGF-β and osteoarthritis – the good and the bad. Nat Med. 2013;19(6):667–669.
  • Appleton CTG, Usmani SE, Bernier SM, et al. Transforming growth factor α suppression of articular chondrocyte phenotype and Sox9 expression in a rat model of osteoarthritis. Arthritis Rheum. 2007;56(11):3693–3705.
  • Sun H, Wu Y, Pan Z, et al. Gefitinib for epidermal growth factor receptor activated osteoarthritis subpopulation treatment. EBioMedicine. 2018;32:223–233.
  • Wei Y, Luo L, Gui T, et al. Targeting cartilage EGFR pathway for osteoarthritis treatment. Sci Transl Med. 2021;13(576). DOI:10.1126/scitranslmed.abb3946.
  • Bellini M, Pest MA, Miranda-Rodrigues M, et al. Overexpression of MIG-6 in the cartilage induces an osteoarthritis-like phenotype in mice. Arthritis Res Ther. 2020;22(1):119.
  • Qin L, Beier F. EGFR signaling: friend or foe for cartilage? JBMR Plus. 2019;3(2):e10177.
  • Jia H, Ma X, Tong W, et al. EGFR signaling is critical for maintaining the superficial layer of articular cartilage and preventing osteoarthritis initiation. Proc Natl Acad Sci USA. 2016;113(50):14360–14365.
  • Regard JB, Zhong Z, Williams BO, et al. Wnt signaling in bone development and disease: making stronger bone with Wnts. Cold Spring Harb Perspect Biol. 2012;4(12):a007997–a007997.
  • Zhu M, Tang D, Wu Q, et al. Activation of β-catenin signaling in articular chondrocytes leads to osteoarthritis-like phenotype in adult β-catenin conditional activation mice. J Bone Miner Res. 2009;24(1):12–21.
  • Zhu M, Chen M, Zuscik M, et al. Inhibition of β-catenin signaling in articular chondrocytes results in articular cartilage destruction. Arthritis Rheum. 2008;58(7):2053–2064.
  • Lietman C, Wu B, Lechner S, et al. Inhibition of Wnt/β-catenin signaling ameliorates osteoarthritis in a murine model of experimental osteoarthritis. JCI Insight. 2018;3(3):e96308.
  • van den Bosch MH, Blom AB, van de Loo FA, et al. Induction of matrix metalloproteinase expression by synovial Wnt signaling and association with disease progression in early symptomatic osteoarthritis. Arthritis Rheum. 2017;69(10):1978–1983.
  • Yazici Y, McAlindon TE, Gibofsky A, et al. A phase 2b randomized trial of lorecivivint, a novel intra-articular CLK2/DYRK1A inhibitor and Wnt pathway modulator for knee osteoarthritis. Osteoarthritis Cartilage. 2021;29(5):654–666.
  • Tambiah JRS, Kennedy S, Swearingen CJ, et al. Individual participant symptom responses to intra-articular lorecivivint in knee osteoarthritis: post hoc analysis of a phase 2B trial. Rheumatol Ther. 2021;8(2):973–985.
  • Yazici Y, McAlindon TE, Gibofsky A, et al. Lorecivivint, a novel intra-articular CLK2/DYRK1A inhibitor and wnt pathway modulator for treatment of knee osteoarthritis: a phase 2 randomized trial. Arthritis Rheum. 2020;72(10):1694–1706.
  • Robinson WH, Lepus CM, Wang Q, et al. Low-grade inflammation as a key mediator of the pathogenesis of osteoarthritis. Nat Rev Rheumatol. 2016;12(10):580–592.
  • Wojdasiewicz P, Poniatowski LA, Szukiewicz D. The role of inflammatory and anti-inflammatory cytokines in the pathogenesis of osteoarthritis. Mediators Inflamm. 2014;2014:1–19.
  • Sokolove J, Lepus CM. Role of inflammation in the pathogenesis of osteoarthritis: latest findings and interpretations. Ther Adv Musculoskelet Dis. 2013;5(2):77–94.
  • Scanzello CR, Goldring SR. The role of synovitis in osteoarthritis pathogenesis. Bone. 2012;51(2):249–257.
  • Barreto G, Sandelin J, Salem A, et al. Toll-like receptors and their soluble forms differ in the knee and thumb basal osteoarthritic joints. Acta Orthop. 2017;88(3):326–333.
  • Liu XJ, Liu T, Chen G, et al. TLR signaling adaptor protein MyD88 in primary sensory neurons contributes to persistent inflammatory and neuropathic pain and neuroinflammation. Sci Rep. 2016;6:28188.
  • Schrezenmeier E, Dorner T. Mechanisms of action of hydroxychloroquine and chloroquine: implications for rheumatology. Nat Rev Rhematol. 2020;16(3):155–166.
  • Lee W, Ruijgrok L, Klerk BB, et al. Efficacy of hydroxychloroquine in hand osteoarthritis: a randomized, double-blind, placebo-controlled trial. Arthritis Care Res. 2018;70(9):1320–1325.
  • Kedor C, Detert J, Rau R, et al. Hydroxychloroquine in patients with inflammatory and erosive osteoarthritis of the hands: results of a randomized, double-blind, placebo controlled, multi-centre, investigator-initiated trial (OA TREAT). Ann Rheum Dis. 2020;79(Suppl 1):115–116.
  • Waller KA, Zhang LX, Elsaid KA, et al. Role of lubricin and boundary lubrication in the prevention of chondrocyte apoptosis. Proc Natl Acad Sci USA. 2013;110(15):5852–5857.
  • Iqbal SM, Leonard C, Regmi SC, et al. Lubricin/Proteoglycan 4 binds to and regulates the activity of toll-like receptors in vitro. Sci Rep. 2016;6(1):18910.
  • Al-Sharif A, Jamal M, Zhang LX, et al. Lubricin/Proteoglycan 4 binding to CD44 receptor: a mechanism of the suppression of proinflammatory cytokine-induced synoviocytes proliferation by lubricin. Arthritis Rheum. 2015;67(6):1503–1513.
  • Maenohara Y, Chijimatsu R, Tachibana N, et al. Lubricin contributes to homeostasis of articular cartilage by modulating differentiation of superficial zone cells. J Bone Miner Res. 2021;36(4):792–802.
  • Nemirov D, Nakagawa Y, Sun Z, et al. Effect of lubricin mimetics on the inhibition of osteoarthritis in a rat anterior cruciate ligament transection model. Am J Sports Med. 2020;48(3):624–634.
  • Wu CL, Harasymowicz NS, Klimak MA, et al. The role of macrophages in osteoarthritis and cartilage repair. Osteoarthritis Cartilage. 2020;28(5):544–54.
  • Blom AB, van Lent PLEM, Holthuysen AEM, et al. Synovial lining macrophages mediate osteophyte formation during experimental osteoarthritis. Osteoarthritis Cartilage. 2004;12(8):627–635.
  • Wu CL, McNeill J, Goon K, et al. Conditional macrophage depletion increases inflammation and does not inhibit the development of osteoarthritis in obese macrophage fas-induced apoptosis-transgenic mice. Arthritis Rheum. 2017;69(9):1772–1783.
  • Grol MW, Lee BH. Gene therapy for repair and regeneration of bone and cartilage. Curr Opin Pharmacol. 2018;40:59–66.
  • Jenei-Lanzl Z, Meurer A, Zaucke F. Interleukin-1β signaling in osteoarthritis – chondrocytes in focus. Cell Signal. 2019;53:212–223.
  • Chevalier X, Goupille P, Beaulieu AD, et al. Intraarticular injection of Anakinra in osteoarthritis of the knee: a multicenter, randomized, double-blind, placebo-controlled study. Arthritis Rheum. 2009;61(3):344–352.
  • Nixon AJ, Grol MW, Lang HM, et al. Disease-modifying osteoarthritis treatment with interleukin-1 receptor antagonist gene therapy in small and large animal models. Arthritis Rheum. 2018;70(11):1757–1768.
  • Stone A, Grol MW, Ruan MZC, et al. Combinatorial Prg4 and Il-1ra Gene Therapy Protects Against Hyperalgesia and Cartilage Degeneration in Post-Traumatic Osteoarthritis. Hum Gene Ther. 2018;30(2):225–235.
  • Spil WEV, Kubassova O, Boesen M, et al. Osteoarthritis phenotypes and novel therapeutic targets. Biochem Pharmacol. 2019;165:41–48.
  • Moon PM, Shao ZY, Wambiekele, et al. Global deletion of pannexin 3 resulting in accelerated development of aging-induced osteoarthritis in mice. Arthritis Rheum. 2021;73(7):1178–1188.
  • Moon PM, Penuela S, Barr K, et al. Deletion of Panx3 prevents the development of surgically induced osteoarthritis. J Mol Med. 2015;93(8):845–856.
  • O’Conor CJ, Griffin TM, Leidtke W, et al. Increased susceptibility of Trpv4 -deficient mice to obesity and obesity-induced osteoarthritis with very high-fat diet. Ann Rheum Dis. 2013;72(2):300–304.
  • O’Conor CJ, Ramalingam S, Zelenki NA, et al. Cartilage-specific knockout of the mechanosensory ion channel TRPV4 decreases age-related osteoarthritis. Sci Rep. 2016;6(1):29053.
  • Clark AL, Votta BJ, Kumar S, et al. Chondroprotective role of the osmotically sensitive ion channel transient receptor potential vanilloid 4: age- and sex-dependent progression of osteoarthritis in Trpv4-deficient mice. Arthritis Rheum. 2010;62(10):2973–2983.
  • Ratneswaran A, Beier F. An approach towards accountability: suggestions for increased reproducibility in surgical destabilization of medial meniscus (DMM) models. Osteoarthritis Cartilage. 2017;25(11):1747–1750.

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