Published: 2022-10-27

Osteoarthritis: insights into pathogenesis and futuristic treatment strategies

Ajay Singh, Vikramaditya Rai, Sushmita Pandey, Manisha Chavan, Deepthi Ketha


Osteoarthritis is the most common musculoskeletal condition world over that causes significant health, economic, and societal burdens. Till date, no therapeutic approaches have been able to stop or delay the progression of osteoarthritis satisfactorily. Structural and clinical features of the disease are characterized by a high inter-patient variability. This heterogeneity is believed to be a major factor associated with the complexity of osteoarthritis and the on-going difficulty to identify a single therapy for all sub-groups. The objective of this review is to highlight recent advances in the understanding of the pathophysiology of osteoarthritis and latest biological treatments available, their limitations and to bring to notice the latest state-of-the-art on-going research on novel therapies. For this study we searched different online databases such as PubMed and Cochrane Library from inception to January 2022. We identified eligible studies on the pathophysiologic findings, prevalence, or incidence of knee osteoarthritis, available treatments, and current research for future therapies. Besides the availability of vast literature on cartilage extracellular matrix and its changes in osteoarthritis, the complicated mechanism of the disease still has missing links in the chain. Presently, biological treatments such as platelet rich plasma, bone marrow mesenchymal stem cells and autologous fragmented adipose tissue containing structural vascular fraction are commonly used. In future, gene therapy could become a potential option for treating the disease. More extensive insights into the pathophysiology of osteoarthritis will be helpful in designing therapies that can curb structural progression and promote cartilage regeneration thus providing more potent relief from painful and disabling condition associated with osteoarthritis.


Osteoarthritis, Pathophysiology, Platelet rich plasma, Mesenchymal stem cells, Gene therapy, Monoclonal antibodies

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Mabey T, Honsawek S. Cytokines as biochemical markers for knee osteoarthritis. World J Orthop. 2015;6:95-105.

Splete H. Osteoarthritis burden grows worldwide, Global Burden Disease Study finds. Arthritis and Rheumatology. 2022. Available at: https://www. Accessed on 05 February 2022.

Cui A, Li H, Lu H. Global, regional prevalence, incidence and risk factors of knee osteoarthritis in population-based studies. E Clin Med. 2020;29(30):100587.

Zhang Y, Jordan JM. Epidemeology of osteoarthritis. Clin Geriatr Med. 2010;26:355-69.

GBD 2015 Disease and Injury Incidence and Prevalence Collaborators Global, regional, and national incidence, prevalence, and years lived with disability for 310 diseases and injuries, 1990-2015: A systematic analysis for the Global Burden of Disease study 2015. Lancet. 2016;388:1542-602.

Prince M J, Wu F, Guo Y, Gutierrez- Robledo IM, O’Donnell M, Sullivan R. The burden of disease in older people and implications for healthy policy and practice. Lancet. 2015;385:549-62.

Felson DT. Osteoarthritis as a disease of mechanics. Osteoarthr Cartil. 2013;21:10-5.

Swingler TE, Niu L, Smith P, Le L, Barter MJ. The function of microRNA in cartilage and osteoarthritis. Clin Exp Rheumatol. 2019;37:40-7.

Wang H, Bai J, He B, Hu X, Liu D. Osteoarthritis and the risk of cardiovascular disease: A meta-analysis of observational studies. Sci Rep. 2016;6:1-7.

Veronese N, Cereda E, Maggi S, Luchini C, Solmi M, Smith T, et al. Osteoarthritis and mortality: A prospective cohort study and systematic review with meta-analysis. Semin Arthritis Rheum. 2016;46:160-7.

Vina ER, Kwoh CK. Epidemeology of osteoarthritis. Curr Opin Rheumatol. 2015;29:462-82.

Hunter DJ, Bierma-Zeinstra S. Osteoarthritis. Lancet. 2019;393:1745-59.

Fernandez – Puente P, Calomia V, Gonzalez-Rodrfguez L, Lourido L, Camacho-Encina M, Oreiro N, et al.Multiplexed mass spectrometry monitoring of biomarker candidates for osteoarthritis. J Proteomics. 2017;152:216-25.

Vilim V, Olejarovam M, Machacek S, Gatterova J, Kraus VB, Pavelka K. Serum levels of cartilage oligometric matrix protein (COMP) correlate with radiographic progression of knee osteoarthritis. Osteoarthr Cartil. 2002;10(9):707-13.

Cornish SM, Peeler JD. No effect of creatinine monohydrate supplementation on inflammatory and cartilage degradation biomarkers in individuals with knee osteoarthritis. Nutr Res. 2018;51;57-66.

Holmbeck K, Bianco P, Caterina J, Yamada S, Kromer M, Kuznetsov SA, et al. Deficient mice develop dwarfism, osteopenia, arthritis, and connective tissue disease due to inadequate collagen turnover. Cell. 1999;99(1):81-92.

Armiento AR, Stoddart MJ, Alini M, Eglin D. Biomaterials for articular cartilage tissue engineering: learning from biology. Acta Biomater. 2018;65:1-20.

Pearle AD, Warren RF, Rodeo SA. Basic science of articular cartilage and osteoarthritis. Clin Sports Med. 2005;24(1):1-12.

Mortel-Palletier J, Boileau C, Palletier J, Roughley PJ. Cartilage in normal and osteoarthritic conditions. Best Pract Res. 2008;22(2):351-84.

Poole AR, Kobayashi M, Yasuda T. Type II collagen degradation and its regulation in articular cartilage in osteoarthritis. Ann Rheum Dis. 2002;61(2):78-81.

Silver FH, Bradica G, Tria A. Elastic energy storage in human articular cartilage: estimation of the elastic modulus for type II collagen and changes associated with osteoarthritis. Matrix Biol. 2002;21(2):129-37.

Goldring MB. Articular cartilage degradation in osteoarthritis. HSS J. 2012;8(1):7-9.

Hoff P, Buttergereit F, Burmester GR, Jakstadt M, Gaber T, Andreas K, et al. Osteoarthritis synovial fluid activates pro-inflammatory cytokines in primary human chondrocytes. Int Orthop. 2013;37(1):145-51.

Karan A, Karan MA, Vural P, Nilgun EI, Cemil T, Aksoy C, et al. Nitric oxide levels in patients with knee osteoarthritis. Clin Rheumatol. 2003;22(6):397-9.

Amin AR, Di Cesare PE, Vyas P, E Tzeng, Billiar TR, et al. The expression and regulation of nitric oxide synthase in human osteoarthritis affected chondrocytes: evidence for upregulated neuronal nitric oxide synthase. J Exp Med. 1995;182(6):2097-102.

Davidson ENB, Scharstuhl A, Vitters EL, vander- kraan PM, van-den Berg WB. Reduced transforming growth factor-beta signalling in cartilage of old mice: role in impaired repair capacity. Arthritis Res Therap. 2005;7(6):R1338-47.

Verzijl N, DeGroot J, Ben ZC. Crosslinking by advanced glycation end products increases the stiffness of the collagen network in human articular cartilage: a possible mechanism through which age is a risk factor for osteoarthritis. Arthritis Rheum. 2002;46(1):114-23.

Goldring MB, Goldring SR. Articular cartilage and subchondral bone in the pathogenesis of osteoarthritis. Ann N.Y. Acad Sci. 2010;1192:114-23.

Pullig O, Weseloh G, Klatt AR, Wagener R, Swoboda B. Matrilin 3 in human articular cartilage: increased expression in osteoarthritis. Osteoarthritis Cartilage. 2002;10(4):253-63.

Vincourt J, Etienne S, Grossin L, Cottet J, Bantsimba-Malanda C, Netter P, et al. Matrilin-3 switches from anti to pro-anabolic upon integration to the extracellular matrix. Matrix Biol. 2012:31(5):290-8.

Mechalopoulos E, Knight RL, Korossis S, Kearney JN, Fisher J, Ingham E. development of methods for studying the differentiation of human mesenchymal stem cells under cyclic compressive strain. Tissue Engg. 2012;18(4):252-62.

Cho HJ, Morey V, Kang JY, Kim KW, Kim TK. Prevalence and risk factors of spine, shoulder, hand,hip,and knee osteoarthritis in community- dwelling Koreans older than age of 65 years. Clin Orthop Relat Res. 2015;473(10):3307-14.

Kolasinski SL, Neogi T, Hochberg MC. 2019 American College of Rheumatology/Arthritis Foundation Guideline for the Management od Osteoarthritis of the Hand, Hip and Knee. Arthritis Rhematol. 2020;72(2):220-33.

Reichenbach S, Felson DT, Hincapie CA. Effect of biomechanical footwear on knee pain in people with knee osteoarthritis. The BIOTOK Randomized Clinical Trial. JAMA. 2020;323(18):1802-12.

Andia I, Maffuli N. Platelet-rich plasma for managing pain and inflammation in osteoarthritis. Nat Rev Rheumatol. 2013;9:721-30.

Wu Q, Luo X, Xiong Y, Liu G, Wang J, Chen X, et al. Platelet –rich plasma versus hyaluronic acid in knee osteoarthritis: A meta-analysis with the consistent ratio of injection. J Orthop Surg. 2020;28:1-9.

Gato–Calvo L, Magalhaes J, Ruiz-Romero C, Blanco FJ, Burguera EF. Platelet-rich plasm in osteoarthritis treatment: Review of current evidence. Ther Adv Chronic Dis. 2019;10:1-18.

Sundaram K, Vargac-Hernandez JS, Sanchez TR, Moreu NM, Mont MA, Higuera CA, et al. Are subchondral intraosseous injections effective and safe for the treatment of knee osteoarthritis? A systematic review. J Knee Surg. 2019;32:1046-57.

Sanchez M, Delgado D, Pompei O, Perez JC, Sanchez P, Garate A, et al. Treating severe knee osteoarthritis with combination of intra-osseous and intra-articular infilterations of platelet-rich plasma. An observational study. Cartilage. 2019;10:245-53.

Daghestani HN, Kraus VB. Inflammatory biomarkers in osteoarthritis. Osteoarthr Cartil. 2015;23:1890-6.

Caplan AI. Medicinal signalling cells: They work, so use them. Nature. 2019;566:39.

Yang Y, Li P, Zhu S, Bi R. Comparison of early- stage changes of osteoarthritis in cartilage and subchondral bone between two different rat models. Peer J. 2020;8:e8934.

Caplan AI, Hariri R. Body management: Mesenchymal stem cells control the internal regenerator. Stem Cells Transl Med. 2015;4:695-701.

Caplan AI. What’s in a name? Tissue Engg Part A. 2010;16:2415-7.

McGonagle D, Baboolal TG, Jones E. Native joint-resident mesenchymal stem cells for cartilage repair in osteoarthritis. Nat Rev Rheumatol. 2017;13:719-30.

De Windt TS, Saris DBF, Slaper-Cortenbach ICM, Van Rijen MHP, Gawlitta D, Creemers LB, et al. Direct cell-cell contact with chondrocytes is a key mechanism in multipotent mesenchymal stromal cell mediated chondrogenesis. Tissue Engg Part A. 2015;21:2536-47.

Hassan HT, El-Sheemy M. Adult bone-marrow stem cells and their potential in medicine. J R Soc Med. 2004;97:465-71.

Chahal J, Gomez-Aristizabal A, Shestopaloff K, Bhatt S, Chaboureau A, Fazio A, 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 Cell Transl Med. 2019;8:746-57.

Gupta PK, Chullikana A, Rangaswamy M, Shetty N, Pandey V, Aggarwal V, et al. Efficacy and safety of adult human bone marrow-derived, cultured, pooled, allogenic mesenchymal stromal cells ( Stempeucel®): Preclinical and clinical trial in osteoarthritis of the knee joint. Arthritis Res Ther. 2016;18:301.

Vega A, Martin-Ferrero MA, Del Canto F, Alberca M, Garcia V, Munar A, et al. Treatment of knee osteoarthritis with allogeneic bone marrow mesenchymal stem cells: A randomized controlled trial. Transplantation. 2015;99:1681-90.

Awad ME, Hussein KA, Helwa I, Abdelsamid MF, Aguilar-Perez A, Mohsen I, et al. Meta-analysis and evidence base for the efficacy of autologous bone marrow mesenchymal stem cells in knee cartilage repair.: Methodological guidelines and quality assessment. Stem Cells Int. 2019;2019:1-15.

Kim SH, Ha CW, Park YB, Nam E, Lee JE, Lee HJ. Intra-articular injection of mesenchymal stem cells for clinical outcomes and cartilage repair in osteoarthritis of the knee: Ameta-analysis of randomized controlled trials. Arch Orthop Trauma Surg.2019; 139:971-80.

Hudetz D, Jelec Z, Rod E, Boric I, Plecko M, Primorac D. The Future oof Cartilage Repair: In Personalized medicine in healthcare systems: Legal, medical and economic implications. Springer International Publishing: Cham, Switzerland. 2019;375-411.

Polancee D, Zenic L, Hudetz D, Boric I, Jelec Z, Rod E, et al. Immunophenotyping of a stromal vascular fraction from microfragmented lipoaspirate used in osteoarthritis cartilage treatment and its lipoaspirate counterpart. Genes. 2019;10:474.

Russo A, Screpis D, Di Donato SL, Bonetti S, Piovan G, Zorzi C. Autologous micro-fragmented adipose tissue for the treatment of diffuse degenerative knee osteoarthritis: an update at 3-year follow-up. J Exp Orthop. 2018;5:52.

Mautner K, Bowers R, Easley K, Fausel Z, Robinson R. Functional outcomes following microfragmented adipose tissue versus bone marrow aspirateconcentrate injections for symptomatic knee osteoarthritis. Stem Cells Transl Med. 2019;8:1149-56.

Russo A, Condello V, Guerriero M, Zorzi C. Autologous and microfragmented adipose tissue for the treatment of diffuse degenerative knee osteoarthritis. J Exp Orthop. 2017;4:33.

Peretti GM, Ulivi M, De Girolamo V, Lombardo MD, Mangiavini L. Evaluation of the use ofautologous micro-fragmented adipose tissue in the treatment of knee osteoarthritis: preliminary results of a randomized controlled trial. J Biol Regul Homeost Agents. 2018;32:193-9.

Freitag J, Bates D, Wickham J, Shah K, Huguenin L, Tenen A, et al. Adipose derived mesenchymal stem cell therapy in the treatment of knee osteoarthritis: A randomized controlled trial. Regen Med. 2019;14:213-30.

Jayaram P, Ikpeama U, Rothenberg JB, Malnga GA Bone-marrow derived and adipose-derived mesenchymal stem cell therapy in primary knee osteoarthritis: A narrative review. PM&R. 2019;11:177-91.

Wu X, Wang Y, Xiao Y, Crawford R, Prasadam I, Mao X. Extra-cellular vescicles:Potential role in osteoarthritis regenerative medicine. J Orthop Transl. 2020;21:73-80.

Lener T, Gimona M, Aigner L, Borger V, Buzas E, Camussi G, et al. Applying extra cellular vesicles-based therapeutics in clinical trials – An ISEV position paper. J Extracell Vesicles. 2015;4:30087.

Morrison TJ, Jackson MV, Cunningham EK, Kissenpfennig A, McAuley DF, O’Cane CM. Injury models by extracellular vescicle mitochondrial transfer. Am J Respir Crit Care Med. 2017;196:1275-86.

Tan SSH, Tjio CKE, Wong JRY, Wong KL Chew JRJ, Hui JHP, et al. Mesenchymal stem cell exosomes for cartilage regeneration: A systematic review of preclinical in vivo studies. Tissue Engg Part B Rev. 2020;2019:0326.

Sun Q, Zhang Y, Yang G, Chen X, Zhang Y, Cao G, et al. Transforming growth- factor-beta-regulated miR-24 promotes skeletal muscle differentiation. Nucleic Acids Res.2008;36:2690-9.

Fleury A, Martinez MC, Lay LS. Extracellular vesicles as therapeutic tools in cardiovascular diseases. Front Immunol. 2014;5:370.

Dell´Isola A, Allan R, Smith SL, Marreiros SSP, Steultjens M. Identification of clinical phenotypes in knee osteoarthritis: A systemetic review of the literature. BMC Musculoskelet Disord. 2016;17:1-12.

Van Spil WE, Kubassova O, Boesen M, Bay-Jensen AC, Mobasheri A. Osteoarthritis phenotypes and novel therapeutic targets. Biochem Pharmacol. 2019;165:41-8.

Bone morphogenetic protein 7 inhibits cartilage degradation in a rabbit model of osteoarthritis. Nat Clin Pract Rheumatol. 2009;5:4.

Hyashi M, Muneta T, Ju YJ, Mochizuki T, Sekiya I. Weekly intra-articular injections of bone morphogenetic protein-7 inhibits osteoarthritis progression. Arthritis Res Ther. 2008;10:R118.

Stöve J, Schneider-Wald B, Scharf HP, Schwartz ML. Bone morphogenetic protein 7 (bmp-7) stimulates proteoglycan synthesis in human osteoarthritic chondrocytes in vitro. Biomed Pharmacother. 2006;60:639-43.

Hunter DJ, Pike MC, Jonas BL, Kissin E, Krop J, Mcalindon T. Phase 1 safety and tolerability study of BMP-7 in symptomatic kneeosteoarthritis. BMC Musculoskelet Disord. 2010;11:232.

Chen TM, Chen YH, Sun H, Tsai SJ. Fibroblast growth factors: Potential novel targets for regenerative therapy of osteoarthritis. Clin J Physiol. 2019;62:2.

Meloni G, Farran A, Mohanraj B, Guehering H, Cocca R, Rabut E, et al. Recombinant human FGF18 preserves depth-dependent mechanical inhomogeneity in articular cartilage. Eur Celle Mater. 2019;38:23-38.

Shepard HM, Phillips GL, Thanos CD, Feldmann M. Developments in therapy with monoclonal antibodies and related proteins. Clin Med J R Coll Physicians Lond. 2017;17:220-32.

Kan SL, Li Y, Ning GZ, Yuan ZF, Chen LX, Bi MC, Sun JC, et al. Tenezumab for patients with osteoarthritis of the knee: A meta-analysis. PloS One. 2016;11;e0157105.

Schnitzer TJ, Easton R, Pang S, Levinson DJ, Pixton G, Viktrupt L, et al. Effect of Tenezumab on joint pain, physical function, and patient global assessment of osteoarthritis among patients with osteoarthritis of the knee and hip: A randomized clinical trial. JAMA J Am Med Assoc. 2019;322:37-48.

Tiseo PJ, Kivitz AJ, Ervin JE, Ren H, Mellis SJ. Fazinumab (REGN475), an antibody against nerve growth factor for the treatment of pain: Results from a double-blind, placebo-controlled exploratory study in osteoarthritis of the knee. Pain. 2014;155:1245-52.

Miller RE, Tran PB, Ishihara S, Larkin J, Malfait AM. Therapeutic effects of an anti- ADAMTS-5 antibody on joint damage and mechanical allodynia in a murine model of osteoarthritis. Osteoarthr Cartil. 2016;24:299-306.

Oo WM, Yu SPC, Daniel MS, Hunter DJ. Disease-modifying drugs in osteoarthritis: Current understanding and future therapeutics. Expert Opin Emerg Drugs. 2018;23:331-47.

Nixon AJ, Grol MW, Lang HM, Ruan MZC, Stone A, Begum L, et al. Disease- modifying osteoarthritis treatment with Interleukin-1 receptor antagonist gene therapy in small and large animal models. Arthritis Rheumatol. 2018;70:1757-68.

Zhao L, Huang J, Fan Y, Li J, You T, He S, Xiao G, et al. Exploration of CRISPR/Cas9-based gene editing as therapy for osteoarthritis. Ann Rheum Dis. 2019;78:676-82.

Hu Q, Ecker M. Overview of MMP-13 as a promising target for the treatment of osteoarthritis. Int J Mol Sci. 2021;22(4):1742.