Mesenchymal stem cells for cartilage repair in osteoarthritis

Abstract

Osteoarthritis (OA) is a degenerative disease of the connective tissue and progresses with age in the older population or develops in young athletes following sports-related injury. The articular cartilage is especially vulnerable to damage and has poor potential for regeneration because of the absence of vasculature within the tissue. Normal load-bearing capacity and biomechanical properties of thinning cartilage are severely compromised during the course of disease progression. Although surgical and pharmaceutical interventions are currently available for treating OA, restoration of normal cartilage function has been difficult to achieve. Since the tissue is composed primarily of chondrocytes distributed in a specialized extracellular matrix bed, bone marrow stromal cells (BMSCs), also known as bone marrow-derived 'mesenchymal stem cells' or 'mesenchymal stromal cells', with inherent chondrogenic differentiation potential appear to be ideally suited for therapeutic use in cartilage regeneration. BMSCs can be easily isolated and massively expanded in culture in an undifferentiated state for therapeutic use. Owing to their potential to modulate local microenvironment via anti-inflammatory and immunosuppressive functions, BMSCs have an additional advantage for allogeneic application. Moreover, by secreting various bioactive soluble factors, BMSCs can protect the cartilage from further tissue destruction and facilitate regeneration of the remaining progenitor cells in situ. This review broadly describes the advances made during the last several years in BMSCs and their therapeutic potential for repairing cartilage damage in OA.

Figure 1

Pathogenesis of osteoarthritis. Osteoarthritis is a progressively degenerative disease of multiple etiology in which injury and aging lead to gradual breakdown of articular cartilage. The pathogenesis is categorized by severe inflammation, recruitment of inflammatory cells, proinflammatory cytokine production, and activation of proteinases that results in extracellular matrix (ECM) degradation and ultimately apoptotic cell death of differentiated chondrocytes. IL, interleukin; MMP, matrix metalloproteinase; TNF-α, tumor necrosis factor-alpha.

Figure 2

Possible mechanisms operative in cartilage regeneration by mesenchymal stem cells. The anti-inflammatory and immunosuppressive properties of bone marrow stromal cells (BMSCs) ensure that these cells can reduce inflammation in the knee. Concurrently, BMSCs may initiate the repair process by differentiating into chondrocytes or by inducing proliferation and differentiation of the remaining healthy chondroprogenitos into mature chondrocytes or both. A whole host of transcription factors, biological modulators, and extracellular matrix proteins expressed or produced by BMSCs may play a pivotal role in enhancing neocartilage formation. The various factors implicated for cartilage tissue synthesis are depicted in this figure. BMP, bone morphogenic protein; FGF, fibroblast growth factor; Gli3, gliobastoma transcription factor 1; HoxA, homeobox protein A; IGF-1, insulin-like growth factor 1; IL, interleukin; PTHrP, parathyroid hormone-related protein; Runx2, Runt related transcription factor 2; SOX9, SRY (sex determining region Y)-box 9 gene; STAT 1, signal tranducers and activators of transcription factor 1; TGF-β, transforming growth factor-beta.