Stem Cell Therapy for Osteoarthritis

Osteoarthritis (OA) is a debilitating joint disorder characterized by excessive stiffness, joint pain, crepitus, and erosion of articular cartilage.1 With a multifactorial etiology, OA is considered the product of a combination of systemic and local factors. According to a study by Zhang et al, systemic risk factors include age, gender, ethnicity, bone density, hormonal levels, and diet, while local risk factors include obesity, joint injury, joint deformity, muscle weakness, and participation in sports.Additionally, OA is the most common joint disorder in the United States and the most common reason for total hip and total knee replacement surgery.3 At the global scale, OA is projected to affect 130 million people by 2050, of which 40 million will develop severe OA.2 With this in mind, the continued development of more effective therapeutic approaches – such as stem cell therapy – is necessary to mitigate the social burden and economic pressures presented by OA.  

Patients with OA experience a loss in tensile and shear strength in the cartilage due to the degradation of collagen and proteoglycan networks. Though OA is commonly associated with a loss of articular cartilage, it also affects all tissues of the joint, particularly the subchondral bone.4 The pathogenesis of OA entails increased accumulation of advanced glycation end products (AGEs), oxidative stress, and senescence-related phenotypes, which reduce the healing properties of cartilage and adversely affect the osteoarthritic microenvironment. Aging also leads to thinning of cartilage and decreased water content due to deleterious effects on the extracellular matrix and chondrocytes – which normally synthesize proteglycans.5 Lastly, the synthesis of irregular and small aggrecans downregulates the response of chondrocytes to cytokines and impairs the structural integrity of cartilage.6 Overall, a variety of age-related and metabolic factors can disrupt articular tissues and initiate or exacerbate OA. 

Current methods for managing OA include awareness, prevention, diagnosis, non-pharmacological and pharmacological treatments. When non-pharmacological strategies fail, pharmacological treatments – such as NSAIDs, opioids, and surgery – are employed. Unfortunately, traditional and current surgical treatments are limited and incapable of reversing the progression of OA.7 Therefore, cell-based therapies must be employed to repair and regenerate articular tissues. Intra-articular administration of pluripotent and various multipotent mesenchymal stem cells represents a promising therapy due to the potential to differentiate towards a chondrogenic lineage. Additionally, supplementation with growth factors allows stem cells to achieve high healing responses in osteoarthritic cartilage.8 Recent developments in tissue engineering make it possible to exploit the multilineage potential of stem cells to mimic the process of cartilage synthesis both in vivo and in vitro; in patients with OA, this approach can be used to regenerate damaged cartilage.  

The efficacy of cell-based therapies depends not only on the source and type of stem cell, but also on environmental conditions, growth factors, and chemical and mechanical stimuli. Researchers have explored several types of stem cells for cartilage regeneration, including embryonic stem cells, induced pluripotent stem cells, mesenchymal stem cells, bone marrow-derived stem cells, adipose-derived stem cells, and synovium-derived stem cells (SMSCs). Most recently, SMSCs catapulted to the forefront of cell-based OA therapy due to their regenerative chondrogenic capabilities.8 In a rat knee OA model, for example, injected SMSCs migrated to the synovium and retained their undifferentiated properties while also displaying increased genetic expression of chondroprotective proteins, such as BMP-2 and TSG-6. Amazingly, this suggests the ability of SMSCs to retain their MSC characteristics and inhibit the advancement of OA through specified genetic expression.9 Additional studies in pig knee joint models provide further evidence for the application of SMSCs to treat OA.10 Thus, cell-based therapies represent a promising approach for treating OA and mitigating its social and economic burdens.  

1) Elders M. J. The increasing impact of arthritis on public health. The Journal of Rheumatology Supplement. 2000;60:6–8. 

2) Zhang, Yuqing, and Joanne M Jordan. Epidemiology of osteoarthritis. Clinics in geriatric medicine vol. 26,3 (2010): 355-69.  

3) DeFrances CJ, Podgornik MN. 2004 National Hospital Discharge Survey. Adv Data. 2006;371:1–19. 

4) Setton L. A., Elliott D. M., Mow V. C. Altered mechanics of cartilage with osteoarthritis: human osteoarthritis and an experimental model of joint degeneration. Osteoarthritis and Cartilage. 1999;7(1):2–14.  

5) Buckwalter J., Martin J., Mankin H. Synovial joint degeneration and the syndrome of osteoarthritis. Instructional Course Lectures. 2000;49:481–489. 

6) Martin J., Buckwalter J. The role of chondrocyte–matrix interactions in maintaining and repairing articular cartilage. Biorheology. 2000;37(1-2):129–140. 

7) Hunter D. J., Felson D. T. Osteoarthritis. BMJ. 2006;332(7542):639–642. 

8) Dubey, N. K., Mishra, V. K., Dubey, R., Syed-Abdul, S., Wang, J. R., Wang, P. D., & Deng, W. P. (2018). Combating Osteoarthritis through Stem Cell Therapies by Rejuvenating Cartilage: A Review. Stem cells international2018, 5421019. 

9) Ozeki N., Muneta T., Koga H., et al. Not single but periodic injections of synovial mesenchymal stem cells maintain viable cells in knees and inhibit osteoarthritis progression in rats. Osteoarthritis and Cartilage. 2016;24(6):1061–1070.  

10) Hatsushika D., Muneta T., Nakamura T., et al. Repetitive allogeneic intraarticular injections of synovial mesenchymal stem cells promote meniscus regeneration in a porcine massive meniscus defect model. Osteoarthritis and Cartilage. 2014;22(7):941–950.