Mesenchymal Stem Cell Therapy in Osteoarthritis and Regenerative Medicine

Introduction 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. 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). 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). 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 sig