Ryan James

Background:  Osteoarthritis (OA) is the most common degenerative disease seen in the world, with women being up to 40% more likely to develop the disease.¹ The activation of cytokines and matrix metalloproteinases (MMPs) are directly responsible for the destruction of cartilage tissue in OA.^1,2 In OA, proinflammatory cytokines such as IL-1β increase in levels and cause the release of matrix metalloproteinases (MMPs) which inhibit the expression of cartilage ECM component.¹ The exact pathogenesis of OA is not completely understood, which greatly increases the challenge of finding effective treatments. Common pharmacological treatments and prevention include NSAIDs or Duloxetine (SNRI) to help reduce pain, the current surgical option would be a total joint replacement.¹ Current treatments mainly focus on alleviating pain and do not offer any mechanistic way of reversing the damage done in OA. Recent research has explored mesenchymal stem cells (MSCs) as a potential treatment for OA. MSCs are pluripotent progenitor cells with the potential to differentiate into the damaged tissue that needs to be replaced in OA.³

Objective: In this narrative review we explore the use of MSCs for their anti-inflammatory and immunomodulatory properties to hinder and even reverse the tissue damage in OA.

Search methods:  An online search in the PubMed database from 2019 to 2024 was carried out with the following keywords: “Osteoarthritis”, “mesenchymal stem cells”, “mesenchymal stem cell-derived exosome”, “NF-Kβ pathway”, and “inflammatory response”.

Results:  Studies showed that unmodified Human adipose MSCs injected into osteoarthritic knees resulted in the reversal of damage and an average cartilage volume increase of 124mm³ over 72 weeks.⁴ This demonstrated the potential use of MSCs for future treatment of OA. Exosomes from MSCs inhibit the NF-Kβ pathway by interfering with the migration of p65.⁵ Once the exosomes are internalized there is a significant reduction in gene expression of IL-6, IL-8, and MCP-1 in both chondrocytes and synoviocytes.⁵ Pretreating MSCs with IL-1β caused the expression of a new combination of miRNA with chondro-protective properties on derived exosomes.⁶ IL-1β preconditioning caused upregulation of 7 miRNAs, downregulation of 4, 37 activated, and 17 silenced.⁶ The pretreated exosomes also displayed an increased speed of penetrance over 16 hours when injected into cartilage, especially in collagen-rich areas.⁶ SW982 cells exposed to IL-1β pretreated exosomes displayed low levels of IL-1β, IL-6, MCP-1, and elevated levels of SOCS3 and SOCS6.⁷ OA patients injected with MSC-derived exosomes that overexpress miR-136-5p resulted in the reduced expression of ELF3 and MMP-13, and increased expression of collagen type II, aggrecan, and SOX 9.⁸ Overall this results in the proliferation and migration of chondrocytes.^4-8

Conclusion:  Studies found that MSC-based osteoarthritis treatment focuses on properly modulating inflammatory cytokines in the affected tissues and reversing the damage done. Current therapies for osteoarthritis are short-term, come with severe side effects, or require invasive surgery. The research into MSC-derived exosomes and various pre-conditioning methods of mesenchymal stem cells is making drastic steps toward the treatment of OA. Further clinical trials exploring the combination of the above-stated mechanisms are particularly promising.

Work Cited:

1. Kim YG, Choi J, Kim K. Mesenchymal Stem Cell-Derived Exosomes for Effective Cartilage Tissue Repair and Treatment of Osteoarthritis. Biotechnol J. 2020;15(12):e2000082. doi:10.1002/biot.202000082
2. Giorgino R, Albano D, Fusco S, Peretti GM, Mangiavini L, Messina C. Knee Osteoarthritis: Epidemiology, Pathogenesis, and Mesenchymal Stem Cells: What Else Is New? An Update. Int J Mol Sci. 2023;24(7):6405. Published 2023 Mar 29. doi:10.3390/ijms24076405
3. Zhu C, Wu W, Qu X. Mesenchymal stem cells in osteoarthritis therapy: a review. Am J Transl Res. 2021;13(2):448-461. Published 2021 Feb 15.
4. Song Y, Du H, Dai C, et al. Human adipose-derived mesenchymal stem cells for osteoarthritis: a pilot study with long-term follow-up and repeated injections. Regen Med. 2018;13(3):295-307. doi:10.2217/rme-2017-0152
5. Cavallo C, Merli G, Borzì RM, et al. Small Extracellular Vesicles from adipose derived stromal cells significantly attenuate in vitro the NF-κB dependent inflammatory/catabolic environment of osteoarthritis. Sci Rep. 2021;11(1):1053. Published 2021 Jan 13. doi:10.1038/s41598-020-80032-7
6. Colombini A, Ragni E, Mortati L, et al. Adipose-Derived Mesenchymal Stromal Cells Treated with Interleukin 1 Beta Produced Chondro-Protective Vesicles Able to Fast Penetrate in Cartilage. Cells. 2021;10(5):1180. Published 2021 May 12. doi:10.3390/cells10051180
7. Kim M, Shin DI, Choi BH, Min BH. Exosomes from IL-1β-Primed Mesenchymal Stem Cells Inhibited IL-1β- and TNF-α-Mediated Inflammatory Responses in Osteoarthritic SW982 Cells. Tissue Eng Regen Med. 2021;18(4):525-536. doi:10.1007/s13770-020-00324-x
8. Chen X, Shi Y, Xue P, Ma X, Li J, Zhang J. Mesenchymal stem cell-derived exosomal microRNA-136-5p inhibits chondrocyte degeneration in traumatic osteoarthritis by targeting ELF3. Arthritis Res Ther. 2020;22(1):256. Published 2020 Oct 27. doi:10.1186/s13075-020-02325-6
9. Al-Ghadban S, Bunnell BA. Adipose Tissue-Derived Stem Cells: Immunomodulatory Effects and Therapeutic Potential. Physiology (Bethesda). 2020;35(2):125-133. doi:10.1152/physiol.00021.2019