What makes the permanent articular cartilage permanent?

Articular cartilage functions by providing a specialized mechanically competent extracellular matrix to withstand load bearing, thus protecting the underlying bones and allowing their near friction-free articulation in the joints. The resident chondrocytes maintain this function throughout life and do so by retaining a stable phenotype that resists hypertrophy and vascular invasion from the bone. This articular phenotype is distinct from the chondrocytes that drive endochondral ossification, which undergo hypertrophy and apoptosis followed by vascularization and bone formation (1). Unfortunately, stem cells used for cartilage repair seem to have a similar fate, making the repair tissue inadequate for normal joint function (2). How the articular chondrocyte avoids this and maintains its specialized phenotype is one of the fundamentally important issues in skeletal biology, yet the mechanisms remain unclear. Recent studies, however, have begun to provide some much needed insights. Although different growth factors (including transforming growth factor family members, bone morphogenetic proteins, and fibroblast growth factor family members) are important in skeletal development, there is relatively little evidence that these molecules are endogenously produced in physiologically significant amounts by adult articular cartilage. However, Klinger and colleagues, whose article appears elsewhere in this issue of Arthritis & Rheumatism (3), have identified a critical role for secreted matrix protein chondromodulin 1 in stabilizing the chondrocyte phenotype and inhibiting vascular invasion and endochondral ossification in stem cell–mediated articular cartilage repair (3). In their study, using a miniature pig model of cartilage repair, chondromodulin 1 was overexpressed in osteochondral progenitor cells (cells infected with adeno-associated virus vectors carrying chondromodulin 1 complementary DNA [AAV-Chm-1]), or AAV-Chm-1 vectors were directly administered to cartilage defects undergoing microfracture to induce repair. In both cases of chondromodulin 1 treatment, elaboration of a type II collagen–rich matrix was seen at 6 weeks, and most importantly, the tissue resisted calcification and vascular invasion over an extended experimental period (6 months). When progenitor cells were administered to cartilage defects with intact subchondral bone, although little calcification was observed, the repair tissue was fibrocartilaginous, with strong staining for type I collagen and less staining for type II collagen compared to the equivalent chondromodulin 1 treatment. Chondromodulin 1 has been shown to have antiangiogenic properties (4), but its mechanism of action is far from fully elucidated. Since Klinger and colleagues found no effect of chondromodulin 1 overexpression on VEGF mRNA levels, it appears not to inhibit this key angiogenic factor, at least in vitro. However, the situation in vivo is liable to be far more complex, and it will be of great interest to assess the levels of VEGF in chondromodulin 1–treated cartilage repair tissue. Klinger and colleagues also suggest that chondromodulin 1 prevents chondrocyte hypertrophy through suppression of type X collagen in cultured osteochondral progenitor cells. This in vitro finding must now be investigated in vivo, and it will also be of great interest to investigate if runt-related transcription factor 2 (RUNX-2) is down-regulated by chondromodulin 1, since this transcription factor plays an important role in endochondral ossification through regulation of type X collagen and induction of VEGFA (5,6). The role of SOX9 in this process should also be investigated further. SOX9 has been shown to be essential for early events in cartilage differentiation (7) and for expression of the cartilage-specific matrix genes in human articular chondrocytes (8). Moreover, mutations in SOX9 cause the severe skeletal abnormality of campomelic dysplasia (9). Interestingly, however, SOX9 is greatly down-regulated as chondrocytes undergo hyperChris L. Murphy, PhD: The Kennedy Institute and Imperial College London, London, UK. Address correspondence to Chris L. Murphy, PhD, The Kennedy Institute of Rheumatology, Faculty of Medicine, Imperial College London, 1 Aspenlea Road, London W6 8LH, UK. E-mail: c.murphy@imperial.ac. uk. Submitted for publication February 4, 2011; accepted in revised form March 1, 2011.