219
Views
0
CrossRef citations to date
0
Altmetric
Review

Shedding light on experimental intra-articular drugs for treating knee osteoarthritis

, , , , & ORCID Icon
Pages 509-524 | Received 31 Jan 2023, Accepted 11 Jun 2023, Published online: 23 Jun 2023

References

  • Barnett R. Osteoarthritis. Lancet. 2018 May 19;391:1985. doi: 10.1016/S0140-6736(18)31064-X
  • Katz JN, Arant KR, Loeser RF. Diagnosis and treatment of hip and knee osteoarthritis: a review. JAMA. 2021 Feb 9;325(6):568–578.
  • Hussain SM, Wang Y, Giles GG, et al. Female reproductive and hormonal factors and incidence of primary total knee arthroplasty due to osteoarthritis. Arthritis Rheumatol (Hoboken, NJ). 2018 Jul;70(7):1022–1029.
  • Wang T, He C. Pro-inflammatory cytokines: the link between obesity and osteoarthritis. Cytokine Growth Factor Rev. 2018 Dec;44:38–50. doi: 10.1016/j.cytogfr.2018.10.002
  • Chen L, Yao F, Wang T, et al. Horizontal fissuring at the osteochondral interface: a novel and unique pathological feature in patients with obesity-related osteoarthritis. Ann Rheum Dis. 2020 Jun;79(6):811–818.
  • Zengini E, Hatzikotoulas K, Tachmazidou I, et al. Genome-wide analyses using UK Biobank data provide insights into the genetic architecture of osteoarthritis. Nature Genet. 2018 Apr;50(4):549–558.
  • Cho Y, Jeong S, Kim H, et al. Disease-modifying therapeutic strategies in osteoarthritis: current status and future directions. Exp Mol Med. 2021 Nov;53(11):1689–1696.
  • Kolasinski SL, Neogi T, Hochberg MC, et al. American college of rheumatology/arthritis foundation guideline for the management of osteoarthritis of the hand, hip, and knee. Arthritis Rheumatol (Hoboken, NJ). 2019 [2020 Feb];72:220–233.
  • Bannuru RR, Osani MC, Vaysbrot EE, et al. OARSI guidelines for the non-surgical management of knee, hip, and polyarticular osteoarthritis. Osteoarthritis Cartilage. 2019 Nov;27(11):1578–1589.
  • Arden NK, Perry TA, Bannuru RR, et al. Non-surgical management of knee osteoarthritis: comparison of ESCEO and OARSI 2019 guidelines. Nat Rev Rheumatol. 2021 Jan;17(1):59–66.
  • Leopoldino AO, Machado GC, Ferreira PH, et al. Paracetamol versus placebo for knee and hip osteoarthritis. Cochrane Database Syst Rev. 2019 Feb 25;2:Cd013273.
  • da Costa BR, Nüesch E, Kasteler R, et al. Oral or transdermal opioids for osteoarthritis of the knee or hip. Cochrane Database Syst Rev. 2014 Sep 17; Cd003115. doi: 10.1002/14651858.CD003115.pub4
  • Zeng C, Dubreuil M, LaRochelle MR, et al. Association of tramadol with all-cause mortality among patients with osteoarthritis. JAMA. 2019 Mar 12;321(10):969–982.
  • Jones IA, Togashi R, Wilson ML, et al. Intra-articular treatment options for knee osteoarthritis. Nat Rev Rheumatol. 2019 Feb;15(2):77–90.
  • Migliore A, Paoletta M, Moretti A, et al. The perspectives of intra-articular therapy in the management of osteoarthritis. Expert Opin Drug Delivery. 2020 Sep;17(9):1213–1226.
  • Bucci J, Chen X, LaValley M, et al. Progression of knee osteoarthritis with use of intraarticular glucocorticoids versus hyaluronic acid. Arthritis Rheumatol (Hoboken, NJ). 2022 Feb;74:223–226.
  • da Costa BR, Hari R, Jüni P, et al. Intra-articular corticosteroids for osteoarthritis of the knee. JAMA. 2016 Dec 27;316:2671–2672. doi: 10.1001/jama.2016.17565
  • McAlindon TE, LaValley MP, Harvey WF, et al. Effect of intra-articular triamcinolone vs saline on knee cartilage volume and pain in patients with knee osteoarthritis: a randomized clinical trial. JAMA. 2017 May 16;317(19):1967–1975.
  • Gazendam A, Ekhtiari S, Bozzo A, et al. Intra-articular saline injection is as effective as corticosteroids, platelet-rich plasma and hyaluronic acid for hip osteoarthritis pain: a systematic review and network meta-analysis of randomised controlled trials. Br J Sports Med. 2021 Mar;55:256–261.
  • Fan XL, Zhang Y, Li X, et al. Mechanisms underlying the protective effects of mesenchymal stem cell-based therapy. Cellular and molecular life sciences: cMLS. Cell Mol Life Sci. 2020 Jul;77(14):2771–2794.
  • Chahal J, Gómez-Aristizábal A, Shestopaloff K, et al. Bone marrow mesenchymal stromal cell treatment in patients with osteoarthritis results in overall improvement in pain and symptoms and reduces synovial inflammation. Stem Cells Transl Med. 2019 Aug;8(8):746–757. doi: 10.1002/sctm.18-0183
  • Lamo-Espinosa JM, Mora G, Blanco JF, et al. Intra-articular injection of two different doses of autologous bone marrow mesenchymal stem cells versus hyaluronic acid in the treatment of knee osteoarthritis: multicenter randomized controlled clinical trial (phase I/II). J Transl Med. 2016 Aug 26;14:246.
  • Szwedowski D, Szczepanek J, Paczesny Ł, et al. The effect of platelet-rich plasma on the intra-articular microenvironment in knee osteoarthritis. Int J Mol Sci. 2021;22(11):5492. doi: 10.3390/ijms22115492
  • Bennell KL, Paterson KL, Metcalf BR, et al. Effect of Intra-articular platelet-rich plasma vs placebo injection on pain and medial tibial cartilage volume in patients with knee osteoarthritis: the RESTORE randomized clinical trial. JAMA. 2021;326(20):2021–2030. doi: 10.1001/jama.2021.19415
  • Paget LDA, Reurink G, de Vos RJ, et al. Effect of platelet-rich plasma injections vs placebo on ankle symptoms and function in patients with ankle osteoarthritis: a randomized clinical trial. JAMA. 2021 Oct 26;326(16):1595–1605.
  • Li J, Wang X, Ruan G, et al. Sprifermin: a recombinant human fibroblast growth factor 18 for the treatment of knee osteoarthritis. Expert Opin Investig Drugs. 2021 Sep;30(9):923–930.
  • Eckstein F, Hochberg MC, Guehring H, et al. Long-term structural and symptomatic effects of intra-articular sprifermin in patients with knee osteoarthritis: 5-year results from the FORWARD study. Ann Rheum Dis. 2021 May 7;80(8):1062–1069. doi: 10.1136/annrheumdis-2020-219181
  • Ha CW, Noh MJ, Choi KB, et al. Initial phase I safety of retrovirally transduced human chondrocytes expressing transforming growth factor-beta-1 in degenerative arthritis patients. Cytotherapy. 2012 Feb;14(2):247–256.
  • 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 Mar;29(1):48–59.
  • 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 May;29(5):654–666.
  • Gerwin N, Scotti C, Halleux C, et al. Angiopoietin-like 3-derivative LNA043 for cartilage regeneration in osteoarthritis: a randomized phase 1 trial. Nat Med. 2022 Dec;28(12):2633–2645. doi: 10.1038/s41591-022-02059-9
  • Gui T, Luo L, Chhay B, et al. Superoxide dismutase-loaded porous polymersomes as highly efficient antioxidant nanoparticles targeting synovium for osteoarthritis therapy. Biomaterials. 2022;283:121437. doi: 10.1016/j.biomaterials.2022.121437
  • Feng K, Chen Z, Pengcheng L, et al. Quercetin attenuates oxidative stress-induced apoptosis via SIRT1/AMPK-mediated inhibition of ER stress in rat chondrocytes and prevents the progression of osteoarthritis in a rat model. J Cell Physiol. 2019;234(10):18192–18205. doi: 10.1002/jcp.28452
  • Wang FS, Kuo CW, Ko JY, et al. Irisin mitigates oxidative stress, chondrocyte dysfunction and osteoarthritis development through regulating mitochondrial integrity and autophagy. Antioxidants. 2020 Sep 1;9:810.
  • Wu J, Kuang L, Chen C, et al. MiR-100-5p-abundant exosomes derived from infrapatellar fat pad MSCs protect articular cartilage and ameliorate gait abnormalities via inhibition of mTOR in osteoarthritis. Biomaterials. 2019 Jun;206:87–100.
  • Xu K, He Y, Moqbel SAA, et al. SIRT3 ameliorates osteoarthritis via regulating chondrocyte autophagy and apoptosis through the PI3K/Akt/mTOR pathway. Int j biol macromol. 2021 Apr 1;175:351–360.
  • Chen X, Gong W, Shao X, et al. METTL3-mediated m 6 a modification of ATG7 regulates autophagy-GATA4 axis to promote cellular senescence and osteoarthritis progression. Ann Rheum Dis. 2021 Oct 27;81:85–97.
  • Dai H, Chen R, Gui C, et al. Eliminating senescent chondrogenic progenitor cells enhances chondrogenesis under intermittent hydrostatic pressure for the treatment of OA. Stem Cell Res Ther. 2020 May 25;11(1):199.
  • Chang J, Wang Y, Shao L, et al. Clearance of senescent cells by ABT263 rejuvenates aged hematopoietic stem cells in mice. Nat Med. 2016 Jan;22(1):78–83.
  • 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 Jun;23(6):775–781.
  • Fleischmann RM, Bliddal H, Blanco FJ, et al. A phase ii trial of lutikizumab, an anti-interleukin-1α/β dual variable domain immunoglobulin, in knee osteoarthritis patients with synovitis. Arthritis Rheumatol (Hoboken, NJ). 2019 Jul;71:1056–1069.
  • Güler-Yüksel M, Allaart CF, Watt I, et al. Treatment with TNF-α inhibitor infliximab might reduce hand osteoarthritis in patients with rheumatoid arthritis. Osteoarthritis Cartilage. 2010 Oct;18(10):1256–1262.
  • Fioravanti A, Fabbroni M, Cerase A, et al. Treatment of erosive osteoarthritis of the hands by intra-articular infliximab injections: a pilot study. Rheumatol Int. 2009 Jun;29(8):961–965.
  • Kloppenburg M, Ramonda R, Bobacz K, et al. Etanercept in patients with inflammatory hand osteoarthritis (EHOA): a multicentre, randomised, double-blind, placebo-controlled trial. Ann Rheum Dis. 2018 Dec;77(12):1757–1764.
  • Bi R, Chen K, Wang Y, et al. Regulating fibrocartilage stem cells via tnf-α/nf-κb in TMJ osteoarthritis. J Dent Res. 2022 Mar;101:312–322.
  • Bendele AM, Neelagiri M, Neelagiri V, et al. Development of a selective matrix metalloproteinase 13 (MMP-13) inhibitor for the treatment of Osteoarthritis. Eur J Med Chem. 2021 Nov 15;224:113666.
  • Cortet B, Lombion S, Naissant B, et al. Non-inferiority of a single injection of sodium hyaluronate plus sorbitol to hylan G-F20: a 6-month randomized controlled trial. Adv Ther. 2021;38(5):2271–2283. doi: 10.1007/s12325-021-01648-3
  • Nishida Y, Kano K, Nobuoka Y, et al. Efficacy and safety of diclofenac-hyaluronate conjugate (diclofenac etalhyaluronate) for knee osteoarthritis: a randomized phase iii trial in Japan. Arthritis Rheumatol (Hoboken, NJ). 2021 Sep;73:1646–1655.
  • Zhang K, Julius D, Cheng Y. Structural snapshots of TRPV1 reveal mechanism of polymodal functionality. Cell. 2021 Sep 30;184(20):5138–50.e12.
  • Iadarola MJ, Sapio MR, Raithel SJ, et al. Long-term pain relief in canine osteoarthritis by a single intra-articular injection of resiniferatoxin, a potent TRPV1 agonist. Pain. 2018;159(10):2105–2114. doi: 10.1097/j.pain.0000000000001314
  • Stevens RM, Ervin J, Nezzer J, et al. Randomized, double-blind, placebo-controlled trial of intraarticular trans capsaicin for pain associated with osteoarthritis of the knee (Hoboken NJ), et al. Arthritis & rheumat. 2019 Sep;71:1524–1533. doi: 10.1002/art.40894
  • Shimonkevitz R, Thomas G, Slone DS, et al. A diketopiperazine fragment of human serum albumin modulates T-lymphocyte cytokine production through rap1. J Trauma. 2008 Jan;64(1):35–41.
  • Frederick ED, Hausburg MA, Thomas GW, et al. The low molecular weight fraction of human serum albumin upregulates COX2, prostaglandin E2, and prostaglandin D2 under inflammatory conditions in osteoarthritic knee synovial fibroblasts. Biochem Biophys Rep. 2016 Dec;8:68–74.
  • Bar-Or D, Salottolo KM, Loose H, et al. A randomized clinical trial to evaluate two doses of an intra-articular injection of LMWF-5A in adults with pain due to osteoarthritis of the knee. PLoS ONE. 2014;9(2):e87910. doi: 10.1371/journal.pone.0087910
  • Schwappach J, Dryden SM, Salottolo KM. Preliminary trial of intra-articular LMWF-5A for osteoarthritis of the knee. Orthopedics. 2017 Jan 1;40(1):e49–e53. doi: 10.3928/01477447-20160926-02
  • Krupka E, Jiang GL, Jan C. Efficacy and safety of intra-articular injection of tropomyosin receptor kinase a inhibitor in painful knee osteoarthritis: a randomized, double-blind and placebo-controlled study. Osteoarthritis Cartilage. 2019 Nov;27(11):1599–1607. doi: 10.1016/j.joca.2019.05.028
  • Mendes JG, Natour J, Nunes-Tamashiro JC, et al. Comparison between intra-articular Botulinum toxin type A, corticosteroid, and saline in knee osteoarthritis: a randomized controlled trial. Clin Rehabil. 2019;33(6):1015–1026. doi: 10.1177/0269215519827996
  • Sconza C, Leonardi G, Carfì C, et al. Intra-articular injection of botulinum toxin for the treatment of knee osteoarthritis: a systematic review of randomized controlled trials. Int J Mol Sci. 2023 Jan 12;24(2):1486.
  • Bei HP, Hung PM, Yeung HL, et al. Bone-a-petite: engineering exosomes towards bone, osteochondral, and cartilage repair. small (Weinheim an der bergstrasse. Germany). 2021 Dec;17:e2101741.
  • Xie Y, Zinkle A, Chen L, et al. Fibroblast growth factor signalling in osteoarthritis and cartilage repair. Nat Rev Rheumatol. 2020 Oct;16(10):547–564.
  • Bei HP, Hung PM, Yeung HL, et al. Bone-a-petite: engineering exosomes towards bone. Osteochondral, And Cartilage Repair. 2021;17:2101741. doi: 10.1002/smll.202101741
  • Lu Y, Chen J, Li L, et al. Hierarchical functional nanoparticles boost osteoarthritis therapy by utilizing joint-resident mesenchymal stem cells. J Nanobiotechnol. 2022 Feb 19;20(1):89.
  • Davatchi F, Abdollahi BS, Mohyeddin M, et al. Mesenchymal stem cell therapy for knee osteoarthritis. Preliminary report of four patients. Int J Rheum Dis. 2011 May;14(2):211–215.
  • Lee WS, Kim HJ, Kim KI, et al. Intra-articular injection of autologous adipose tissue-derived mesenchymal stem cells for the treatment of knee osteoarthritis: a phase iib, randomized, placebo-controlled clinical trial. Stem Cells Transl Med. 2019 Jun;8(6):504–511.
  • Pers YM, Rackwitz L, Ferreira R, et al. Adipose mesenchymal stromal cell-based therapy for severe osteoarthritis of the knee: a phase i dose-escalation trial. Stem Cells Transl Med. 2016 Jul;5(7):847–856.
  • Matas J, Orrego M, Amenabar D, et al. Umbilical cord-derived mesenchymal stromal cells (MSCs) for knee osteoarthritis: repeated msc dosing is superior to a single MSC dose and to hyaluronic acid in a controlled randomized phase i/ii trial. Stem Cells Transl Med. 2019 Mar;8(3):215–224.
  • Wehling P, Evans C, Wehling J, et al. Effectiveness of intra-articular therapies in osteoarthritis: a literature review. Therapeutic advances in musculoskeletal disease. Ther Adv Musculoskelet Dis. 2017 Aug;9(8):183–196.
  • Everts P, Onishi K, Jayaram P, et al. Platelet-rich plasma: new performance understandings and therapeutic considerations in 2020. Int J Mol Sci. 2020 Oct 21;21:7794.
  • Mehranfar S, Abdi Rad I, Mostafav E, et al. The use of stromal vascular fraction (SVF), platelet-rich plasma (PRP) and stem cells in the treatment of osteoarthritis: an overview of clinical trials. Artific Cells Nanomed Biotechnol. 2019 Dec;47(1):882–890.
  • Gobbi A, Karnatzikos G, Mahajan V, et al. Platelet-rich plasma treatment in symptomatic patients with knee osteoarthritis: preliminary results in a group of active patients. Sports Health. 2012 Mar;4(2):162–172.
  • Ahmad HS, Farrag SE, Okasha AE, et al. Clinical outcomes are associated with changes in ultrasonographic structural appearance after platelet-rich plasma treatment for knee osteoarthritis. Int J Rheum Dis. 2018 May;21(5):960–966.
  • Huang Y, Liu X, Xu X, et al. Intra-articular injections of platelet-rich plasma, hyaluronic acid or corticosteroids for knee osteoarthritis: a prospective randomized controlled study. Der Orthopade. 2019 Mar;48:239–247.
  • Campbell KA, Saltzman BM, Mascarenhas R, et al. Does intra-articular platelet-rich plasma injection provide clinically superior outcomes compared with other therapies in the treatment of knee osteoarthritis? a systematic review of overlapping meta-analyses. Arthros J Arthros Related Surgery. 2015 Nov;31:2213–2221.
  • Lohmander LS, Hellot S, Dreher D, et al. Intraarticular sprifermin (recombinant human fibroblast growth factor 18) in knee osteoarthritis: a randomized, double-blind, placebo-controlled trial. Arthritis Rheumatol (Hoboken, NJ). 2014 Jul;66:1820–1831.
  • Hochberg MC, Guermazi A, Guehring H, et al. Effect of intra-articular sprifermin vs placebo on femorotibial joint cartilage thickness in patients with osteoarthritis: the FORWARD randomized clinical trial. JAMA. 2019 Oct 8;322(14):1360–1370.
  • Cherifi C, Monteagudo S, Lories RJ. Promising targets for therapy of osteoarthritis: a review on the Wnt and TGF-β signalling pathways. Ther Adv Musculoskelet Dis. 2021;13:1759720x211006959. doi: 10.1177/1759720X211006959
  • Wang C, Shen J, Ying J, et al. FoxO1 is a crucial mediator of TGF-β/TAK1 signaling and protects against osteoarthritis by maintaining articular cartilage homeostasis. Proc Natl Acad Sci USA. 2020 Dec 1;117:30488–30497.
  • Lories RJ, Corr M, Lane NE. To Wnt or not to Wnt: the bone and joint health dilemma. Nat Rev Rheumatol. 2013 Jun;9(6):328–339. doi: 10.1038/nrrheum.2013.25
  • Wang Y, Fan X, Xing L, et al. Wnt signaling: a promising target for osteoarthritis therapy. Cell Commun Signal. 2019 Aug 16;17:97.
  • McGuire D, Bowes M, Brett A, et al. Study TPX-100-5: intra-articular TPX-100 significantly delays pathological bone shape change and stabilizes cartilage in moderate to severe bilateral knee OA. Arthritis Res Ther. 2021 Sep 17;23(1):242.
  • Fujii Y, Liu L, Yagasaki L, et al. Cartilage Homeostasis and Osteoarthritis. Int J Mol Sci. 2022;23(11):6316. doi: 10.3390/ijms23116316
  • Lynskey SJ, Macaluso MJ, Gill SD, et al. Biomarkers of osteoarthritis-a narrative review on causal links with metabolic syndrome. Life (Basel Switzerland); 2023 Mar 8Vol. 13.
  • Lepetsos P, Papavassiliou KA, Papavassiliou AG. Redox and NF-κB signaling in osteoarthritis. Free Radic Biol Med. 2019;132. doi: 10.1016/j.freeradbiomed.2018.09.025
  • Rahman MM, Watton PN, Neu CP, et al. A chemo-mechano-biological modeling framework for cartilage evolving in health, disease, injury, and treatment. Computer methods and programs in biomedicine. Comput Methods Programs Biomed. 2023 Apr;231:107419.
  • Lismont C, Nordgren M, Van Veldhoven PP, et al. Redox interplay between mitochondria and peroxisomes. Front Cell Dev Biol. 2015;3:35. doi: 10.3389/fcell.2015.00035
  • Luo J, Mills K, le Cessie S, et al. Ageing, age-related diseases and oxidative stress: what to do next? Ageing Res Rev. 2020 Jan 01;57:100982.
  • Mok SW, Fu SC, Cheuk YC, et al. Intra-articular delivery of quercetin using thermosensitive hydrogel attenuate cartilage degradation in an osteoarthritis rat model. Cartilage. 2020 Oct;11(4):490–499.
  • Hu Y, Gui Z, Zhou 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 Dec;145:146–160.
  • Lotz MK, Caramés B. Autophagy and cartilage homeostasis mechanisms in joint health, aging and OA. Nat Rev Rheumatol. 2011;7(10):579–587. doi: 10.1038/nrrheum.2011.109
  • Rockel JS, Kapoor M. Autophagy: controlling cell fate in rheumatic diseases. Nat Rev Rheumatol. 2016 Sep;12(9):517–531. doi: 10.1038/nrrheum.2016.92
  • Valenti MT, Dalle Carbonare L, Zipeto D, et al. Control of the autophagy pathway in osteoarthritis: key regulators, therapeutic targets and therapeutic strategies. Int J Mol Sci. 2021 Mar 7;22(5):2700.
  • Coryell PR, Diekman BO, Loeser RF. Mechanisms and therapeutic implications of cellular senescence in osteoarthritis. Nat Rev Rheumatol. 2021 Jan;17(1):47–57. doi: 10.1038/s41584-020-00533-7
  • Xu M, Bradley EW, Weivoda MM, et al. Transplanted senescent cells induce an osteoarthritis-like condition in mice. J Gerontol A Biol Sci Med Sci. 2017 Jun 1;72(6):780–785.
  • Gil TH, Zheng H, Lee HG, et al. Senolytic drugs relieve pain by reducing peripheral nociceptive signaling without modifying joint tissue damage in spontaneous osteoarthritis. Aging. 2022 Aug 10;14(15):6006–6027.
  • Zhu Y, Tchkonia T, Pirtskhalava T, et al. The Achilles’ heel of senescent cells: from transcriptome to senolytic drugs. Aging Cell. 2015 Aug;14(4):644–658.
  • Yang H, Chen C, Chen H, et al. Navitoclax (ABT263) reduces inflammation and promotes chondrogenic phenotype by clearing senescent osteoarthritic chondrocytes in osteoarthritis. Aging. 2020 Jul 1;12(13):12750–12770.
  • Kim EC, Kim JR. Senotherapeutics: emerging strategy for healthy aging and age-related disease. BMB Rep. 2019 Jan;52:47–55. doi: 10.5483/BMBRep.2019.52.1.293
  • Deng Y, Lu J, Li W, et al. Reciprocal inhibition of YAP/TAZ and NF-κB regulates osteoarthritic cartilage degradation. Nat Commun. 2018 Nov 1;9(1):4564.
  • Chang SH, Mori D, Kobayashi H, et al. Excessive mechanical loading promotes osteoarthritis through the gremlin-1-NF-κB pathway. Nat Commun. 2019 Mar 29;10:1442.
  • Wang F, Liu J, Chen X, et al. IL-1β receptor antagonist (IL-1Ra) combined with autophagy inducer (TAT-Beclin1) is an effective alternative for attenuating extracellular matrix degradation in rat and human osteoarthritis chondrocytes. Arthritis Res Ther. 2019 Jul 10;21(1):171.
  • Chien SY, Tsai CH, Liu SC, et al. Noggin inhibits IL-1β and BMP-2 expression, and attenuates cartilage degeneration and subchondral bone destruction in experimental osteoarthritis. Cells. 2020 Apr 10;9(4):927.
  • Schieker M, Conaghan PG, Mindeholm L, et al. Effects of interleukin-1β inhibition on incident hip and knee replacement: exploratory analyses from a randomized, double-blind, placebo-controlled trial. Ann Intern Med. 2020 Oct 6;173(7):509–515.
  • Urech DM, Feige U, Ewert S, et al. Anti-inflammatory and cartilage-protecting effects of an intra-articularly injected anti-TNF{alpha} single-chain Fv antibody (ESBA105) designed for local therapeutic use. Ann Rheum Dis. 2010 Feb;69:443–449.
  • Chen JJ, Huang JF, Du WX, et al. Expression and significance of MMP3 in synovium of knee joint at different stage in osteoarthritis patients. Asian Pac J Trop Med. 2014 Apr;7(4):297–300.
  • Wang M, Sampson ER, Jin H, et al. MMP13 is a critical target gene during the progression of osteoarthritis. Arthritis Res Ther. 2013 Jan 8;15(1):R5.
  • Hoshi H, Akagi R, Yamaguchi S, et al. Effect of inhibiting MMP13 and ADAMTS5 by intra-articular injection of small interfering RNA in a surgically induced osteoarthritis model of mice. Cell Tissue Res. 2017 May;368(2):379–387.
  • Sulastri D, Arnadi A, Afriwardi A, et al. Risk factor of elevated matrix metalloproteinase-3 gene expression in synovial fluid in knee osteoarthritis women. PLoS ONE. 2023;18(3):e0283831. doi: 10.1371/journal.pone.0283831
  • Rezuş E, Burlui A, Cardoneanu A, et al. From pathogenesis to therapy in knee osteoarthritis: bench-to-bedside. Int J Mol Sci. 2021 Mar 7;22(5):2697.
  • J M-P, B AJ, C FM, et al. Osteoarthritis. Nat Rev Dis Primers. 2016;2:16072. doi: 10.1038/nrdp.2016.72
  • Tenti S, Bruyère O, Cheleschi S, et al. An update on the use of conventional and biological disease-modifying anti-rheumatic drugs in hand osteoarthritis. Ther Adv Musculoskelet Dis. 2023;15:1759720x231158618. doi: 10.1177/1759720X231158618
  • Li C, Cao Z, Li W, et al. A review on the wide range applications of hyaluronic acid as a promising rejuvenating biomacromolecule in the treatments of bone related diseases. Int j biol macromol. 2020 Dec 15;165:1264–1275.
  • Maheu E, Bannuru RR, Herrero-Beaumont G, et al. Why we should definitely include intra-articular hyaluronic acid as a therapeutic option in the management of knee osteoarthritis: results of an extensive critical literature review. Semin Arthritis Rheum. 2019 Feb 01;48:563–572.
  • Altman RD, Manjoo A, Fierlinger A, et al. The mechanism of action for hyaluronic acid treatment in the osteoarthritic knee: a systematic review. BMC Musculoskelet Disord. 2015 Oct 26;16:321.
  • Murphy JF, Lennon F, Steele C, et al. Engagement of CD44 modulates cyclooxygenase induction, VEGF generation, and proliferation in human vascular endothelial cells. Faseb J. 2005 Mar;19:446–448.
  • Julovi SM, Ito H, Nishitani K, et al. Hyaluronan inhibits matrix metalloproteinase-13 in human arthritic chondrocytes via CD44 and P38. J Orthop Res. 2011 Feb;29:258–264.
  • Xing D, Wang B, Liu Q, et al. Intra-articular hyaluronic acid in treating knee osteoarthritis: a PRISMA-Compliant systematic review of overlapping meta-analysis. Sci Rep. 2016 Sep 12;6(1):32790.
  • Phillips M, Bhandari M, Grant J, et al. A systematic review of current clinical practice guidelines on intra-articular hyaluronic acid, corticosteroid, and platelet-rich plasma injection for knee osteoarthritis: an international perspective. Orthop J Sports Med. 2021 Aug;9(8):23259671211030272.
  • Printz JO, Lee JJ, Knesek M, et al. Conflict of interest in the assessment of hyaluronic acid injections for osteoarthritis of the knee: an updated systematic review. J Arthroplasty. 2013 Sep;28(8):30–3.e1.
  • Bruyère O, Honvo G, Vidovic E, et al. Assessment of the response profile to hyaluronic acid plus sorbitol injection in patients with knee osteoarthritis: post-hoc analysis of a 6-month randomized controlled trial. Biomolecules. 2021 Oct 11;11:1498.
  • Conrozier T, Eymard F, Afif N, et al. Safety and efficacy of intra-articular injections of a combination of hyaluronic acid and mannitol (HAnOX-M) in patients with symptomatic knee osteoarthritis: results of a double-blind, controlled, multicenter, randomized trial. Knee. 2016 Oct;23(5):842–848.
  • Rivera F, Bertignone L, Grandi G, et al. Effectiveness of intra-articular injections of sodium hyaluronate-chondroitin sulfate in knee osteoarthritis: a multicenter prospective study. J Orthop Traumatol. 2016 Mar;17:27–33.
  • Palmieri B, Rottigni V, Iannitti T. Preliminary study of highly cross-linked hyaluronic acid-based combination therapy for management of knee osteoarthritis-related pain. Drug Design Develop Therapy. 2013;7:7–12. doi: 10.2147/DDDT.S37330
  • Nishida Y, Kano K, Nobuoka Y, et al. Sustained-release diclofenac conjugated to hyaluronate (diclofenac etalhyaluronate) for knee osteoarthritis: a randomized phase 2 study. Rheumatology (Oxford). 2021 Mar 2;60(3):1435–1444.
  • Stagni C, Rocchi M, Mazzotta A, et al. Randomised, double-blind comparison of a fixed co-formulation of intra-articular polynucleotides and hyaluronic acid versus hyaluronic acid alone in the treatment of knee osteoarthritis: two-year follow-up. BMC Musculoskelet Disord. 2021 Sep 12;22:773.
  • Campbell JN, Stevens R, Hanson P, et al. Injectable capsaicin for the management of pain due to osteoarthritis. Molecules. 2021 Feb 3;26:778.
  • Arora V, Campbell JN, Chung MK. Fight fire with fire: neurobiology of capsaicin-induced analgesia for chronic pain. Pharmacol Ther. 2021 Apr;220:107743. doi: 10.1016/j.pharmthera.2020.107743
  • Mazzaferro EM, Edwards T. Update on albumin therapy in critical illness. Vet Clin North Am Small Anim Pract. 2020 Nov;50(6):1289–1305. doi: 10.1016/j.cvsm.2020.07.005
  • Bar-Or D, Thomas GW, Bar-Or R, et al. Commercial human albumin preparations for clinical use are immunosuppressive in vitro. Crit Care Med. 2006 Jun;34(6):1707–1712.
  • Wise BL, Seidel MF, Lane NE. The evolution of nerve growth factor inhibition in clinical medicine. Nat Rev Rheumatol. 2021 Jan;17(1):34–46. doi: 10.1038/s41584-020-00528-4
  • Koya Y, Tanaka H, Yoshimi E, et al. A novel anti-NGF PEGylated Fab’ provides analgesia with lower risk of adverse effects. MAbs. 2023 Jan;15(1):2149055.
  • Flannery CR, Moran N, Blasioli D, et al. Efficacy of a novel, locally delivered TrkA inhibitor in preclinical models of OA and joint pain. Osteoarthritis Cartilage. 2015;23:A45–A6. doi: 10.1016/j.joca.2015.02.100
  • Rossetto O, Pirazzini M, Montecucco C. Botulinum neurotoxins: genetic, structural and mechanistic insights. Nature Rev Microbiol. 2014 Aug;12(8):535–549. doi: 10.1038/nrmicro3295
  • Mendes JG, Natour J, Nunes-Tamashiro JC, et al. Comparison between intra-articular Botulinum toxin type A, corticosteroid, and saline in knee osteoarthritis: a randomized controlled trial. Clin Rehabilitat. 2019 Jun;33(6):1015–1026.
  • McAlindon TE, Schmidt U, Bugarin D, et al. Efficacy and safety of single-dose onabotulinumtoxinA in the treatment of symptoms of osteoarthritis of the knee: results of a placebo-controlled, double-blind study. Osteoarthritis Cartilage. 2018 Oct;26(10):1291–1299.
  • Rezasoltani Z, Dadarkhah A, Tabatabaee SM, et al. Therapeutic effects of intra-articular botulinum neurotoxin versus physical therapy in knee osteoarthritis. Anesth Pain Med. 2021 Jun;11:e112789.
  • Rezasoltani Z, Azizi S, Najafi S, et al. Physical therapy, intra-articular dextrose prolotherapy, botulinum neurotoxin, and hyaluronic acid for knee osteoarthritis: randomized clinical trial. Int J Rehabi Res. 2020 Sep;43(3):219–227.
  • Su D, Ai Y, Zhu G, et al. Genetically predicted circulating levels of cytokines and the risk of osteoarthritis: a mendelian randomization study. Front Genet. 2023;14:1131198. doi: 10.3389/fgene.2023.1131198
  • Yu L, Luo R, Qin G, et al. Efficacy and safety of anti-interleukin-1 therapeutics in the treatment of knee osteoarthritis: a systematic review and meta-analysis of randomized controlled trials. J Orthop Surg Res. 2023 Feb 13;18:100.
  • Saraf A, Hussain A, Bishnoi S, et al. Serial intraarticular injections of growth factor concentrate in knee osteoarthritis: a placebo controlled randomized study. J Orthop. 2023 Mar;37:46–52.
  • Lefebvre V, Behringer RR, de Crombrugghe B. L-Sox5, Sox6 and Sox9 control essential steps of the chondrocyte differentiation pathway. Osteoarthritis Cartilage. 2001;9(Suppl A):S69–S75. doi:10.1053/joca.2001.0447
  • Robbins PD, Evans CH, Chernajovsky Y. Gene therapy for arthritis. Gene Ther. 2003;10(10):902–911. doi: 10.1038/sj.gt.3302040
  • Evans CH, Ghivizzani SC, Robbins PD. Arthritis gene therapy and its tortuous path into the clinic. Transl Res. 2013;161(4):205–216. doi: 10.1016/j.trsl.2013.01.002
  • Bellavia D, Veronesi F, Carina V, et al. Gene therapy for chondral and osteochondral regeneration: is the future now? Cell Mol Life Sci. 2018;75:649–667. doi: 10.1007/s00018-017-2637-3
  • Evans CH, Ghivizzani SC, Robbins PD. Gene delivery to joints by intra-articular injection. Hum Gene Ther. 2018;29(1):2–14. doi:10.1089/hum.2017.181
  • Madry H, Cucchiarini M. Gene therapy for human osteoarthritis: principles and clinical translation. Expert Opin Biol Ther. 2016;16(3):331–346. doi: 10.1517/14712598.2016.1124084
  • Hidaka C, Goodrich LR, Chen C-T, et al. Acceleration of cartilage repair by genetically modified chondrocytes over expressing bone morphogenetic protein-7. J Orthop Res. 2003;21(4):573–583. doi: 10.1016/S0736-0266(02)00264-4
  • 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 & Rheumat. 2018;70(11):1757–1768. doi: 10.1002/art.40668
  • Ajrawat P, Dwyer T, Chahal J. Autologous interleukin 1 receptor antagonist blood-derived products for knee osteoarthritis: a systematic review. Arthroscopy: The Journal Of Arthroscopic & Related Surgery. 2019;35(7):2211–2221. doi:10.1016/j.arthro.2018.12.035
  • Watkins LR, Chavez RA, Landry R, et al. Targeted interleukin-10 plasmid DNA therapy in the treatment of osteoarthritis: toxicology and pain efficacy assessments. Brain Behav Immun. 2020;90:155–166. doi: 10.1016/j.bbi.2020.08.005
  • Rice SJ, Beier F, Young DA, et al. Interplay between genetics and epigenetics in osteoarthritis. Nat Rev Rheumatol. 2020;16(5):268–281. doi: 10.1038/s41584-020-0407-3
  • Ghafouri-Fard S, Poulet C, Malaise M, et al. The emerging role of non-coding RNAs in osteoarthritis. Front Immunol. 2021;12:773171. doi: 10.3389/fimmu.2021.773171
  • Reynard LN, Barter MJ. Osteoarthritis year in review 2019: genetics, genomics and epigenetics. Osteoarthritis Cartilage. 2020;28(3):275–284. doi:10.1016/j.joca.2019.11.010
  • Panni S, Lovering RC, Porras P, et al. Non-coding RNA regulatory networks. Biochim Biophys Acta, Gene Regul Mech. 2020;1863(6):194417. doi: 10.1016/j.bbagrm.2019.194417
  • Ali SA, Peffers MJ, Ormseth MJ, et al. The non-coding RNA interactome in joint health and disease. Nat Rev Rheumatol. 2021;17(11):692–705. doi: 10.1038/s41584-021-00687-y
  • Palazzo AF, Lee ES. Non-coding RNA: what is functional and what is junk? Front Genet. 2015;6:2. doi: 10.3389/fgene.2015.00002
  • Esteller M. Non-coding RNAs in human disease. Nat Rev Genet. 2011;12(12):861–874. doi:10.1038/nrg3074
  • D’Adamo S, Cetrullo S, Minguzzi M, et al. MicroRNAs and autophagy: fine players in the control of chondrocyte homeostatic activities in osteoarthritis. Oxid Med Cell Longev. 2017;2017:3720128. doi: 10.1155/2017/3720128
  • Miyaki S, Asahara H. Macro view of microRNA function in osteoarthritis. Nat Rev Rheumatol. 2012;8(9):543–552. doi:10.1038/nrrheum.2012.128
  • Rotllan N, Price N, Pati P, et al. microRnas in lipoprotein metabolism and cardiometabolic disorders. Atherosclerosis. 2016;246:352–360. doi: 10.1016/j.atherosclerosis.2016.01.025
  • Swingler TE, Niu L, Smith P, et al. The function of microRnas in cartilage and osteoarthritis. Clin Exp Rheumatol. 2019 Sep;37(Suppl 120):40–47.
  • Ramos YFM, Mobasheri A. MicroRNAs and regulation of autophagy in chondrocytes. Methods in molecular biologyVol. 2245. (Clifton NJ) 2021p. 179–194
  • Cao Y, Tang S, Nie X, et al. Decreased miR-214-3p activates NF-κB pathway and aggravates osteoarthritis progression. EBioMedicine. 2021;65:103283. doi: 10.1016/j.ebiom.2021.103283
  • Chang T, Xie J, Li H, et al. MicroRNA-30a promotes extracellular matrix degradation in articular cartilage via downregulation of Sox9. Cell Prolif. 2016;49(2):207–218. doi: 10.1111/cpr.12246
  • Zhang X, Wang C, Zhao J, et al. MiR-146a facilitates osteoarthritis by regulating cartilage homeostasis via targeting Camk2d and Ppp3r2. Cell Death Dis. 2017;8(4):e2734. doi: 10.1038/cddis.2017.146
  • Tian L, Su Z, Ma X, et al. Inhibition of miR-203 ameliorates osteoarthritis cartilage degradation in the postmenopausal rat model: involvement of estrogen receptor α. Hum Gene Ther Clin Dev. 2019;30(4):160–168. doi: 10.1089/humc.2019.101
  • Pearson MJ, Jones SW. Review: long noncoding RNAs in the regulation of inflammatory pathways in rheumatoid arthritis and osteoarthritis. Arthritis & Rheumat. 2016;68(11):2575–2583. doi: 10.1002/art.39759
  • Ballantyne MD, McDonald RA, Baker AH. lncRNA/MicroRNA interactions in the vasculature. Clin Pharmacol Ther. 2016;99:494–501. doi: 10.1002/cpt.355
  • Chillón I, Marcia M. The molecular structure of long non-coding RNAs: emerging patterns and functional implications. Crit Rev Biochem Mol Biol. 2020;55(6):662–690. doi: 10.1080/10409238.2020.1828259
  • He AT, Liu J, Li F, et al. Targeting circular RNAs as a therapeutic approach: current strategies and challenges. Signal Transduct Target Ther. 2021;6(1):185. doi: 10.1038/s41392-021-00569-5
  • Hu J, Wang Z, Shan Y, et al. Long non-coding RNA HOTAIR promotes osteoarthritis progression via miR-17-5p/FUT2/β-catenin axis. Cell Death Dis. 2018;9(7):711. doi: 10.1038/s41419-018-0746-z
  • Wang Y, Cao L, Wang Q, et al. LncRNA FOXD2-AS1 induces chondrocyte proliferation through sponging miR-27a-3p in osteoarthritis. Artif Cells Nanomed Biotechnol. 2019;47(1):1241–1247. doi: 10.1080/21691401.2019.1596940
  • Shen S, Wu Y, Chen J, et al. CircSERPINE2 protects against osteoarthritis by targeting miR-1271 and ETS-related gene. Ann Rheum Dis. 2019;78(6):826–836. doi: 10.1136/annrheumdis-2018-214786
  • Boffa A, Di Martino A, Andriolo L, et al. Bone marrow aspirate concentrate injections provide similar results versus viscosupplementation up to 24 months of follow-up in patients with symptomatic knee osteoarthritis. A randomized controlled trial. Knee Surg Sports Traumatol Arthrosc. 2022 Dec;30(12):3958–3967.
  • Dai W, Leng X, Wang J, et al. Intra-articular mesenchymal stromal cell injections are no different from placebo in the treatment of knee osteoarthritis: a systematic review and meta-analysis of randomized controlled trials. Arthros J Arthros Related Surgery. 2021 Jan;37:340–358.
  • Schäfer N, Grässel S. Targeted therapy for osteoarthritis: progress and pitfalls. Nat Med. 2022 Dec 01;28:2473–2475. doi: 10.1038/s41591-022-02057-x
  • Deveza LA, Nelson AE, Loeser RF. Phenotypes of osteoarthritis: current state and future implications. Clin Exp Rheumatol. 2019 Sep;37(Suppl 120):64–72. doi: 10.1016/j.joca.2019.06.011
  • Van Spil WE, Kubassova O, Boesen M, et al. Osteoarthritis phenotypes and novel therapeutic targets. Biochem Pharmacol. 2019 Jul;165:41–48.
  • Zhang Z, Huang C, Jiang Q, et al. Guidelines for the diagnosis and treatment of osteoarthritis in China (2019 edition). Ann translat Med. 2020 Oct;8(19):1213.
  • Mahmoudian A, Lohmander LS, Jafari H, et al. Towards classification criteria for early-stage knee osteoarthritis: a population-based study to enrich for progressors. Semin Arthritis Rheum. 2021 Feb;51(1):285–291.
  • Iijima H, Fukutani N, Aoyama T, et al. Clinical phenotype classifications based on static varus alignment and varus thrust in Japanese patients with medial knee osteoarthritis. Arthritis & rheumatology. (Hoboken NJ); 2015 SepVol. 67p. 2354–2362.
  • Ashinsky BG, Bouhrara M, Coletta CE, et al. Predicting early symptomatic osteoarthritis in the human knee using machine learning classification of magnetic resonance images from the osteoarthritis initiative. J Orthop Res. 2017 Oct;35:2243–2250.
  • Li J, Fu S, Gong Z, et al. MRI-based texture analysis of infrapatellar fat pad to predict knee osteoarthritis incidence. Radiology. 2022 Sep;304(3):611–621.
  • Lee JJ, Namiri NK, Astuto B, et al. Personalized risk model and leveraging of magnetic resonance imaging-based structural phenotypes and clinical factors to predict incidence of radiographic osteoarthritis. Arthritis Care Res (Hoboken). 2023 Mar;75:501–508.
  • Daghestani HN, Pieper CF, Kraus VB. Soluble macrophage biomarkers indicate inflammatory phenotypes in patients with knee osteoarthritis. Arthritis Rheumatol (Hoboken, NJ). 2015 Apr;67:956–965. doi: 10.1002/art.39006
  • Trajerova M, Kriegova E, Mikulkova Z, et al. Knee osteoarthritis phenotypes based on synovial fluid immune cells correlate with clinical outcome trajectories. Osteoarthritis Cartilage. 2022 Dec;30(12):1583–1592.
  • Angelini F, Widera P, Mobasheri A, et al. Osteoarthritis endotype discovery via clustering of biochemical marker data. Ann Rheum Dis. 2022 May;81(5):666–675.
  • Manukyan G, Gallo J, Mikulkova Z, et al. Phenotypic and functional characterisation of synovial fluid-derived neutrophils in knee osteoarthritis and knee infection. Osteoarthritis Cartilage. 2023 Jan;31(1):72–82.
  • Jin X, Beguerie JR, Zhang W, et al. Circulating C reactive protein in osteoarthritis: a systematic review and meta-analysis. Ann Rheumatic Dis. 2015;74(4):703–710. doi: 10.1136/annrheumdis-2013-204494
  • Huang ZY, Perry E, Huebner JL, et al. Biomarkers of inflammation - LBP and TLR- predict progression of knee osteoarthritis in the DOXY clinical trial. Osteoarthritis Cartilage. 2018;26:1658–1665. doi: 10.1016/j.joca.2018.08.005
  • Yuan C, Pan Z, Zhao K, et al. Classification of four distinct osteoarthritis subtypes with a knee joint tissue transcriptome atlas. Bone Res. 2020 Nov 12;8(1):38.
  • Steinberg J, Southam L, Fontalis A, et al. Linking chondrocyte and synovial transcriptional profile to clinical phenotype in osteoarthritis. Ann Rheum Dis. 2021 Aug;80(8):1070–1074.
  • Bruno MC, Cristiano MC, Celia C, et al. Injectable drug delivery systems for osteoarthritis and rheumatoid arthritis. ACS Nano. 2022 Dec 27;16(12):19665–19690.
  • Brown S, Kumar S, Sharma B. Intra-articular targeting of nanomaterials for the treatment of osteoarthritis. Acta Biomaterialia. 2019 Jul 15;93:239–257. doi: 10.1016/j.actbio.2019.03.010
  • Mao L, Wu W, Wang M, et al. Targeted treatment for osteoarthritis: drugs and delivery system. Drug Delivery. 2021 Dec;28(1):1861–1876.
  • Large DE, Abdelmessih RG, Fink EA, et al. Liposome composition in drug delivery design, synthesis, characterization, and clinical application. Adv Drug Delivery Rev. 2021 Sep;176:113851.

Reprints and Corporate Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

To request a reprint or corporate permissions for this article, please click on the relevant link below:

Academic Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

Obtain permissions instantly via Rightslink by clicking on the button below:

If you are unable to obtain permissions via Rightslink, please complete and submit this Permissions form. For more information, please visit our Permissions help page.