Technology Insight: Adult Mesenchymal Stem Cells for Osteoarthritis Therapy

Ulrich Nöth; Andre F. Steinert; Rocky S. Tuan

Nat Clin Pract Rheumatol. 2008;4(7):371-380.

Summary and Introduction

Summary

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.

Introduction

Osteoarthritis (OA), the most common form of joint disease, is characterized by degeneration of the articular cartilage and, ultimately, joint destruction.^[1] Currently, OA is a major cause of disability in the elderly; the prevalence of this disease is expected to increase dramatically over the next 20 years with an increasingly aged population.^[2] The burden of OA is exacerbated by the inadequacies of current therapies. Nonpharmacologic and pharmacologic treatments are used for early and moderately early cases of OA, but protection of articular cartilage has so far not been convincingly shown.^[3,4] Surgical intervention is often indicated when the symptoms cannot be controlled and the disease progresses.^[5] Whether arthroscopic lavage and/or debridement can provide symptomatic relief is unclear.^[6] Methods for the repair of articular cartilage lesions include the transplantation of osteochondral grafts, microfracturing, and autologous chondrocyte implantation, with or without the assistance of a scaffold matrix to deliver the cells;^{[7,8,9,10,11,12]} however, all of these techniques are limited to the repair of focal lesions.^[13] Consequently, patients with OA are currently excluded from these treatments. In the case of joint malalignment,^[14] osteotomy can provide pain relief for several years, until the new weight-bearing articular cartilage erodes, but this tactic merely buys time until a total knee replacement becomes necessary. The challenge for researchers to develop disease-modifying OA treatments is, therefore, of paramount importance.

Adult mesenchymal stem cells (MSCs), which have the ability to differentiate into cells of the chondrogenic lineage, have emerged as a candidate cell type with great potential for cell-based articular cartilage repair technologies. MSCs can be isolated from a variety of adult tissues, readily culture-expanded without losing their multilineage differentiation potential, and have been induced to undergo chondrogenic differentiation in vitro and in vivo.^[15,16,17] Unlike chondrocytes, the use of MSCs is not hindered by the limited availability of healthy articular cartilage or an intrinsic tendency of the cells to lose their phenotype during expansion. The use of MSCs also obviates the need for a cartilage biopsy and, thereby, avoids morbidity caused by damage to the donor-site articular surface.

In this Review, we will discuss current MSC-based strategies for the treatment of OA. We first address the etiopathophysiology of OA and the mechanisms responsible for breakdown of the cartilage extracellular matrix. We then discuss the potential of MSCs for articular cartilage repair in patients with OA, with particular respect to the chondrogenic differentiation potential of MSCs, and review the currently used experimental strategies (intra-articular injection, matrix-guided technologies, and gene therapy). An example of the repair of articular cartilage defects by use of a hydrogel seeded with MSCs is presented, to highlight the current strategies, limitations and perspectives of using MSCs to treat OA.

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