Secondary Logo

Journal Logo

Mesenchymal Stem Cell Therapy in Osteoarthritis and Regenerative Medicine

Freitag, Julien, MBBS, BMedSci, FACSEP1,2; Kenihan, Michael Austin, Dip Tech Phys, FASMF, FFIMS2

doi: 10.1249/JSR.0000000000000541
International Federation of Sports Medicine: FIMS International Perspectives

1Charles Sturt University, Melbourne, Victoria, Australia; and

2Melbourne Stem Cell Centre, Magellan Stem Cells, Melbourne, Victoria, Australia

Address for correspondence: Michael Austin Kenihan, Dip Tech Phys, FASMF, FFIMS, Melbourne Stem Cell Centre, Melbourne, Victoria, Australia; E-mail;

Back to Top | Article Outline


Stem cell therapy is seen as a potential new approach to the treatment of a range of chronic disease states. This perspective will discuss progress being made with the use of mesenchymal stem cells for the treatment of osteoarthritis (OA) with particular reference to current studies and the published literature to assess the potential of this emerging area of medicine.

Back to Top | Article Outline

Etiology of OA Disease

Osteoarthritis is a progressive and painful disease with multifactorial etiopathogenesis. As OA progresses, observed structural changes include loss of cartilage thickness, subchondral sclerosis, periarticular bone formation and soft tissue changes including synovitis. Simplistically, the underlying pathobiology of OA can be regarded as an imbalance between proinflammatory catabolic and anabolic reparative pathways with a cytokine imbalance skewed toward proinflammatory molecules that include interleukin (IL)-1 and tumor necrosis factor (TNF). This cytokine imbalance activates proteolytic degradative enzymes that override normal repair processes, leading to the destruction of cartilage. This leads to synovitis, degeneration of articular cartilage, loss of extracellular matrix, and ultimately complete loss of the cartilage surface accompanied by progressive pain and functional impairment.

Osteoarthritis is a highly prevalent condition in the Western world with up to 80% of people over the age of 65 years showing radiological evidence of OA. Symptomatic OA affects 10% of males and 18% of females over the age of 45 years (1–4). The prevalence is expected to significantly increase given the increasing proportion of older people in the population (1,2). Osteoarthritis is considered the fourth leading cause of disability worldwide and is an important factor effecting disability-adjusted life years (5,6). It is estimated that 130 million individuals will be affected by OA globally, of which 40 million will develop severe OA (7). In addition, OA disease remains a significant problem for the aging sporting population and further options for treatments need to be explored.

The articular cartilage has a low capacity for self-healing and the clinical utility of traditional surgical treatment is currently limited and incapable of reversing the degenerative process. Considering these limitations, new methods, including cell-based therapies, may be an alternative with potential to regenerate the structure and function of articular tissues (8).

Back to Top | Article Outline

Mesenchymal Stem Cells

Hemopoietic stem cells (HSC) have had remarkable clinical success for many decades, and thus serve as an important proof of concept for cell-based therapies. The next form of stem cells most likely to provide clinical improvements are broadly termed “mesenchymal stem cells” (MSCs) also known as “mesenchymal stromal cells.” The latter definition is more appropriate because of the common heterogeneity of the cells. MSCs have the capacity to differentiate along mesodermal cell lines, including adipocytes, osteoblasts, and chondrocytes (9–11). The presence of MSCs throughout the body suggests an intrinsic role in tissue repair and regeneration.

In vitro studies have successfully shown the ability of MSCs to differentiate along a chondrogenic path with TGFβ and insulin-like growth factor-1 (IGF-1) acting synergistically to stimulate chondrogenesis among MSCs (12,13). Importantly, the expression of collagen type 2 and proteoglycans associated with hyaline cartilage are similar in in vitro MSC-derived chondrocytes to mature adult chondrocytes indicating the potential of MSC chondrocytes to create cartilage which exhibits similar load-bearing properties to native cartilage (13). Although initial interest in the potential role MSCs may have in joint repair was based upon evidence of their ability to differentiate into both cartilage and bone, it is now apparent that this may not be their sole path of action and disease modification.

Although MSCs may have the potential to influence joint repair through direct differentiation into chondrocytes, MSCs also have been observed to influence the local environment and tissue repair through the secretion of essential reparative cytokines (including TGFβ, VEGF, EGF) and an array of bioactive trophic molecules (14–16). This reparative pathway is supported by analysis of mRNA levels within cartilage chondrocytes present at end stage arthritis indicating that endogenous cells are not inert and remain metabolically active and able to synthesize cartilage proteins in response to trophic cytokine stimulus.

Further to their role in the trophic stimulation of native chondrocytes, MSCs are observed to directly modulate the pro-inflammatory environment of arthritis by suppression of inflammatory cell proliferation and inhibition of monocyte and myeloid dendritic cell maturation resulting in an immunomodulatory and anti-inflammatory effect (17). This immunomodulatory mechanism raises potential for their use in both autoimmune-mediated inflammatory conditions including inflammatory arthropathies but also OA where there is an increasing understanding of the role of inflammation in progressive joint degeneration (18).

In a number of nonclinical and clinical studies, intra-articular injections (IA) of MSCs have resulted in improvements in pain and function. Importantly, recent studies in humans have shown disease modification following MSC injections, with stabilization of arthritis and cartilage regrowth observed (19–23).

Back to Top | Article Outline

Clinical Trials and Safety

Systematic review of clinical trials involving both autologous and allogeneic MSC therapies has indicated safety following either intravascular or IA injections (24,25). A recent meta-analysis of trials involving a total of 1012 participants receiving intravascular MSC therapy for various clinical conditions including ischemic stroke, Crohn’s disease, cardiomyopathy, ischemic heart disease, and graft versus host disease, with the longest follow-up to 92 months, identified no significant adverse events other than transient self-limiting fever (24). Systematic review of eight clinical studies involving the use of IA injections (into joints — knees, hips, foot/ankle, shoulder, hand/wrist, elbow) of autologous bone marrow-derived expanded MSCs in a total of 844 procedures, with a mean follow-up of 21 months, showed no association with adverse events such as infection, death, or malignancy (25).

Unfortunately, methods to achieve isolated autologous MSC therapies are both labor-intensive and costly, and therefore limit their application within medicine. Due to a lack of expression of immune relevant surface markers (MHC class II) and costimulatory molecules (26) allogeneic MSCs are considered immune “evasive” (27), and consequently are regarded as safe to use in genetically unrelated and unmatched recipients (24). This suggests that allogeneic MSC therapies could be beneficial in patients with various disorders requiring tissue regeneration, and such treatments may be logistically more convenient and achieved at a fraction of the cost that would be required to harvest, isolate, and expand cell populations for an individual patient within the autologous setting.

Back to Top | Article Outline

Nonclinical Overview

Mesenchymal stem cells have the dual capacities of being able to readily convert to “structural cells,” such as muscle, bone, chondrocytes (cartilage), fat, and nerve tissue but they also exhibit potent immunosuppressive, anti-inflammatory, and trophic properties. In the body, MSCs regulate the level of inflammation (at least some of which is essential for repair) and promote endogenous repair. Although this is often successful de novo, the MSC number and probable function at the site of injury or disease is frequently insufficient to affect full or even partial recovery.

Mesenchymal stem cells have consistently been shown to not induce allogeneic rejection in humans and in animal models (28). These findings are supported by in vitro coculture studies indicating that three broad mechanisms contribute to this effect. First, MSCs are hypoimmunogenic often lacking MHC-II and co-stimulatory molecule expression. Secondly, these stem cells prevent T cell responses indirectly through modulation of dendritic cells and directly by disrupting natural killer (NK) cells as well as CD8+ and CD4+ T-cell function. Third, MSCs induce a suppressive local microenvironment through the production of prostaglandins and IL-10 as well as by the expression of indoleamine 2,3-dioxygenase which depletes the local milieu of tryptophan. Comparison is made to maternal tolerance of the fetal allograft and contrasted with the immune evasion mechanisms of tumor cells (28). Mesenchymal stem cells are a highly regulated self-renewing population of cells with potent mechanisms to avoid allogeneic rejection — they have been termed immune “evasive” and hence offer potential in the treatment of unmatched recipients.

Positive data from nonclinical studies has prompted a 50% increase in the number of registered clinical trials assessing the use of MSCs in the treatment of numerous conditions between 2013 and 2017.

Back to Top | Article Outline

Clinical Overview

Importantly, preclinical evidence of the beneficial role of MSC therapies in arthritis has been reflected by early clinical trials. Early Phase I and II trials using expanded and isolated adipose-derived MSCs in the treatment of OA have shown both radiological evidence of cartilage regeneration and also significant pain and functional improvement (29). Similarly, the use of allogeneic bone marrow–derived MSCs has been associated with symptomatic and radiological improvements at 12 months of follow-up (23).

Our group has demonstrated the clinical efficacy of autologous adipose-derived MSCs in the treatment of isolated chondral defects (30,31). Long-term follow-up showed consistent improvement in pain and function as measured by the Knee Injury and Osteoarthritis Outcome score (KOOS), Western Ontario McMaster Universities Arthritis Index (WOMAC) score and the Numeric Pain rating scale (NPRS). Structural outcomes with follow up magnetic resonance imaging (MRI) showed significant cartilage regeneration. The use of the novel noninvasive cartilage quality assessment of MRI T2 mapping showed consistent values ≤40 through the deep and superficial areas of the regenerated tissue indicating normal hyaline cartilage morphology.

Based on our past results and experience with autologous adipose-derived MSC therapies in OA, our research team with support from Magellan Biologicals are conducting a Phase I/II allogeneic donor MSC ascending dose double blind study with an aim to demonstrate both safety and efficacy in the treatment of OA with donor cells. This promising development could move routine stem cells treatment for OA ever closer.

Back to Top | Article Outline

Concluding Remarks

The field of regenerative medicine is growing and showing increasing potential. Should more studies show clinical efficacy with patients suffering with OA in particular, a new field of therapy will open for such people. This will assist in reducing the significant financial burden and patient morbidity experienced with this and potentially other degenerative diseases.

Back to Top | Article Outline


1. United Nations. World population to 2300. [cited 2018 June 3.] Available from:
2. Dubey NK, Mishra VK, Dubey R, et al. Combating osteoarthritis through stem cell therapies by rejuvenating cartilage: a review. Stem Cells Int. 2018; 2018:5421019. doi: 10.1155/2018/5421019.
3. Zhou S, Eid K, Glowacki J. Cooperation between TGF-beta and Wnt pathways during chondrocyte and adipocyte differentiation of human marrow stromal cells. J. Bone Miner. 2004; 19:463–70.
4. Longobardi L, O’Rear L, Aakula S, et al. Effect of IGF-I in the chondrogenesis of bone marrow mesenchymal stem cells in the presence or absence of TGF-beta signalling. J. Bone Miner. 2016; 21:626–36.
5. Caplan AI, Correa D. The MSC: an injury drugstore. J. Cell Stem Cells. 2011; 9:11–5.
6. Nakagami H, Morishita R, Maeda K, et al. Adipose tissue-derived stromal cells as a novel option for regenerative cell therapy. J. Atheroscler. Thromb. 2006; 13:77–81.
7. Caplan A. Mesenchymal stem cells. J. Orthop. Res. 1991; 9:641–50.
8. Caplan A. Why are MSCs therapeutic? New data: new insight. J. Pathol. 2009; 217:318–24.
9. Djouad F, Bouffi C, Ghannam S, et al. Mesenchymal stem cells: innovative therapeutic tools for rheumatic diseases. Nat. Rev. Rheumatol. 2009; 5:392–9.
10. Pak J. Regeneration of human bones in hip osteonecrosis and human cartilage in knee osteoarthritis with autologous adipose-derived stem cells: a case series. J. Med. Case. 2011; 5:296.
11. Kuroda R, Ishida K, Matsumoto T, et al. Treatment of a full-thickness articular cartilage defect in the femoral condyle of an athlete with autologous bone-marrow stromal cells. Osteoarthr. Cartil. 2007; 15:226–31.
12. Saw KY, Anz A, Siew-Yoke JC, et al. Articular cartilage regeneration with autologous peripheral blood stem cells versus hyaluronic acid: a randomised controlled trial. Art Ther. 2013; 29:684–94.
13. Vangsness CT, Farr J, Boyd J, et al. Adult human mesenchymal stem cells delivered via intra-articular injection to the knee following partial medial meniscectomy. J. Bone Joint Surg. 2014; 96:90–8.
14. Vega A, Martin-Ferrero MA, Del Canto F, et al. Treatment of knee osteoarthritis with allogeneic bone marrow mesenchymal stem cells: a randomized controlled trial. Transplantation. 2015; 19:1681–90.
15. Lalu ML, McIntyre L, Pugliese C, et al. Safety of cell therapy with mesenchymal stromal cells (safe cell): a systematic review and meta-analysis of clinical trials. PLoS One. 2012; 7:e47559.
16. Peeters CM, Leijs MJ, Reijman M, et al. Safety of intra-articular cell-therapy with culture-expanded stem cells in humans: a systematic literature review. Osteoarthritis Cartilage. 2013; 21:1465–73.
17. Niemeyer P, Seckinger A, Simank HG, et al. Allogenic transplantation of human mesenchymal stem cells for tissue engineering purposes: an in vitro study. Der. Orthopade. 2004; 33:1346–53.
18. Ankrum JA, Ong JF, Karp JM. Mesenchymal stem cells: immune evasive, not immune privileged. Nat. Biotechnol. 2014; 32:252–60.
19. Ryan JM, Barry FP, Murphy JM, et al. Mesenchymal stem cells avoid allogeneic rejection. J. Inflamm. 2005; 2:8.
20. Jo CH, Lee YG, Shin WH, et al. Intra-articular injection of mesenchymal stem cells for the treatment of osteoarthritis of the knee: a proof of concept clinical trial. Stem Cells. 2014; 32:1254–66.
21. Freitag J, Li D, Wickham J, et al. Effect of autologous adipose-derived mesenchymal stem cell therapy in the treatment of a post-traumatic chondral defect of the knee. BMJ Case Reports. 2017; 1136/bcr-2017-220852.
22. Freitag J, Shah K, Wickham J, et al. The effect of autologous adipose derived mesenchymal stem cell therapy in the treatment of a large osteochondral defect of the knee following unsuccessful surgical intervention of osteochondritis dissecans—a case study. BMC Musculoskelet. Disord. 2017; 18:298.
23. Peat G, McCarney R, Croft P. Knee pain and osteoarthritis in older adults: a review of community burden and current use of primary health care. Ann. Rheum. Dis. 2001; 60:91–7.
24. Gupta S, Hawker GA, Laporte A, et al. The economic burden of disabling hip and knee osteoarthritis (OA) from the perspective of individuals living with this condition. Rheumatology. 2005; 44:1531–7.
25. Issa S, Sharma L. Epidemiology of osteoarthritis: an update. Curr. Rheumatol. Rep. 2006; 8:7–15.
26. Zhou Q, Yang W, Chen J, et al. Metabolic syndrome meets osteoarthritis. Nat. Rev. Rheumatol. 2012; 8:729–37.
27. Fransen M, Bridgett L, March L, et al. The epidemiology of osteoarthritis in Asia. Int. J. Rheum. Dis. 2011; 14:113–21.
28. Brooks Peter M. Impact of osteoarthritis on individuals and society: how much disability? Social consequences and health economic implications. Curr. Opin. Rheumatol. 2002; 14:573–7.
29. Barry FP, Murphy JM. Mesenchymal stem cells: clinical applications and biological characterization. Int. J. Biochem. Cell Biol. 2004; 36:568–84.
30. Arinzeh TL. Mesenchymal stem cells for bone repair: preclinical studies and potential orthopaedic applications. Foot Ankle Clin. 2005; 10:651–65.
31. Noel D, Djouad F, Jorgense C. Regenerative medicine through mesenchymal stem cells for bone and cartilage repair. Curr. Opin. Investig. Drugs. 2002; 3:1000–4.
Copyright © 2018 by the American College of Sports Medicine.