Ulrich Nöth; Andre F. Steinert; Rocky S. Tuan
07/03/2008; Nat Clin Pract Rheumatol. 2008;4(7):371-380. © 2008 Nature Publishing Group
Despite the high prevalence and morbidity of osteoarthritis (OA), an effective treatment for this disease is currently lacking.
Restoration of the diseased articular cartilage in patients with OA is, therefore, a challenge of considerable appeal to researchers and clinicians. Techniques that cause multipotent adult mesenchymal stem cells (MSCs) to differentiate into cells of the chondrogenic lineage have led to a variety of experimental strategies to investigate whether MSCs instead of chondrocytes can be used for the regeneration and maintenance of articular cartilage. MSC-based strategies should provide practical advantages for the patient with OA.
These strategies include use of MSCs as progenitor cells to engineer cartilage implants that can be used to repair chondral and osteochondral lesions, or as trophic producers of bioactive factors to initiate endogenous regenerative activities in the OA joint. Targeted gene therapy might further enhance these activities of MSCs. Delivery of MSCs might be attained by direct intra-articular injection or by graft of engineered constructs derived from cell-seeded scaffolds; this latter approach could provide a three-dimensional construct with mechanical properties that are congruous with the weight-bearing function of the joint. Promising experimental and clinical data are beginning to emerge in support of the use of MSCs for regenerative applications.OA is associated with the loss of homeostasis in joint tissues, particularly in the articular cartilage and the underlying bone. An insufficient repair response in articular cartilage, which results from a reduction in cell number and the loss of phenotypic stability, is a major contributor to disease progression. Further investigation will determine whether the titers of existing MSCs -- both locally and throughout the body -- as well as the quality of these cells might be important in the rate and extent of the repair of the damaged tissue.
The delivery of an appropriate MSC population is currently being investigated in the search for new therapeutic approaches to treat OA. The principal attraction of MSCs lies in their proliferative and chondrodifferentiation abilities, since articular chondrocytes are in limited supply. Understanding the biological activities and mechanisms of action of MSCs is crucial for a rational approach to their clinical application; specifically, conditions must be optimized to maintain MSC-derived chondrocytes in a stable, hyaline, chondrocyte-like state, without hypertrophy. Although MSC-based approaches might be developed and adapted for the treatment of both localized cartilage lesions and diseased or degenerate cartilage, as in OA, these states should be recognized as different entities.
Although direct intra-articular injection of cells is considered a technically simple approach to treatment of advanced OA, whether this approach can elicit beneficial effects (such as minimizing further cartilage damage) in human OA joints remains to be seen -- and, if so, to what extent and under which conditions. The engineering design of matrix and scaffold material for cell-based articular cartilage repair has taken substantial strides, but the ideal scaffold material is still being sought, particularly for OA joints. Defects such as kissing lesions necessitate the design and engineering of new biomaterials that can be seeded with cells and can withstand significant mechanical loads. The use of MSCs in combination with bioactive substrates, natural or synthetic, also has significant clinical potential and is likely to be important in future, MSC-based, cartilage-repair technologies. In this context, MSCs might also offer promise in the future as vehicles for therapeutic gene delivery. In the long term, we hope that MSC-based technologies will permit the engineering of cartilage not only for repair of focal lesions but also as a treatment option for OA joints, to realize the ultimate goal of a fully biological prosthesis.