Osteoarthritis: Mechanisms and Therapeutic Advances

Abstract

Osteoarthritis (OA) is a chronic joint disease characterized by a complex pathological mechanism, including chondrocyte dysfunction, synovial inflammation, subchondral bone remodeling, and molecular regulation abnormalities. Key signaling pathways such as nuclear factor-κB, mitoase-activated protein kinase, and transforming growth factor-β are disrupted, leading to cytokine imbalance, oxidative stress, and excessive protease activity, which collectively contribute to cartilage degeneration. This review summarizes the potential causes of OA, focusing on cellular and structural abnormalities in cartilage, synovial tissue, and subchondral bone, as well as dysregulation of signaling pathways, gene regulation, and molecular mechanisms. Given the limitations of current diagnostic methods for OA, biomarkers may offer new hope. Emerging therapeutic strategies for OA include biologics, intelligent drug delivery, and tissue engineering, aiming to modulate the immune microenvironment while promoting cartilage repair. However, these approaches face challenges such as long-term safety and scalability. Future research may require deeper multidisciplinary collaboration and combination therapies to revolutionize the management of OA and improve patient outcomes.

Keywords

chondrocyte / osteoarthritis (OA) / pathogenesis / signaling pathway / therapy

References

[1] I. Bernabei, A. So, N. Busso, S. Nasi, “Cartilage Calcification in Osteoarthritis: Mechanisms and Clinical Relevance,” Nature Reviews Rheumatology 19 (2023): 10-27.

[2] I. J. Wallace, S. Worthington, D. T. Felson, et al., “Knee Osteoarthritis Has Doubled in Prevalence Since the Mid-20th Century,” Proceedings of the National Academy of Sciences of the United States of America 114 (2017): 9332-9336.

[3] D. J. Hunter, D. Schofield, E. Callander, “The Individual and Socioeconomic Impact of Osteoarthritis,” Nature Reviews Rheumatology 10 (2014): 437-441.

[4] S.-H. Liu, J. B. Driban, C. B. Eaton, T. E. McAlindon, L. R. Harrold, K. L. Lapane, “Objectively Measured Physical Activity and Symptoms Change in Knee Osteoarthritis,” American Journal of Medicine 129 (2016): 497-505.e1.

[5] K. W. Kim, J. W. Han, H. J. Cho, et al., “Association Between Comorbid Depression and Osteoarthritis Symptom Severity in Patients With Knee Osteoarthritis,” The Journal of Bone and Joint Surgery, American Volume 93 (2011): 556-563.

[6] A. M. Rathbun, M. D. Shardell, A. S. Ryan, et al., “Association Between Disease Progression and Depression Onset in Persons With Radiographic Knee Osteoarthritis,” Rheumatology 59 (2020): 3390-3399.

[7] J. N. Katz, K. R. Arant, R. F. Loeser, “Diagnosis and Treatment of Hip and Knee Osteoarthritis: A Review,” Jama 325 (2021): 568.

[8] K. D. Allen, L. M. Thoma, Y. M. Golightly, “Epidemiology of Osteoarthritis,” Osteoarthritis and Cartilage 30, 184-195 (2022).

[9] J. D. Steinmetz, G. T. Culbreth, L. M. Haile, et al., “Global, Regional, and National Burden of Osteoarthritis, 1990-2020 and Projections to 2050: A Systematic Analysis for the Global Burden of Disease Study 2021,” The Lancet Rheumatology 5 (2023): e508-e522.

[10] S. Tang, C. Zhang, W. M. Oo, et al., “Osteoarthritis,” Nature Reviews Disease Primers 11 (2025): 10.

[11] S. Safiri, A.-A. Kolahi, E. Smith, et al., “Global, Regional and National Burden of Osteoarthritis 1990-2017: A Systematic Analysis of the Global Burden of Disease Study 2017,” Annals of the Rheumatic Diseases 79 (2020): 819-828.

[12] V. P. Leifer, J. N. Katz, E. Losina, “The Burden of OA-Health Services and Economics,” Osteoarthritis and Cartilage 30 (2022): 10-16.

[13] A. Latourte, M. Kloppenburg, P. Richette, “Emerging Pharmaceutical Therapies for Osteoarthritis,” Nature Reviews Rheumatology 16 (2020): 673-688.

[14] A. Mahmoudian, L. S. Lohmander, A. Mobasheri, M. Englund, F. P. Luyten, “Early-Stage Symptomatic Osteoarthritis of the Knee — Time for Action,” Nature Reviews Rheumatology 17 (2021): 621-632.

[15] S. J. J. Drummen, J. Runhaar, S. M. Bierma-Zeinstra, et al., “Early-Stage vs Established Knee Osteoarthritis: A Comparative Observational Study on Prevalence and Changes in Pain, Function and Quality of Life After Supervised Exercise and Education Among 10,365 Patients,” Osteoarthritis and Cartilage 33 (2024): 364-372, https://doi.org/10.1016/j.joca.2024.11.007.

[16] I. A. Jones, R. Togashi, M. L. Wilson, N. Heckmann, C. T. Vangsness, “Intra-Articular Treatment Options for Knee Osteoarthritis,” Nature Reviews Rheumatology 15 (2019): 77-90.

[17] A. H. Alyami, M. A. Alkhotani, A. A. Alsiraihi, et al., “Predictors of Persistent Pain After Total Knee Arthroplasty,” Life 14 (2024): 1300.

[18] J. Yan, W. Qin, B. Xiao, et al., “Pathological Calcification in Osteoarthritis: An Outcome or a Disease Initiator?,” Biological Reviews 95 (2020): 960-985.

[19] E. S. Mameri, S. P. Dasari, L. M. Fortier, et al., “Review of Meniscus Anatomy and Biomechanics,” Current Reviews in Musculoskeletal Medicine 15 (2022): 323-335.

[20] J.-G. Park, S.-B. Han, H. C. Rhim, O. H. Jeon, K.-M. Jang, “Anatomy of the Anterolateral Ligament of the Knee Joint,” World Journal of Clinical Cases 10 (2022): 7215-7223.

[21] M. P. Aparisi Gómez, G. M. Marcheggiani Muccioli, G. Guglielmi, S. Zaffagnini, A. Bazzocchi, “Particularities on Anatomy and Normal Postsurgical Appearances of the Knee,” Radiologic Clinics of North America 61 (2023): 219-247.

[22] J. D. Hassebrock, M. T. Gulbrandsen, W. L. Asprey, J. L. Makovicka, A. Chhabra, “Knee Ligament Anatomy and Biomechanics,” Sports Medicine and Arthroscopy Review 28 (2020): 80-86.

[23] R. E. Wilusz, J. Sanchez-Adams, F. Guilak, “The Structure and Function of the Pericellular Matrix of Articular Cartilage,” Matrix Biology 39 (2014): 25-32.

[24] A. A. Rahnemai-Azar, R. M. Miller, D. Guenther, et al., “Structural Properties of the Anterolateral Capsule and Iliotibial Band of the Knee,” American Journal of Sports Medicine 44 (2016): 892-897.

[25] S.-Q. Xiao, M. Cheng, L. Wang, et al., “The Role of Apoptosis in the Pathogenesis of Osteoarthritis,” International Orthopaedics 47 (2023): 1895-1919.

[26] R. Li, K. Sun, “Regulation of Chondrocyte Apoptosis in Osteoarthritis by Endoplasmic Reticulum Stress,” Cell Stress & Chaperones 29 (2024): 750-763.

[27] H. Yuan, N. Yi, D. Li, et al., “PPARγ Regulates Osteoarthritis Chondrocytes Apoptosis Through Caspase-3 Dependent Mitochondrial Pathway,” Scientific Reports 14 (2024): 11237.

[28] Z. Zhang, J. Ma, Y. Yi, et al., “Isoliensinine Suppresses Chondrocytes Pyroptosis Against Osteoarthritis via the MAPK/NF-κB Signaling Pathway,” International Immunopharmacology 143 (2024): 113589.

[29] J. Ma, H. Zhang, Z. Wang, et al., “Lycopodium Japonicum Thunb. Inhibits Chondrocyte Apoptosis, Senescence and Inflammation in Osteoarthritis Through STING/NF-κB Signaling Pathway,” Journal of Ethnopharmacology 335 (2024): 118660.

[30] T. Saito, S. Tanaka, “Molecular Mechanisms Underlying Osteoarthritis Development: Notch and NF-κB,” Arthritis Research & Therapy 19 (2017): 94.

[31] T. Cai, H. Ye, H. Jiang, et al., “Stevioside Targets the NF-κB and MAPK Pathways for Inhibiting Inflammation and Apoptosis of Chondrocytes and Ameliorates Osteoarthritis in Vivo,” International Immunopharmacology 115 (2023): 109683.

[32] J. Xu, Y. Yu, K. Chen, et al., “Astragalus Polysaccharides Ameliorate Osteoarthritis via Inhibiting Apoptosis by Regulating ROS-Mediated ASK1/p38 MAPK Signaling Pathway Targeting on TXN,” International Journal of Biological Macromolecules 258 (2024): 129004.

[33] Z. Li, Z. Chen, J. Chen, et al., “Monotropein Attenuates Apoptosis and Pyroptosis in Chondrocytes and Alleviates Osteoarthritis Progression in Mice,” Chinese Medicine 18 (2023): 42.

[34] M.-C. Trojani, S. Santucci-Darmanin, V. Breuil, G. F. Carle, V. Pierrefite-Carle, “Autophagy and Bone Diseases,” Joint, Bone, Spine 89 (2022): 105301.

[35] L. Tang, J. Ding, K. Yang, Z. Zong, R. Wu, H. Li, “New Insights Into the Mechanisms and Therapeutic Strategies of Chondrocyte Autophagy in Osteoarthritis,” Journal of Molecular Medicine 102 (2024): 1229-1244.

[36] H. Wang, Y. Liu, D. Wang, et al., “The Upstream Pathway of mTOR-Mediated Autophagy in Liver Diseases,” Cells 8 (2019): 1597.

[37] J. Huang, Z. Chen, Z. Wu, et al., “Geniposide Stimulates Autophagy by Activating the GLP-1R/AMPK/mTOR Signaling in Osteoarthritis Chondrocytes,” Biomedicine & Pharmacotherapy 167 (2023): 115595.

[38] C. Cheng, Y. Wu, Y. Huang, et al., “Epigenetic Modification and Exosome Effects on Autophagy in Osteoarthritis,” Biochemical Pharmacology 218 (2023): 115930.

[39] H. Yang, Y. Wen, M. Zhang, et al., “MTORC1 Coordinates the Autophagy and Apoptosis Signaling in Articular Chondrocytes in Osteoarthritic Temporomandibular Joint,” Autophagy 16 (2020): 271-288.

[40] Z. Chen, M. Tang, Z. Wu, et al., “Increased Rab1a Accelerates Osteoarthritis by Inhibiting Autophagy via Activation of the mTORC1-S6K Pathway,” Journal of Advanced Research (2024): S2090123224005010, https://doi.org/10.1016/j.jare.2024.11.009.

[41] Y. Jiang, W. Luo, F. Zhou, P. Gong, Y. Xiong, “The Role of FOXO1-Mediated Autophagy in the Regulation of Bone Formation,” Cell Cycle 22 (2023): 829-840.

[42] K. I. Lee, S. Choi, T. Matsuzaki, et al., “FOXO1 and FOXO3 Transcription Factors Have Unique Functions in Meniscus Development and Homeostasis During Aging and Osteoarthritis,” Proceedings of the National Academy of Sciences of the United States of America 117, no. 6 (2020): 3135-3143.

[43] S. Liao, Q. Zheng, H. Shen, et al., “HECTD1-Mediated Ubiquitination and Degradation of Rubicon Regulates Autophagy and Osteoarthritis Pathogenesis,” Arthritis & Rheumatology 75 (2023): 387-400.

[44] A. Brockmueller, C. Buhrmann, P. Shayan, M. Shakibaei, “Calebin A Modulates Inflammatory and Autophagy Signals for the Prevention and Treatment of Osteoarthritis,” Frontiers in Immunology 15 (2024): 1363947.

[45] M. Rahmati, G. Nalesso, A. Mobasheri, M. Mozafari, “Aging and Osteoarthritis: Central Role of the Extracellular Matrix,” Ageing Research Reviews 40 (2017): 20-30.

[46] J. Yang, J. Luo, X. Tian, Y. Zhao, Y. Li, X. Wu, “Progress in Understanding Oxidative Stress, Aging, and Aging-Related Diseases,” Antioxidants 13 (2024): 394.

[47] O. H. Jeon, N. David, J. Campisi, J. H. Elisseeff, “Senescent Cells and Osteoarthritis: A Painful Connection,” Journal of Clinical Investigation 128 (2018): 1229-1237.

[48] B. O. Diekman, R. F. Loeser, “Aging and the Emerging Role of Cellular Senescence in Osteoarthritis,” Osteoarthritis and Cartilage 32 (2024): 365-371.

[49] S. Wakale, X. Wu, Y. Sonar, et al., “How Are Aging and Osteoarthritis Related?,” Aging and Disease 14 (2023): 592.

[50] W.-L. Duan, L.-N. Zhang, R. Bohara, et al., “Adhesive Hydrogels in Osteoarthritis: From Design to Application,” Military Medical Research 10 (2023): 4.

[51] L. Zheng, S. He, H. Wang, J. Li, Y. Liu, S. Liu, “Targeting Cellular Senescence in Aging and Age-Related Diseases: Challenges, Considerations, and the Emerging Role of Senolytic and Senomorphic Therapies,” Aging and Disease 15 (2024): 2554-2594.

[52] M. M. Ansari, M. Ghosh, D.-S. Lee, Y.-O. Son, “Senolytic Therapeutics: An Emerging Treatment Modality for Osteoarthritis,” Ageing Research Reviews 96 (2024): 102275.

[53] H. Cao, M. Chen, X. Cui, et al., “Cell-Free Osteoarthritis Treatment With Sustained-Release of Chondrocyte-Targeting Exosomes From Umbilical Cord-Derived Mesenchymal Stem Cells to Rejuvenate Aging Chondrocytes,” ACS Nano 17 (2023): 13358-13376.

[54] W. S. Hambright, V. R. Duke, A. D. Goff, et al., “Clinical Validation of C12FDG as a Marker Associated With Senescence and Osteoarthritic Phenotypes,” Aging Cell 23 (2024): e14113.

[55] A. E. Rapp, F. Zaucke, “Cartilage Extracellular Matrix-Derived Matrikines in Osteoarthritis,” American Journal of Physiology-Cell Physiology 324 (2023): C377-C394.

[56] Q. Hu, M. Ecker, “Overview of MMP-13 as a Promising Target for the Treatment of Osteoarthritis,” International Journal of Molecular Sciences 22 (2021): 1742.

[57] E. Toropitsyn, M. Pravda, D. Rebenda, I. Ščigalková, M. Vrbka, V. Velebný, “A Composite Device for Viscosupplementation Treatment Resistant to Degradation by Reactive Oxygen Species and Hyaluronidase,” Journal of Biomedical Materials Research. Part B, Applied Biomaterials 110 (2022): 2595-2611.

[58] L. Zhao, R. Zhou, Q. Wang, Y. Cheng, M. Gao, C. Huang, “MicroRNA-320c Inhibits Articular Chondrocytes Proliferation and Induces Apoptosis by Targeting Mitogen-Activated Protein Kinase 1 (MAPK1),” International Journal of Rheumatic Diseases 24 (2021): 402-410.

[59] S. Hayashi, T. Nishiyama, Y. Miura, et al., “DcR3 Induces Cell Proliferation Through MAPK Signaling in Chondrocytes of Osteoarthritis,” Osteoarthritis and Cartilage 19 (2011): 903-910.

[60] B. A. C. Housmans, M. Neefjes, D. A. M. Surtel, et al., “Synovial Fluid From End-Stage Osteoarthritis Induces Proliferation and Fibrosis of Articular Chondrocytes via MAPK and RhoGTPase Signaling,” Osteoarthritis and Cartilage 30 (2022): 862-874.

[61] J. Chen, F. Chen, X. Wu, et al., “DLX5 Promotes Col10a1 Expression and Chondrocyte Hypertrophy and Is Involved in Osteoarthritis Progression,” Genes & Diseases 10 (2023): 2097-2108.

[62] J. Wu, Y. Pan, Y. Yu, et al., “Axial Compressive Loading Attenuates Early Osteoarthritis by Reducing Subchondral Bone Remodeling,” American Journal of Sports Medicine 51 (2023): 1752-1764.

[63] Y. Jia, H. Le, X. Wang, et al., “Double-Edged Role of Mechanical Stimuli and Underlying Mechanisms in Cartilage Tissue Engineering,” Frontiers in Bioengineering and Biotechnology 11 (2023): 1271762.

[64] A. Mathiessen, P. G. Conaghan, “Synovitis in Osteoarthritis: Current Understanding With Therapeutic Implications,” Arthritis Research & Therapy 19 (2017): 18.

[65] S. N. Wijesinghe, C. Ditchfield, S. Flynn, et al., “Immunomodulation and Fibroblast Dynamics Driving Nociceptive Joint Pain Within Inflammatory Synovium: Unravelling Mechanisms for Therapeutic Advancements in Osteoarthritis,” Osteoarthritis and Cartilage 32 (2024): 1358-1370.

[66] E. Sanchez-Lopez, R. Coras, A. Torres, N. E. Lane, M. Guma, “Synovial Inflammation in Osteoarthritis Progression,” Nature Reviews Rheumatology 18 (2022): 258-275.

[67] A. Gómez-Aristizábal, R. Gandhi, N. N. Mahomed, K. W. Marshall, S. Viswanathan, “Synovial Fluid Monocyte/Macrophage Subsets and Their Correlation to Patient-Reported Outcomes in Osteoarthritic Patients: A Cohort Study,” Arthritis Research & Therapy 21 (2019): 26.

[68] Z. Zou, H. Li, K. Yu, et al., “The Potential Role of Synovial Cells in the Progression and Treatment of Osteoarthritis,” Exploration 3 (2023): 20220132.

[69] M. M. Temple-Wong, S. Ren, P. Quach, et al., “Hyaluronan Concentration and Size Distribution in Human Knee Synovial Fluid: Variations With Age and Cartilage Degeneration,” Arthritis Research & Therapy 18 (2016): 18.

[70] G. Zhen, Q. Guo, Y. Li, et al., “Mechanical Stress Determines the Configuration of TGFβ Activation in Articular Cartilage,” Nature Communications 12 (2021): 1706.

[71] C. M. Mazur, J. J. Woo, C. S. Yee, et al., “Osteocyte Dysfunction Promotes Osteoarthritis Through MMP13-Dependent Suppression of Subchondral Bone Homeostasis,” Bone Research 7 (2019): 34.

[72] A. Weber, P. M. B. Chan, C. Wen, “Do Immune Cells Lead the Way in Subchondral Bone Disturbance in Osteoarthritis?,” Progress in Biophysics and Molecular Biology 148 (2019): 21-31.

[73] D. J. Hunter, L. Gerstenfeld, G. Bishop, et al., “Bone Marrow Lesions From Osteoarthritis Knees Are Characterized by Sclerotic Bone That Is Less Well Mineralized,” Arthritis Research & Therapy 11 (2009): R11.

[74] S. Donell, “Subchondral Bone Remodelling in Osteoarthritis,” EFORT Open Reviews 4 (2019): 221-229.

[75] A. Jiang, P. Xu, S. Sun, et al., “Cellular Alterations and Crosstalk in the Osteochondral Joint in Osteoarthritis and Promising Therapeutic Strategies,” Connective Tissue Research 62 (2021): 709-719.

[76] N. Maruotti, A. Corrado, F. P. Cantatore, “Osteoblast Role in Osteoarthritis Pathogenesis,” Journal of Cellular Physiology 232 (2017): 2957-2963.

[77] X. Zhao, L. Ma, H. Guo, et al., “Osteoclasts Secrete Leukemia Inhibitory Factor to Promote Abnormal Bone Remodeling of Subchondral Bone in Osteoarthritis,” BMC Musculoskeletal Disorders [Electronic Resource] 23 (2022): 87.

[78] W. Chen, Q. Wang, H. Tao, et al., “Subchondral Osteoclasts and Osteoarthritis: New Insights and Potential Therapeutic Avenues,” Acta Biochimica et Biophysica Sinica 56, no. 4 (2024): 499-512.

[79] T. Ono, H. Takayanagi, “Osteoimmunology in Bone Fracture Healing,” Current Osteoporosis Reports 15 (2017): 367-375.

[80] E. Aydin, M. Balikoglu-Yilmaz, S. S. Imre, F. Koc, L. Kazanci, A. T. Ozturk, “Regulatory B Cell Is Critical in Bone Union Process Through Suppressing Proinflammatory Cytokines and Stimulating Foxp3 in Treg Cells,” Journal of Craniofacial Surgery 27 (2016): e750-e752.

[81] Y. Wang, X. Fan, L. Xing, F. Tian, “Wnt Signaling: A Promising Target for Osteoarthritis Therapy,” Cell Communication and Signaling 17 (2019): 97.

[82] Z. Iqbal, J. Xia, G. Murtaza, et al., “Targeting WNT Signalling Pathways as New Therapeutic Strategies for Osteoarthritis,” Journal of Drug Targeting 31 (2023): 1027-1049.

[83] A. Stampella, S. Monteagudo, R. Lories, “Wnt Signaling as Target for the Treatment of Osteoarthritis,” Best Practice & Research. Clinical Rheumatology 31 (2017): 721-729.

[84] Y. Zhou, T. Wang, J. L. Hamilton, D. Chen, “Wnt/β-Catenin Signaling in Osteoarthritis and in Other Forms of Arthritis,” Current Rheumatology Reports 19 (2017): 53.

[85] R. Bai, M. Z. Miao, H. Li, et al., “Increased Wnt/β-Catenin Signaling Contributes to Autophagy Inhibition Resulting From a Dietary Magnesium Deficiency in Injury-Induced Osteoarthritis,” Arthritis Research & Therapy 24 (2022): 165.

[86] X. Ye, X. Liu, “Wnt16 Signaling in Bone Homeostasis and Osteoarthristis,” Frontiers in Endocrinology 13 (2022): 1095711.

[87] C. Wu, J. Yu, G. Xu, et al., “Wnt16 Protects Chondrocytes From Lumbar Facet Joint Osteoarthritis Through the Wnt/β-Catenin Pathway in Low Back Pain Patients,” Somatosensory & Motor Research 38 (2021): 339-346.

[88] X. Liu, X. Li, B. Hua, X. Yang, J. Zheng, S. Liu, “WNT16 is Upregulated Early in Mouse TMJ Osteoarthritis and Protects Fibrochondrocytes Against IL-1β Induced Inflammatory Response by Regulation of RUNX2/MMP13 Cascade,” Bone 143 (2021): 115793.

[89] Y. Zhu, L. Cao, M. Yuan, et al., “Microgel Encapsulated Mesoporous Silica Nanoparticles for Releasing Wnt16 to Synergistically Treat Temporomandibular Joint Osteoarthritis,” Advancement of Science 11 (2024): 2404396.

[90] G. Huang, S. Chubinskaya, W. Liao, R. F. Loeser, “Wnt5a Induces Catabolic Signaling and Matrix Metalloproteinase Production in Human Articular Chondrocytes,” Osteoarthritis and Cartilage 25 (2017): 1505-1515.

[91] X. Martineau, É. Abed, J. Martel-Pelletier, J.-P. Pelletier, D. Lajeunesse, “Alteration of Wnt5a Expression and of the Non-Canonical Wnt/PCP and Wnt/PKC-Ca2+ Pathways in Human Osteoarthritis Osteoblasts,” PLoS ONE 12 (2017): e0180711.

[92] S. Suthon, R. S. Perkins, V. Bryja, G. A. Miranda-Carboni, S. A. Krum, “WNT5B in Physiology and Disease,” Frontiers in Cell and Developmental Biology 9 (2021): 667581.

[93] E. Jimi, F. Huang, C. Nakatomi, “NF-κB Signaling Regulates Physiological and Pathological Chondrogenesis,” International Journal of Molecular Sciences 20 (2019): 6275.

[94] H. Yu, L. Lin, Z. Zhang, H. Zhang, H. Hu, “Targeting NF-κB Pathway for the Therapy of Diseases: Mechanism and Clinical Study,” Signal Transduction and Targeted Therapy 5 (2020): 209.

[95] F. De Luca, “Regulatory Role of NF-κB in Growth Plate Chondrogenesis and Its Functional Interaction With Growth Hormone,” Molecular and Cellular Endocrinology 514 (2020): 110916.

[96] T. Feng, Q. Wu, “A Review of Non-Coding RNA Related to NF-κB Signaling Pathway in the Pathogenesis of Osteoarthritis,” International Immunopharmacology 106 (2022): 108607.

[97] H. Kobayashi, S. H. Chang, D. Mori, et al., “Biphasic Regulation of Chondrocytes by Rela Through Induction of Anti-Apoptotic and Catabolic Target Genes,” Nature Communications 7 (2016): 13336.

[98] L. Wang, C. He, “Nrf2-Mediated Anti-Inflammatory Polarization of Macrophages as Therapeutic Targets for Osteoarthritis,” Frontiers in Immunology 13 (2022): 967193.

[99] H.-Y. Liu, C.-F. Chang, C.-C. Lu, et al., “The Role of Mitochondrial Metabolism, AMPK-SIRT Mediated Pathway, LncRNA and MicroRNA in Osteoarthritis,” Biomedicines 10 (2022): 1477.

[100] S. Zhou, W. Lu, L. Chen, et al., “AMPK Deficiency in Chondrocytes Accelerated the Progression of Instability-Induced and Ageing-Associated Osteoarthritis in Adult Mice,” Scientific Reports 7 (2017): 43245.

[101] D. Yi, H. Yu, K. Lu, et al., “AMPK Signaling in Energy Control, Cartilage Biology, and Osteoarthritis,” Frontiers in Cell and Developmental Biology 9 (2021): 696602.

[102] A. Fazio, A. Di Martino, M. Brunello, et al., “The Involvement of Signaling Pathways in the Pathogenesis of Osteoarthritis: An Update,” Journal of Orthopaedic Translation 47 (2024): 116-124.

[103] J. Liu, J. Liu, R. Li, et al., “AMPK, a Hub for the Microenvironmental Regulation of Bone Homeostasis and Diseases,” Journal of Cellular Physiology 239 (2024): e31393.

[104] Y. Chen, Y. Liu, K. Jiang, Z. Wen, X. Cao, S. Wu, “Linear Ubiquitination of LKB1 Activates AMPK Pathway to Inhibit NLRP3 Inflammasome Response and Reduce Chondrocyte Pyroptosis in Osteoarthritis,” Journal of Orthopaedic Translation 39 (2023): 1-11.

[105] S. Wang, A. Mobasheri, Y. Zhang, Y. Wang, T. Dai, Z. Zhang, “Exogenous Stromal Cell-Derived Factor-1 (SDF-1) Suppresses the NLRP3 Inflammasome and Inhibits Pyroptosis in Synoviocytes From Osteoarthritic Joints via Activation of the AMPK Signaling Pathway,” Inflammopharmacology 29 (2021): 695-704.

[106] H. Xing, C. Liang, C. Wang, X. Xu, Y. Hu, B. Qiu, “Metformin Mitigates Cholesterol Accumulation via the AMPK/SIRT1 Pathway to Protect Osteoarthritis Chondrocytes,” Biochemical and Biophysical Research Communications 632 (2022): 113-121.

[107] Y. Yang, Y. Wang, Y. Kong, et al., “Mechanical Stress Protects Against Osteoarthritis via Regulation of the AMPK/NF-κB Signaling Pathway,” Journal of Cellular Physiology 234 (2019): 9156-9167.

[108] J. Sun, F.-H. Song, J.-Y. Wu, et al., “Sestrin2 Overexpression Attenuates Osteoarthritis Pain via Induction of AMPK/PGC-1α-Mediated Mitochondrial Biogenesis and Suppression of Neuroinflammation,” Brain, Behavior, and Immunity 102 (2022): 53-70.

[109] L. Liu, H. Bai, G. Jiao, et al., “CF101 Alleviates OA Progression and Inhibits the Inflammatory Process via the AMP/ATP/AMPK/mTOR Axis,” Bone 155 (2022): 116264.

[110] P. Liu, J. Zhou, H. Cui, et al., “Vitamin D Plays a Protective Role in Osteoarthritis by Regulating AMPK/mTOR Signalling Pathway to Activate Chondrocyte Autophagy,” Clinical and Experimental Rheumatology 42 (2023): 736-745, https://doi.org/10.55563/clinexprheumatol/chmuts.

[111] Z. Zhu, Y. Huang, J. Li, et al., “AMPK Activator Decelerates Osteoarthritis Development by Inhibition of β-Catenin Signaling in Chondrocytes,” Journal of Orthopaedic Translation 38 (2023): 158-166.

[112] K. Feng, Z. Chen, L. Pengcheng, S. Zhang, X. Wang, “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,” Journal of Cellular Physiology 234 (2019): 18192-18205.

[113] J. Li, B. Zhang, W.-X. Liu, et al., “Metformin Limits Osteoarthritis Development and Progression Through Activation of AMPK Signalling,” Annals of the Rheumatic Diseases 79 (2020): 635-645.

[114] Z. Jin, B. Chang, Y. Wei, et al., “Curcumin Exerts Chondroprotective Effects Against Osteoarthritis by Promoting AMPK/PINK1/Parkin-Mediated Mitophagy,” Biomedicine & Pharmacotherapy 151 (2022): 113092.

[115] T. Wang, C. He, “Pro-Inflammatory Cytokines: The Link Between Obesity and Osteoarthritis,” Cytokine & Growth Factor Reviews 44 (2018): 38-50.

[116] N. Sirikaew, S. Chomdej, S. Tangyuenyong, et al., “Proinflammatory Cytokines and Lipopolysaccharides Up Regulate MMP-3 and MMP-13 Production in Asian Elephant (Elephas Maximus) Chondrocytes: Attenuation by Anti-Arthritic Agents,” BMC Veterinary Research 15 (2019): 419.

[117] D. Wang, J. Qiao, X. Zhao, T. Chen, D. Guan, “Thymoquinone Inhibits IL-1β-Induced Inflammation in Human Osteoarthritis Chondrocytes by Suppressing NF-κB and MAPKs Signaling Pathway,” Inflammation 38 (2015): 2235-2241.

[118] Z. Jenei-Lanzl, A. Meurer, F. Zaucke, “Interleukin-1β Signaling in Osteoarthritis - Chondrocytes in Focus,” Cellular Signalling 53 (2019): 212-223.

[119] L. Wang, H. Xu, X. Li, et al., “Cucurbitacin E Reduces IL-1β-Induced Inflammation and Cartilage Degeneration by Inhibiting the PI3K/Akt Pathway in Osteoarthritic Chondrocytes,” Journal of Translational Medicine 21 (2023): 880.

[120] J. Lu, Z. Miao, Y. Jiang, et al., “Chrysophanol Prevents IL-1β-Induced Inflammation and ECM Degradation in Osteoarthritis via the Sirt6/NF-κB and Nrf2/NF-κB Axis,” Biochemical Pharmacology 208 (2023): 115402.

[121] J. Mao, L. Zhang, “MiR-320a Upregulation Improves IL-1β-Induced Osteoarthritis via Targeting the DAZAP1 and MAPK Pathways,” Journal of Orthopaedic Surgery 18 (2023): 541.

[122] Y. Jiang, M. Yu, X. Hu, et al., “STAT1 Mediates Transmembrane TNF-Alpha-Induced Formation of Death-Inducing Signaling Complex and Apoptotic Signaling via TNFR1,” Cell Death and Differentiation 24 (2017): 660-671.

[123] D. Jang, A.-H. Lee, H.-Y. Shin, et al., “The Role of Tumor Necrosis Factor Alpha (TNF-α) in Autoimmune Disease and Current TNF-α Inhibitors in Therapeutics,” International Journal of Molecular Sciences 22 (2021): 2719.

[124] V. Molnar, V. Matišić, I. Kodvanj, et al., “Cytokines and Chemokines Involved in Osteoarthritis Pathogenesis,” International Journal of Molecular Sciences 22 (2021): 9208.

[125] Y. L. Pobezinskaya, Z. Liu, “The Role of TRADD in Death Receptor Signaling,” Cell Cycle 11 (2012): 871-876.

[126] X. Zhang, M.-F. Hsueh, J. L. Huebner, V. B. Kraus, “TNF-α Carried by Plasma Extracellular Vesicles Predicts Knee Osteoarthritis Progression,” Frontiers in Immunology 12 (2021): 758386.

[127] R. Bi, K. Chen, Y. Wang, et al., “Regulating Fibrocartilage Stem Cells via TNF-α/Nf-κB in TMJ Osteoarthritis,” Journal of Dental Research 101 (2022): 312-322.

[128] S. Liu, C. Cao, Y. Zhang, et al., “PI3K/Akt Inhibitor Partly Decreases TNF-α-Induced Activation of Fibroblast-Like Synoviocytes in Osteoarthritis,” Journal of Orthopaedic Surgery 14 (2019): 425.

[129] L. Li, Z. Li, Y. Li, X. Hu, Y. Zhang, P. Fan, “Profiling of Inflammatory Mediators in the Synovial Fluid Related to Pain in Knee Osteoarthritis,” BMC Musculoskeletal Disorders [Electronic Resource] 21 (2020): 99.

[130] T. Mabey, S. Honsawek, A. Tanavalee, P. Yuktanandana, V. Wilairatana, Y. Poovorawan, “Plasma and Synovial Fluid Inflammatory Cytokine Profiles in Primary Knee Osteoarthritis,” Biomarkers 21 (2016): 639-644.

[131] N. E. McGregor, M. Murat, J. Elango, et al., “IL-6 Exhibits Both Cis- and Trans-Signaling in Osteocytes and Osteoblasts, but Only Trans-Signaling Promotes Bone Formation and Osteoclastogenesis,” Journal of Biological Chemistry 294 (2019): 7850-7863.

[132] H. Reeh, N. Rudolph, U. Billing, et al., “Response to IL-6 Trans- and IL-6 Classic Signalling Is Determined by the Ratio of the IL-6 Receptor α to gp130 Expression: Fusing Experimental Insights and Dynamic Modelling,” Cell Communication and Signaling 17 (2019): 46.

[133] M. Singh, S. Mastana, S. Singh, P. K. Juneja, T. Kaur, P. Singh, “Promoter Polymorphisms in IL-6 Gene Influence Pro-Inflammatory Cytokines for the Risk of Osteoarthritis,” Cytokine 127 (2020): 154985.

[134] H. Yang, X. Zhou, D. Xu, G. Chen, “The IL-6 rs12700386 Polymorphism Is Associated With an Increased Risk of Developing Osteoarthritis in the Knee in the Chinese Han Population: A Case-Control Study,” BMC Medical Genetics 21 (2020): 199.

[135] P. Wojdasiewicz, Ł. A. Poniatowski, D. Szukiewicz, “The Role of Inflammatory and Anti-Inflammatory Cytokines in the Pathogenesis of Osteoarthritis,” Mediators of Inflammation 2014 (2014): 1-19.

[136] E. M. Van Helvoort, E. Van Der Heijden, J. A. G. Van Roon, N. Eijkelkamp, S. C. Mastbergen, “The Role of Interleukin-4 and Interleukin-10 in Osteoarthritic Joint Disease: A Systematic Narrative Review,” Cartilage 13 (2022): 19476035221098167.

[137] Z. He, D. J. Leong, L. Xu, et al., “CITED2 Mediates the Cross-Talk Between Mechanical Loading and IL-4 to Promote Chondroprotection,” Annals of the New York Academy of Sciences 1442 (2019): 128-137.

[138] J. Chen, S. Chen, D. Cai, Q. Wang, J. Qin, “The Role of Sirt6 in Osteoarthritis and Its Effect on Macrophage Polarization,” Bioengineered 13 (2022): 9677-9689.

[139] M. E. R. Van Meegeren, G. Roosendaal, N. W. D. Jansen, et al., “IL-4 Alone and in Combination With IL-10 Protects Against Blood-Induced Cartilage Damage,” Osteoarthritis and Cartilage 20 (2012): 764-772.

[140] E. P. Von Kaeppler, Q. Wang, H. Raghu, M. S. Bloom, H. Wong, W. H. Robinson, “Interleukin 4 Promotes Anti-Inflammatory Macrophages That Clear Cartilage Debris and Inhibits Osteoclast Development to Protect Against Osteoarthritis,” Clinical Immunology 229 (2021): 108784.

[141] C.-Y. Ko, Y.-Y. Lin, D. Achudhan, et al., “Omentin-1 Ameliorates the Progress of Osteoarthritis by Promoting IL-4-Dependent Anti-Inflammatory Responses and M2 Macrophage Polarization,” International Journal of Biological Sciences 19 (2023): 5275-5289.

[142] S. Liu, Z. Deng, K. Chen, et al., “Cartilage Tissue Engineering: From Proinflammatory and Anti‑Inflammatory Cytokines to Osteoarthritis Treatments (Review),” Molecular Medicine Reports 25 (2022): 99.

[143] S. Silawal, M. Willauschus, G. Schulze-Tanzil, C. Gögele, M. Geßlein, S. Schwarz, “IL-10 Could Play a Role in the Interrelation Between Diabetes Mellitus and Osteoarthritis,” International Journal of Molecular Sciences 20 (2019): 768.

[144] P. Behrendt, A. Preusse-Prange, T. Klüter, et al., “IL-10 Reduces Apoptosis and Extracellular Matrix Degradation After Injurious Compression of Mature Articular Cartilage,” Osteoarthritis and Cartilage 24 (2016): 1981-1988.

[145] K. F. Ortved, L. Begum, D. Stefanovski, A. J. Nixon, “AAV-Mediated Overexpression of IL-10 Mitigates the Inflammatory Cascade in Stimulated Equine Chondrocyte Pellets,” Current Gene Therapy 18 (2018): 171-179.

[146] T. Barker, V. E. Rogers, V. T. Henriksen, R. H. Trawick, N. G. Momberger, G. Lynn Rasmussen, “Circulating IL-10 Is Compromised in Patients Predisposed to Developing and in Patients With Severe Knee Osteoarthritis,” Scientific Reports 11 (2021): 1812.

[147] D. Guo, S. Kan, L. Zhang, et al., “IL-10 Enhances Cell-to-Cell Communication in Chondrocytes via STAT3 Signaling Pathway,” Cellular Signalling 105 (2023): 110605.

[148] T. S. Agidigbi, C. Kim, “Reactive Oxygen Species in Osteoclast Differentiation and Possible Pharmaceutical Targets of ROS-Mediated Osteoclast Diseases,” International Journal of Molecular Sciences 20 (2019): 3576.

[149] L. Liu, P. Luo, M. Yang, J. Wang, W. Hou, P. Xu, “The Role of Oxidative Stress in the Development of Knee Osteoarthritis: A Comprehensive Research Review,” Frontiers in Molecular Biosciences 9 (2022): 1001212.

[150] A. Zullo, R. Guida, R. Sciarrillo, F. P. Mancini, “Redox Homeostasis in Cardiovascular Disease: The Role of Mitochondrial Sirtuins,” Frontiers in Endocrinology 13 (2022): 858330.

[151] K. A. Smith, G. B. Waypa, P. T. Schumacker, “Redox Signaling During Hypoxia in Mammalian Cells,” Redox Biology 13 (2017): 228-234.

[152] S. Galadari, A. Rahman, S. Pallichankandy, F. Thayyullathil, “Reactive Oxygen Species and Cancer Paradox: To Promote or to Suppress? Free Radic,” Biology and Medicine 104 (2017): 144-164.

[153] J. Chapman, E. Fielder, J. F. Passos, “Mitochondrial Dysfunction and Cell Senescence: Deciphering a Complex Relationship,” FEBS Letters 593 (2019): 1566-1579.

[154] N. Jiang, B. Xing, R. Peng, et al., “Inhibition of Cpt1a Alleviates Oxidative Stress-Induced Chondrocyte Senescence via Regulating Mitochondrial Dysfunction and Activating Mitophagy,” Mechanisms of Ageing and Development 205 (2022): 111688.

[155] H. Yang, Y. Xie, D. Yang, D. Ren, “Oxidative Stress-Induced Apoptosis in Granulosa Cells Involves JNK, p53 and Puma,” Oncotarget 8 (2017): 25310-25322.

[156] C. Ma, X. Wang, S. He, et al., “Ubiquitinated AIF Is a Major Mediator of Hypoxia-Induced Mitochondrial Dysfunction and Pulmonary Artery Smooth Muscle Cell Proliferation,” Cell BioSciences 12 (2022): 9.

[157] Y. Liu, Z. Zhang, T. Li, H. Xu, H. Zhang, “Senescence in Osteoarthritis: From Mechanism to Potential Treatment,” Arthritis Research & Therapy 24 (2022): 174.

[158] P. Lepetsos, K. A. Papavassiliou, A. G. Papavassiliou, “Redox and NF-κB Signaling in Osteoarthritis. Free Radic,” Biology and Medicine 132 (2019): 90-100.

[159] O.-M. Zahan, O. Serban, C. Gherman, D. Fodor, “The Evaluation of Oxidative Stress in Osteoarthritis,” Medicine and Pharmacy Reports 93, no. 1 (2020): 12-22.

[160] M. H. M. Yunus, A. Nordin, H. Kamal, “Pathophysiological Perspective of Osteoarthritis,” Medicina 56 (2020): 614.

[161] H. Laronha, J. Caldeira, “Structure and Function of Human Matrix Metalloproteinases,” Cells 9 (2020): 1076.

[162] M. Rienks, J. Barallobre-Barreiro, M. Mayr, “The Emerging Role of the ADAMTS Family in Vascular Diseases,” Circulation Research 123 (2018): 1279-1281.

[163] S. Staebler, A. Lichtblau, S. Gurbiel, et al., “MIA/CD-RAP Regulates MMP13 and Is a Potential New Disease-Modifying Target for Osteoarthritis Therapy,” Cells 12 (2023): 229.

[164] J. Larkin, T. A. Lohr, L. Elefante, et al., “Translational Development of an ADAMTS-5 Antibody for Osteoarthritis Disease Modification,” Osteoarthritis and Cartilage 23 (2015): 1254-1266.

[165] T. Li, J. Peng, Q. Li, Y. Shu, P. Zhu, L. Hao, “The Mechanism and Role of ADAMTS Protein Family in Osteoarthritis,” Biomolecules 12 (2022): 959.

[166] M. Z. Cilek, S. De Vega, J. Shiozawa, et al., “Synergistic Upregulation of ADAMTS4 (aggrecanase-1) by Cytokines and Its Suppression in Knee Osteoarthritic Synovial Fibroblasts,” Laboratory Investigation 102 (2022): 102-111.

[167] Q. Yao, X. Wu, C. Tao, et al., “Osteoarthritis: Pathogenic Signaling Pathways and Therapeutic Targets,” Signal Transduction and Targeted Therapy 8 (2023): 56.

[168] Y. Huang, Z. Wang, “Therapeutic Potential of SOX Family Transcription Factors in Osteoarthritis,” Annals of Medicine 57 (2025): 2457520.

[169] B. Tian, L. Zhang, J. Zheng, X. Kang, “The Role of NF-κB-SOX9 Signalling Pathway in Osteoarthritis,” Heliyon 10 (2024): e37191.

[170] Y. E. Sim, C.-L. Kim, D. H. Kim, et al., “Rosmarinic Acid Promotes Cartilage Regeneration Through Sox9 Induction via NF-κB Pathway Inhibition in Mouse Osteoarthritis Progression,” Heliyon 10 (2024): e38936.

[171] Z. Cai, T. Long, Y. Zhao, R. Lin, Y. Wang, “Epigenetic Regulation in Knee Osteoarthritis,” Frontiers in Genetics 13 (2022): 942982.

[172] V. V. Visconti, I. Cariati, S. Fittipaldi, et al., “DNA Methylation Signatures of Bone Metabolism in Osteoporosis and Osteoarthritis Aging-Related Diseases: An Updated Review,” International Journal of Molecular Sciences 22 (2021): 4244.

[173] C. Núñez-Carro, M. Blanco-Blanco, K. M. Villagrán-Andrade, F. J. Blanco, M. C. De Andrés, “Epigenetics as a Therapeutic Target in Osteoarthritis,” Pharmaceuticals 16 (2023): 156.

[174] X. Zhu, F. Chen, K. Lu, A. Wei, Q. Jiang, W. Cao, “PPARγ Preservation via Promoter Demethylation Alleviates Osteoarthritis in Mice,” Annals of the Rheumatic Diseases 78 (2019): 1420-1429.

[175] Z. Liu, T. Lu, L. Ma, Y. Zhang, D. Li, “DNA Demethylation of Promoter Region Orchestrates SPI-1-Induced ADAMTS-5 Expression in Articular Cartilage of Osteoarthritis Mice,” Journal of Cellular Physiology 239 (2024): e31170.

[176] F. Yang, S. Zhou, C. Wang, et al., “Epigenetic Modifications of Interleukin-6 in Synovial Fibroblasts From Osteoarthritis Patients,” Scientific Reports 7 (2017): 43592.

[177] A.-A. Papageorgiou, M. Litsaki, E. Mourmoura, I. Papathanasiou, A. Tsezou, “DNA Methylation Regulates Sirtuin 1 Expression in Osteoarthritic Chondrocytes,” Advances in Medical Sciences 68 (2023): 101-110.

[178] C. Wan, F. Zhang, H. Yao, H. Li, R. S. Tuan, “Histone Modifications and Chondrocyte Fate: Regulation and Therapeutic Implications,” Frontiers in Cell and Developmental Biology 9 (2021): 626708.

[179] D. Husmann, O. Gozani, “Histone Lysine Methyltransferases in Biology and Disease,” Nature Structural & Molecular Biology 26 (2019): 880-889.

[180] M. Ukita, K. Matsushita, M. Tamura, T. Yamaguchi, “Histone H3K9 Methylation Is Involved in Temporomandibular Joint Osteoarthritis,” International Journal of Molecular Medicine 45 (2019): 607-614, https://doi.org/10.3892/ijmm.2019.4446.

[181] S. Yan, T. Lu, H. Yang, L. Ma, Y. Zhang, D. Li, “Decreased Histone H3K9 Dimethylation in Synergy With DNA Demethylation of Spi-1 Binding Site Contributes to ADAMTS-5 Expression in Articular Cartilage of Osteoarthritis Mice,” Journal of Cellular Physiology 239 (2024): e31444.

[182] R. Assi, C. Cherifi, F. M. F. Cornelis, et al., “Inhibition of KDM7A/B Histone Demethylases Restores H3K79 Methylation and Protects Against Osteoarthritis,” Annals of the Rheumatic Diseases 82 (2023): 963-973.

[183] R. Shao, J. Suo, Z. Zhang, et al., “H3K36 Methyltransferase NSD1 Protects Against Osteoarthritis Through Regulating Chondrocyte Differentiation and Cartilage Homeostasis,” Cell Death and Differentiation 31 (2024): 106-118.

[184] P. Wang, Z. Mao, Q. Pan, et al., “Histone Deacetylase-4 and Histone Deacetylase-8 Regulate Interleukin-1β-Induced Cartilage Catabolic Degradation Through MAPK/JNK and ERK Pathways,” International Journal of Molecular Medicine 41, no. 4 (2018): 2117-2127.

[185] H. Kong, M.-L. Sun, X.-A. Zhang, X.-Q. Wang, “Crosstalk Among circRNA/lncRNA, miRNA, and mRNA in Osteoarthritis,” Frontiers in Cell and Developmental Biology 9 (2021): 774370.

[186] C. Wen, L. Lin, R. Zou, F. Lin, Y. Liu, “Mesenchymal Stem Cell-Derived Exosome Mediated Long Non-Coding RNA KLF3-AS1 Represses Autophagy and Apoptosis of Chondrocytes in Osteoarthritis,” Cell Cycle 21 (2022): 289-303.

[187] Y. Gu, G. Wang, P. Chen, “GAS5 Long Non-Coding RNA Interacts With microRNA-205 to Relieve Fibroblast-Like Synoviocyte Inflammation and Ferroptosis in Osteoarthritis,” Apoptosis 30 (2025): 320-333.

[188] A. Yuan, P. Wu, Z. Zhong, Z. He, W. Li, “Long Non-Coding RNA Gm37494 Alleviates Osteoarthritis Chondrocyte Injury via the microRNA-181a-5p/GABRA1 Axis,” Journal of Orthopaedic Surgery 17 (2022): 304.

[189] W. Zhang, C. Hu, C. Zhang, C. Luo, B. Zhong, X. Yu, “MiRNA-132 Regulates the Development of Osteoarthritis in Correlation With the Modulation of PTEN/PI3K/AKT Signaling,” BMC Geriatrics 21 (2021): 175.

[190] L. Zhang, J. Qiu, J. Shi, S. Liu, H. Zou, “MicroRNA-140-5p Represses Chondrocyte Pyroptosis and Relieves Cartilage Injury in Osteoarthritis by Inhibiting Cathepsin B/Nod-Like Receptor Protein 3,” Bioengineered 12 (2021): 9933-9948.

[191] I. Papathanasiou, V. Trachana, E. Mourmoura, A. Tsezou, “DNA Methylation Regulates miR-140-5p and miR-146a Expression in Osteoarthritis,” Life Sciences 228 (2019): 274-284.

[192] W. Xiang, C. Wang, Z. Zhu, D. Wang, Z. Qiu, W. Wang, “Inhibition of SMAD3 Effectively Reduces ADAMTS-5 Expression in the Early Stages of Osteoarthritis,” BMC Musculoskeletal Disorders [Electronic Resource] 24 (2023): 130.

[193] J. Hirvasniemi, J. Runhaar, R. A. Van Der Heijden, et al., “The KNee OsteoArthritis Prediction (KNOAP2020) Challenge: An Image Analysis Challenge to Predict Incident Symptomatic Radiographic Knee Osteoarthritis From MRI and X-Ray Images,” Osteoarthritis and Cartilage 31 (2023): 115-125.

[194] D. Zarringam, D. B. F. Saris, J. E. J. Bekkers, “The Value of SPECT/CT for Knee Osteoarthritis: A Systematic Review,” Cartilage 12 (2021): 431-437.

[195] J. Podlipská, A. Guermazi, P. Lehenkari, et al., “Comparison of Diagnostic Performance of Semi-Quantitative Knee Ultrasound and Knee Radiography With MRI: Oulu Knee Osteoarthritis Study,” Scientific Reports 6 (2016): 22365.

[196] D. Hayashi, F. W. Roemer, A. Guermazi, “Osteoarthritis Year in Review 2024: Imaging,” Osteoarthritis and Cartilage 33 (2025): 88-93.

[197] L. Sharma, “Osteoarthritis of the Knee,” New England Journal of Medicine 384 (2021): 51-59.

[198] H. D. Welhaven, A. H. Welfley, R. K. June, “Osteoarthritis Year in Review 2024: Molecular Biomarkers of Osteoarthritis,” Osteoarthritis and Cartilage 33 (2025): 67-87.

[199] S. S. Pakdaman Kolour, S. Nematollahi, M. Dehbozorgi, et al., “Extracecellulr Vesicles (EVs) microRNAs (miRNAs) Derived From Mesenchymal Stem Cells (MSCs) in Osteoarthritis (OA); Detailed Role in Pathogenesis and Possible Therapeutics,” Heliyon 11 (2025): e42258.

[200] T. F. Aae, T. A. Karlsen, I. K. Haugen, M. A. Risberg, Ø. B. Lian, J. E. Brinchmann, “Evaluating Plasma Extracellular Vesicle microRNAs as Possible Biomarkers for Osteoarthritis,” Osteoarthritis and Cartilage Open 1 (2020): 100018.

[201] M. Liu, N. Haque, J. Huang, G. Zhai, “Osteoarthritis Year in Review 2023: Metabolite and Protein Biomarkers,” Osteoarthritis and Cartilage 31 (2023): 1437-1453.

[202] E. Clarke, L. Varela, R. E. Jenkins, et al., “Proteome and Phospholipidome Interrelationship of Synovial Fluid-Derived Extracellular Vesicles in Equine Osteoarthritis: An Exploratory ‘Multi-Omics’ Study to Identify Composite Biomarkers,” Biochemistry and Biophysics Reports 37 (2024): 101635.

[203] Z. Guo, H. Wang, F. Zhao, et al., “Exosomal Circ-BRWD1 Contributes to Osteoarthritis Development Through the Modulation of miR-1277/TRAF6 Axis,” Arthritis Research & Therapy 23 (2021): 159.

[204] T. Kuroiwa, Y. Tsuboi, T. Michikawa, et al., “DNA Methylation of Bone Morphogenetic Protein 7 in Leukocytes as a Possible Biomarker for Hand Osteoarthritis: A Pilot Study,” Journal of Orthopaedic Research 43 (2025): 84-93.

[205] F. An, B. Sun, Y. Liu, et al., “Advances in Understanding Effects of miRNAs on Apoptosis, Autophagy, and Pyroptosis in Knee Osteoarthritis,” Molecular Genetics and Genomics 298 (2023): 1261-1278.

[206] V. Costa, S. Terrando, D. Bellavia, C. Salvatore, R. Alessandro, G. Giavaresi, “MiR203a-3p as a Potential Biomarker for Synovial Pathology Associated With Osteoarthritis: A Pilot Study,” Journal of Orthopaedic Surgery 19 (2024): 746.

[207] T. G. Wilson, M. Baghel, N. Kaur, et al., “Circulating miR-126-3p Is a Mechanistic Biomarker for Knee Osteoarthritis,” Nature Communications 16 (2025): 2021.

[208] G. Tardif, F. Paré, C. Gotti, et al., “Mass Spectrometry-Based Proteomics Identify Novel Serum Osteoarthritis Biomarkers,” Arthritis Research & Therapy 24 (2022): 120.

[209] W. Udomsinprasert, N. Mookkhan, T. Tabtimnark, et al., “Cartilage Oligomeric Matrix Protein as a Potential Biomarker for Knee Osteoarthritis,” Bone & Joint Research 13 (2024): 261-271.

[210] U. Kalvaityte, C. Matta, E. Bernotiene, P. N. Pushparaj, A. M. Kiapour, A. Mobasheri, “Exploring the Translational Potential of Clusterin as a Biomarker of Early Osteoarthritis,” Journal of Orthopaedic Translation 32 (2022): 77-84.

[211] M. A. Hassan, A. S. Hameed, E. K. Hameed, “Serum Fibulin-3 as a Diagnostic and Prognostic Biomarker in Patients With Knee Osteoarthritis,” Irish Journal of Medical Science 193, no. 6 (2024): 2923-2927.

[212] W. Udomsinprasert, K. Panon, S. Preechanukul, J. Jittikoon, A. Jinawath, S. Honsawek, “Diagnostic Value of Interleukin-34 as a Novel Biomarker for Severity of Knee Osteoarthritis,” Cartilage 13 (2021): 1174S-1184S.

[213] S. Singh, D. Jindal, R. Khanna, “sCTX II Is a Better Biomarker Than sMMP-3 to Identify Early Knee Osteoarthritis,” Journal of Orthopaedic Research 41 (2023): 2455-2461.

[214] B. R. Da Costa, T. V. Pereira, P. Saadat, et al., “Effectiveness and Safety of Non-Steroidal Anti-Inflammatory Drugs and Opioid Treatment for Knee and Hip Osteoarthritis: Network Meta-Analysis,” Bmj (2021): n2321, https://doi.org/10.1136/bmj.n2321.

[215] L. Fuchs, A. Givon, F. Shweiki, T. Hovav, “Arthroscopic Knee Debridement in Osteoarthritis in the Older Age Can be Satisfactory,” Journal of Clinical Orthopaedics and Trauma 38 (2023): 102130.

[216] Z. Salis, J. B. Driban, T. E. McAlindon, A. Sainsbury, “Evaluation of a Measure of End-Stage Knee Osteoarthritis Compared to Total Knee Replacement: An Observational Study Using Multicohort Data,” Seminars in Arthritis and Rheumatism 64 (2024): 152336.

[217] J. Wu, H. Li, F. Hu, P. Luo, “Stevioside Attenuates Osteoarthritis via Regulating Nrf2/HO-1/NF-κB Pathway,” Journal of Orthopaedic Translation 38 (2023): 190-202.

[218] P. Zhang, Y. Jin, W. Xia, X. Wang, Z. Zhou, “Phillygenin Inhibits Inflammation in Chondrocytes via the Nrf2/NF-κB Axis and Ameliorates Osteoarthritis in Mice,” Journal of Orthopaedic Translation 41 (2023): 1-11.

[219] F. Zhou, J. Liu, X. Xu, Y. Luo, S. Yang, “Albiflorin Alleviation Efficacy in Osteoarthritis Injury Using In-Vivo and In-Vitro Models,” Journal of Pharmacy and Pharmacology 75 (2023): 1332-1343.

[220] K. Nazari, S. Hosseindoost, A. R. Dehpour, Y. Kheirandish, H. Shafaroodi, “Evaluating the Protective Effect of Dapsone on Experimental Osteoarthritis Models Induced by MIA in Male Rats,” Journal of Pharmacy and Pharmacology 76 (2024): 1497-1507.

[221] R. R. Pratama, R. A. Sari, I. Sholikhah, et al., “Inhibition of Nitric Oxide Production in RAW 264.7 Cells and Cytokines IL-1β in Osteoarthritis Rat Models of 70 % Ethanol Extract of Arcangelisia Flava (L.) Merr Stems,” Heliyon 10, no. 15 (2024): e35730.

[222] S. Luo, H. Jiang, Q. Li, et al., “The Intra-Articular Delivery of a Low-Dose Adeno-Associated Virus-IL-1 Receptor Antagonist Vector Alleviates the Progress of Arthritis in an Osteoarthritis Rat Model,” Pharmaceutics 16 (2024): 1518.

[223] K. Zhou, M. Yuan, J. Sun, et al., “Co-Delivery of IL-1Ra and SOX9 via AAV Inhibits Inflammation and Promotes Cartilage Repair in Surgically Induced Osteoarthritis Animal Models,” Gene Therapy 32, no. 3 (2025): 211-222.

[224] W. Zheng, T. Zhou, Y. Zhang, et al., “Simplified α2-Macroglobulin as a TNF-α Inhibitor for Inflammation Alleviation in Osteoarthritis and Myocardial Infarction Therapy,” Biomaterials 301 (2023): 122247.

[225] Y. Gong, J. Qiu, J. Ye, et al., “AZ-628 Delays Osteoarthritis Progression via Inhibiting the TNF-α-Induced Chondrocyte Necroptosis and Regulating Osteoclast Formation,” International Immunopharmacology 111 (2022): 109085.

[226] Y.-S. Chiu, O. A. Bamodu, I.-H. Fong, et al., “The JAK Inhibitor Tofacitinib Inhibits Structural Damage in Osteoarthritis by Modulating JAK1/TNF-Alpha/IL-6 Signaling Through Mir-149-5p,” Bone 151 (2021): 116024.

[227] J. Qiao, X. Guo, L. Zhang, H. Zhao, X. He, “Autologous Platelet Rich Plasma Injection Can be Effective in the Management of Osteoarthritis of the Knee: Impact on IL-1 β, TNF-α, hs-CRP,” Journal of Orthopaedic Surgery 19 (2024): 703.

[228] P. Jayaram, P. J. T. Mitchell, T. B. Shybut, B. J. Moseley, B. Lee, “Leukocyte-Rich Platelet-Rich Plasma Is Predominantly Anti-Inflammatory Compared With Leukocyte-Poor Platelet-Rich Plasma in Patients With Mild-Moderate Knee Osteoarthritis: A Prospective, Descriptive Laboratory Study,” American Journal of Sports Medicine 51 (2023): 2133-2140.

[229] I. Romandini, A. Boffa, A. Di Martino, et al., “Leukocytes Do Not Influence the Safety and Efficacy of Platelet-Rich Plasma Injections for the Treatment of Knee Osteoarthritis: A Double-Blind Randomized Controlled Trial,” American Journal of Sports Medicine 52 (2024): 3212-3222.

[230] K. L. Bennell, K. L. Paterson, B. R. Metcalf, 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 326 (2021): 2021.

[231] F. Eckstein, M. C. Hochberg, H. Guehring, et al., “Long-Term Structural and Symptomatic Effects of Intra-Articular Sprifermin in Patients With Knee Osteoarthritis: 5-Year Results From the FORWARD Study,” Annals of the Rheumatic Diseases 80 (2021): 1062-1069.

[232] A. C. Bay-Jensen, A. A. Manginelli, M. Karsdal, et al., “Low Levels of Type II Collagen Formation (PRO-C2) Are Associated With Response to Sprifermin: A Pre-Defined, Exploratory Biomarker Analysis From the FORWARD Study,” Osteoarthritis and Cartilage 30 (2022): 92-99.

[233] T. J. Schnitzer, R. Easton, S. Pang, et al., “Effect of Tanezumab on Joint Pain, Physical Function, and Patient Global Assessment of Osteoarthritis Among Patients With Osteoarthritis of the Hip or Knee: A Randomized Clinical Trial,” Jama 322 (2019): 37.

[234] M. Pallav, L. Zaripova, D. Tazhibaeva, N. Kabdualieva, “POS1126 Clinical Efficacy and Safety of Monoclonal Antibody Against Nerve Growth Factor and Fibroblast Growth FACTOR-18 Therapy of Osteoarthritis,” Annals of the Rheumatic Diseases 81 (2022): 892.

[235] B. L. Wise, M. F. Seidel, N. E. Lane, “The Evolution of Nerve Growth Factor Inhibition in Clinical Medicine,” Nature Reviews Rheumatology 17 (2021): 34-46.

[236] A. Hassanzadeh, N. Vousooghi, R. Rahimnia, et al., “Recent Advances in Mesenchymal Stem/Stromal Cells (MSCs)-Based Approaches for Osteoarthritis (OA) Therapy,” Cell Biology International 47 (2023): 1033-1048.

[237] J. J. Hwang, Y. A. Rim, Y. Nam, J. H. Ju, “Recent Developments in Clinical Applications of Mesenchymal Stem Cells in the Treatment of Rheumatoid Arthritis and Osteoarthritis,” Frontiers in Immunology 12 (2021): 631291.

[238] B. Sadri, M. Hassanzadeh, A. Bagherifard, et al., “Cartilage Regeneration and Inflammation Modulation in Knee Osteoarthritis Following Injection of Allogeneic Adipose-Derived Mesenchymal Stromal Cells: A Phase II, Triple-Blinded, Placebo Controlled, Randomized Trial,” Stem Cell Research & Therapy 14 (2023): 162.

[239] P. K. Gupta, S. Maheshwari, J. J. Cherian, et al., “Efficacy and Safety of Stempeucel in Osteoarthritis of the Knee: A Phase 3 Randomized, Double-Blind, Multicenter, Placebo-Controlled Study,” American Journal of Sports Medicine 51 (2023): 2254-2266.

[240] B.-W. Lee, J. J. Lee, J.-Y. Jung, J. H. Ju, “Intra-Articular Injection of Human Bone Marrow-Derived Mesenchymal Stem Cells in Knee Osteoarthritis: A Randomized,” Double-Blind, Controlled Trial Cell Transplant 34 (2025): 09636897241303275.

[241] A. S. Saleh, “Ameliorative Effects of Undifferentiated and Differentiated BM-MSCs in MIA-Induced Osteoarthritic Wistar Rats: Roles of NF-κB and MMPs Signaling Pathways,” American Journal of Translational Research 16 (2024): 2793-2813.

[242] J. Lin, L. Wang, J. Lin, Q. Liu, “The Role of Extracellular Vesicles in the Pathogenesis, Diagnosis, and Treatment of Osteoarthritis,” Molecules (Basel, Switzerland) 26 (2021): 4987.

[243] H. Yin, M. Li, G. Tian, et al., “The Role of Extracellular Vesicles in Osteoarthritis Treatment via Microenvironment Regulation,” Biomaterials Research 26 (2022): 52.

[244] B. You, C. Zhou, Y. Yang, “MSC-EVs Alleviate Osteoarthritis by Regulating Microenvironmental Cells in the Articular Cavity and Maintaining Cartilage Matrix Homeostasis,” Ageing Research Reviews 85 (2023): 101864.

[245] K. Warmink, J. L. Rios, S. Varderidou-Minasian, et al., “Mesenchymal Stem/Stromal Cells-Derived Extracellular Vesicles as a Potentially More Beneficial Therapeutic Strategy Than MSC-Based Treatment in a Mild Metabolic Osteoarthritis Model,” Stem Cell Research & Therapy 14 (2023): 137.

[246] M. Ai, W. E. Hotham, L. A. Pattison, Q. Ma, F. M. D. Henson, E. S. J. Smith, “Role of Human Mesenchymal Stem Cells and Derived Extracellular Vesicles in Reducing Sensory Neuron Hyperexcitability and Pain Behaviors in Murine Osteoarthritis,” Arthritis & Rheumatology 75 (2023): 352-363.

[247] A. Duan, K. Shen, B. Li, et al., “Extracellular Vesicles Derived From LPS-Preconditioned Human Synovial Mesenchymal Stem Cells Inhibit Extracellular Matrix Degradation and Prevent Osteoarthritis of the Knee in a Mouse Model,” Stem Cell Research & Therapy 12 (2021): 427.

[248] S. Li, J. Liu, S. Liu, W. Jiao, X. Wang, “Chitosan Oligosaccharides Packaged Into Rat Adipose Mesenchymal Stem Cells-Derived Extracellular Vesicles Facilitating Cartilage Injury Repair and Alleviating Osteoarthritis,” Journal of Nanobiotechnology 19 (2021): 343.

[249] Z. Jing, G. Zhang, Y. Cai, J. Liang, L. Lv, X. Dang, “Engineered Extracellular Vesicle-Delivered TGF-β Inhibitor for Attenuating Osteoarthritis by Targeting Subchondral Bone,” Journal of Tissue Engineering 15 (2024): 20417314241257781.

[250] J. Y. Kim, S. Y. Lee, S.-G. Cha, et al., “Combinatory Nanovesicle With siRNA-Loaded Extracellular Vesicle and IGF-1 for Osteoarthritis Treatments,” International Journal of Molecular Sciences 25 (2024): 5242.

[251] L. Liu, W. Zhang, T. Liu, et al., “The Physiological Metabolite α-Ketoglutarate Ameliorates Osteoarthritis by Regulating Mitophagy and Oxidative Stress,” Redox Biology 62 (2023): 102663.

[252] M. Zhang, J. Wu, K. Cai, et al., “From Dysfunction to Healing: Advances in Mitochondrial Therapy for Osteoarthritis,” Journal of Translational Medicine 22 (2024): 1013.

[253] C. Cheung, S. Tu, Y. Feng, C. Wan, H. Ai, Z. Chen, “Mitochondrial Quality Control Dysfunction in Osteoarthritis: Mechanisms, Therapeutic Strategies & Future Prospects,” Archives of Gerontology and Geriatrics 125 (2024): 105522.

[254] K. Sun, X. Jing, J. Guo, X. Yao, F. Guo, “Mitophagy in Degenerative Joint Diseases,” Autophagy 17 (2021): 2082-2092.

[255] A. M. Vega-Letter, C. García-Guerrero, L. Yantén-Fuentes, et al., “Safety and Efficacy of Mesenchymal Stromal Cells Mitochondria Transplantation as a Cell-Free Therapy for Osteoarthritis,” Journal of Translational Medicine 23 (2025): 26.

[256] X. Li, W. Lu, L. Ni, J. Su, D. Wang, Z. Deng, “Mitochondria-Rich Extracellular Vesicles Derived From the Culture Supernatant of Human Synovial Fluid-Derived Mesenchymal Stem Cells Inhibited Senescence of Stressed/Inflammatory Licensed Chondrocytes and Delayed Osteoarthritis Progression,” International Immunopharmacology 147 (2025): 113954.

[257] Y. Zhang, Y. Liu, M. Hou, et al., “Reprogramming of Mitochondrial Respiratory Chain Complex by Targeting SIRT3-COX4I2 Axis Attenuates Osteoarthritis Progression,” Advancement of Science 10 (2023): 2206144.

[258] L. Chen, J. Yang, Z. Cai, et al., “Mitochondrial-Oriented Injectable Hydrogel Microspheres Maintain Homeostasis of Chondrocyte Metabolism to Promote Subcellular Therapy in Osteoarthritis,” Research 7 (2024): 0306.

[259] X. Li, L. Shen, Z. Deng, Z. Huang, “New Treatment for Osteoarthritis: Gene Therapy. Precis,” Clinical Medicine (London, England) 6 (2023): pbad014.

[260] M. Uebelhoer, C. Lambert, J. Grisart, K. Guse, S. Plutizki, Y. Henrotin, “Interleukins, Growth Factors, and Transcription Factors Are Key Targets for Gene Therapy in Osteoarthritis: A Scoping Review,” Frontiers in Medicine 10 (2023): 1148623.

[261] R. Senter, R. Boyce, M. Repic, et al., “Efficacy and Safety of FX201, a Novel Intra-Articular IL-1Ra Gene Therapy for Osteoarthritis Treatment, in a Rat Model,” Human Gene Therapy 33 (2022): 541-549.

[262] L. R. Goodrich, C. W. McIlwraith, J. Grieger, et al., “IL-1ra Gene Therapy in Equine Osteoarthritis Improves Physiological, Anatomical, and Biological Outcomes of Joint Degeneration,” Journal of the American Veterinary Medical Association 262 (2024): S109-S120.

[263] J. M. Hollander, A. Goraltchouk, J. Liu, et al., “Single Injection AAV2-FGF18 Gene Therapy Reduces Cartilage Lossand Subchondral Bone Damage in a Mechanically Induced Model ofOsteoarthritis,” Current Gene Therapy 24 (2024): 331-345.

[264] M. A. Rabie, R. H. Sayed, J. K. Venkatesan, H. Madry, M. Cucchiarini, N. S. El Sayed, “Intra-Articular Injection of rAAV-hFGF-2 Ameliorates Monosodium Iodoacetate-Induced Osteoarthritis in Rats via Inhibiting TLR-4 Signaling and Activating TIMP-1,” Toxicology and Applied Pharmacology 459 (2023): 116361.

[265] Y. Cai, C. Wu, Q. Ou, et al., “Enhanced Osteoarthritis Therapy by Nanoengineered Mesenchymal Stem Cells Using Biomimetic CuS Nanoparticles Loaded With Plasmid DNA Encoding TGF-β1,” Bioactive Materials 19 (2023): 444-457.

[266] Y. Liu, C. Huang, M. Bai, C. Pi, D. Zhang, J. Xie, “The Roles of Runx1 in Skeletal Development and Osteoarthritis: A Concise Review,” Heliyon 8 (2022): e12656.

[267] H. Chen, C. Pi, M. Chen, et al., “Runx1 Alleviates Osteoarthritis Progression in Aging Mice,” Journal of Histotechnology 47 (2024): 57-67.

[268] Y. Li, J. Zhao, S. Guo, D. He, “siRNA Therapy in Osteoarthritis: Targeting Cellular Pathways for Advanced Treatment Approaches,” Frontiers in Immunology 15 (2024): 1382689.

[269] G. Pezzotti, W. Zhu, Y. Terai, et al., “Raman Spectroscopic Insight Into Osteoarthritic Cartilage Regeneration by mRNA Therapeutics Encoding Cartilage-Anabolic Transcription Factor Runx1,” Materials Today Bio 13 (2022): 100210.

[270] M. Sun, B. Ma, Z. Pan, et al., “Targeted Therapy of Osteoarthritis via Intra-Articular Delivery of Lipid-Nanoparticle-Encapsulated Recombinant Human FGF18 mRNA,” Advanced Healthcare Materials 13 (2024): 2400804.

[271] Z.-J. Zhang, Y.-K. Hou, M.-W. Chen, et al., “A pH-Responsive Metal-Organic Framework for the Co-Delivery of HIF-2α siRNA and Curcumin for Enhanced Therapy of Osteoarthritis,” Journal of Nanobiotechnology 21 (2023): 18.

[272] Z. Ji, X. Ren, J. Jin, et al., “Injectable Hydrogel Encapsulating siMMP13 With Anti-ROS and Anti-Apoptotic Functions for Osteoarthritis Treatment,” Journal of Nanobiotechnology 22 (2024): 466.

[273] K. Liu, D. Zhang, W. Wang, “Nanoparticle-Based Drug Delivery System—A Target Strategy for Osteoarthritis Treatment,” Journal of Nanomaterials 2021 (2021): 1-15.

[274] P. Patil, S. Nene, S. Shah, S. B. Singh, S. Srivastava, “Exploration of Novel Drug Delivery Systems in Topical Management of Osteoarthritis,” Drug Delivery and Translational Research 13 (2023): 531-546.

[275] Q. Jiang, S. Zhang, “Stimulus-Responsive Drug Delivery Nanoplatforms for Osteoarthritis Therapy,” Small 19 (2023): 2206929.

[276] S. Liao, S. Jia, Y. Yue, H. Zeng, J. Lin, P. Liu, “Advancements in pH-Responsive Nanoparticles for Osteoarthritis Treatment: Opportunities and Challenges,” Frontiers in Bioengineering and Biotechnology 12 (2024): 1426794.

[277] J. Pan, Y. Cai, C. Zhang, S. Xu, “Intra-Articular Delivery of Geraniol Encapsulated by pH/Redox-Responsive Nanogel Ameliorates Osteoarthritis by Regulating Oxidative Stress and Inflammation,” Journal of Molecular Histology 54 (2023): 579-591.

[278] M. He, Z. Qin, X. Liang, et al., “A pH-Responsive Mesoporous Silica Nanoparticles-Based Drug Delivery System With Controlled Release of Andrographolide for OA Treatment,” Regenerative Biomaterials 8 (2021): rbab020.

[279] K. Chen, J. Wang, J. Cao, et al., “Enzyme-Responsive Microgel With Controlled Drug Release, Lubrication and Adhesion Capability for Osteoarthritis Attenuation,” Acta Biomaterialia 190 (2024): 191-204.

[280] M. Zhang, W. Hu, C. Cai, Y. Wu, J. Li, S. Dong, “Advanced Application of Stimuli-Responsive Drug Delivery System for Inflammatory Arthritis Treatment,” Materials Today Bio 14 (2022): 100223.

[281] J. Liao, Z. Zhu, J. Zou, et al., “Macrophage Membrane-Biomimetic Multi-Layered Nanoparticles Targeting Synovial Angiogenesis for Osteoarthritis Therapy,” Advanced Healthcare Materials 14 (2025): 2401985.

[282] H. M. K. Ebada, M. M. A. Nasra, R. A. Nassra, O. Y. Abdallah, “Chondroitin Sulfate-Functionalized Lipid Nanoreservoirs: A Novel Cartilage-Targeting Approach for Intra-Articular Delivery of Cassic Acid for Osteoarthritis Treatment,” Drug Delivery 29 (2022): 652-663.

[283] C.-M. Zara-Danceanu, J. García-Fernández, D.-D. Herea, et al., “Development and Characterization of Magnetic Nanoemulsion-Based Senolytic Peptides for Osteoarthritis Treatment,” International Journal of Molecular Sciences 26 (2025): 1292.

[284] W. Chen, C. Li, M. Peng, B. Xie, L. Zhang, X. Tang, “Autologous Nasal Chondrocytes Delivered by Injectable Hydrogel for in Vivo Articular Cartilage Regeneration,” Cell and Tissue Banking 19 (2018): 35-46.

[285] K. Zheng, Y. Ma, C. Chiu, M. Xue, C. Zhang, D. Du, “Enhanced Articular Cartilage Regeneration Using Costal Chondrocyte-Derived Scaffold-Free Tissue Engineered Constructs With Ascorbic Acid Treatment,” Journal of Orthopaedic Translation 45 (2024): 140-154.

[286] Ö. Karabıyık Acar, S. Bedir, A. B. Kayitmazer, G. T. Kose, “Chondro-Inductive Hyaluronic Acid/Chitosan Coacervate-Based Scaffolds for Cartilage Tissue Engineering,” International Journal of Biological Macromolecules 188 (2021): 300-312.

[287] S. Li, D. Niu, T. Shi, et al., “Injectable, in Situ Self-Cross-Linking, Self-Healing Poly(l-Glutamic Acid)/Polyethylene Glycol Hydrogels for Cartilage Tissue Engineering,” ACS Biomaterials Science & Engineering 9 (2023): 2625-2635.

[288] T. Nonaka, D. Murata, H. Yoshizato, et al., “Bio-3D Printing of Scaffold-Free ADSC-Derived Cartilage Constructs Comparable to Natural Cartilage in Vitro,” Journal of Orthopaedic Surgery 20 (2025): 182.

[289] Y.-H. Chang, K.-C. Wu, D.-C. Ding, “Induced Pluripotent Stem Cell-Differentiated Chondrocytes Repair Cartilage Defect in a Rabbit Osteoarthritis Model,” Stem Cells International 2020 (2020): 1-16.

[290] A. R. Armiento, M. J. Stoddart, M. Alini, D. Eglin, “Biomaterials for Articular Cartilage Tissue Engineering: Learning From Biology,” Acta Biomaterialia 65 (2018): 1-20.

[291] W. Wei, Y. Ma, X. Yao, et al., “Advanced Hydrogels for the Repair of Cartilage Defects and Regeneration,” Bioactive Materials 6 (2021): 998-1011.

[292] H. Kwon, W. E. Brown, C. A. Lee, et al., “Surgical and Tissue Engineering Strategies for Articular Cartilage and Meniscus Repair,” Nature Reviews Rheumatology 15 (2019): 550-570.

[293] Q. Li, S. Xu, Q. Feng, et al., “3D Printed Silk-Gelatin Hydrogel Scaffold With Different Porous Structure and Cell Seeding Strategy for Cartilage Regeneration,” Bioactive Materials 6 (2021): 3396-3410.

[294] Z. Qiao, M. Lian, Y. Han, et al., “Bioinspired Stratified Electrowritten Fiber-Reinforced Hydrogel Constructs With Layer-Specific Induction Capacity for Functional Osteochondral Regeneration,” Biomaterials 266 (2021): 120385.

[295] Y. Liu, L. Peng, L. Li, et al., “3D-Bioprinted BMSC-Laden Biomimetic Multiphasic Scaffolds for Efficient Repair of Osteochondral Defects in an Osteoarthritic Rat Model,” Biomaterials 279 (2021): 121216.

[296] P. Li, L. Fu, Z. Liao, et al., “Chitosan Hydrogel/3D-Printed Poly(ε-Caprolactone) Hybrid Scaffold Containing Synovial Mesenchymal Stem Cells for Cartilage Regeneration Based on Tetrahedral Framework Nucleic Acid Recruitment,” Biomaterials 278 (2021): 121131.

[297] D. Liu, X. Wang, C. Gao, et al., “Biodegradable Piezoelectric-Conductive Integrated Hydrogel Scaffold for Repair of Osteochondral Defects,” Advanced Materials 36 (2024): 2409400.

[298] S. Taghizadeh, L. Tayebi, M. Akbarzadeh, P. Lohrasbi, A. Savardashtaki, “Magnetic Hydrogel Applications in Articular Cartilage Tissue Engineering,” Journal of Biomedical Materials Research. Part A 112 (2024): 260-275.

[299] J. Zhang, M. Zhang, R. Lin, et al., “Chondrogenic Preconditioning of Mesenchymal Stem/Stromal Cells Within a Magnetic Scaffold for Osteochondral Repair,” Biofabrication 14 (2022): 025020.

[300] F. Gang, Q. Zhang, L. Jiang, et al., “Thermochemotherapy Meets Tissue Engineering for Rheumatoid Arthritis Treatment,” Advanced Functional Materials 31 (2021): 2104131.

[301] M. Chen, Z. Jiang, X. Zou, X. You, Z. Cai, J. Huang, “Advancements in Tissue Engineering for Articular Cartilage Regeneration,” Heliyon 10 (2024): e25400.

[302] S. Bordbar, Z. Li, N. Lotfibakhshaiesh, et al., “Cartilage Tissue Engineering Using Decellularized Biomatrix Hydrogel Containing TGF-β-Loaded Alginate Microspheres in Mechanically Loaded Bioreactor,” Scientific Reports 14 (2024): 11991.

[303] Z. Zhang, S. Lin, Y. Yan, X. You, H. Ye, “Enhanced Efficacy of Transforming Growth Factor-β1 Loaded an Injectable Cross-Linked Thiolated Chitosan and Carboxymethyl Cellulose-Based Hydrogels for Cartilage Tissue Engineering,” Journal of Biomaterials Science, Polymer Edition 32 (2021): 2402-2422.

[304] E. Kalvand, H. Bakhshandeh, S. Nadri, M. Habibizadeh, K. Rostamizadeh, “Poly-ε-Caprolactone (PCL)/Poly-l-Lactic Acid (PLLA) Nanofibers Loaded by Nanoparticles-Containing TGF-β1 With Linearly Arranged Transforming Structure as a Scaffold in Cartilage Tissue Engineering,” Journal of Biomedical Materials Research. Part A 111 (2023): 1838-1849.

[305] Y. Li, Y. Liu, Q. Guo, “Silk Fibroin Hydrogel Scaffolds Incorporated With Chitosan Nanoparticles Repair Articular Cartilage Defects by Regulating TGF-β1 and BMP-2,” Arthritis Research & Therapy 23 (2021): 50.

[306] M. Sarsenova, Y. Raimagambetov, A. Issabekova, et al., “Regeneration of Osteochondral Defects by Combined Delivery of Synovium-Derived Mesenchymal Stem Cells, TGF-β1 and BMP-4 in Heparin-Conjugated Fibrin Hydrogel,” Polymers 14 (2022): 5343.

[307] F. Dehghani Nazhvani, L. Mohammadi Amirabad, A. Azari, et al., “Effects of in Vitro Low Oxygen Tension Preconditioning of Buccal Fat Pad Stem Cells on in Vivo Articular Cartilage Tissue Repair,” Life Sciences 280 (2021): 119728.

[308] S. Zhang, Y. Yao, “The Role of Mechanical Regulation in Cartilage Tissue Engineering,” Current Stem Cell Research & Therapy 16 (2021): 939-948.

[309] H. A. Abusharkh, O. M. Reynolds, J. Mendenhall, et al., “Combining Stretching and Gallic Acid to Decrease Inflammation Indices and Promote Extracellular Matrix Production in Osteoarthritic Human Articular Chondrocytes,” Experimental Cell Research 408 (2021): 112841.

[310] M. Sani, R. Hosseinie, M. Latifi, et al., “Engineered Artificial Articular Cartilage Made of Decellularized Extracellular Matrix by Mechanical and IGF-1 Stimulation,” Biomaterials Advances 139 (2022): 213019.

RIGHTS & PERMISSIONS

2025 The Author(s). MedComm published by Sichuan International Medical Exchange & Promotion Association (SCIMEA) and John Wiley & Sons Australia, Ltd.