Regulating the Regulators of Chondrocyte Hypertrophy

THE DEVELOPMENT, growth, and maintenance of a functional skeleton relies on the existence of several different types of chondrocytes with markedly different fates. The articular chondrocytes on the surface of joints are expected to persist throughout life, producing extracellular matrix components which provide a cushion to distribute load on bone at joints. In contrast, it is the changing dynamics of the underlying cartilage at the epiphyseal growth plate that permits a very different function: growth and development. Chondrocytes of this region undergo a series of changes including hypertrophy, release of extracellular matrix vesicles, and alterations in production of extracellular matrix proteins, prior to mineralization and replacement by bone. As chondrocytes progress toward terminal differentiation, morphological, and biosynthetic changes occur. Proliferating chondrocytes exit the cell cycle and become flattened before fully maturing into round, hypertrophic chondrocytes which secrete and organize a different extracellular matrix, characterized by high levels of alkaline phosphatase (ALP), diminished levels of collagens type II and IX, and production of a new hypertrophic chondrocytespecific product, type X collagen. In addition to normal bone formation during development of the skeleton, this process of endochondral ossification has also been implicated in fracture repair and such pathologic processes as osteoarthritis and ectopic bone formation. The fundamental importance of chondrocyte maturation in the growth, development, and repair of the skeleton has led to intense investigation of the growth factors that regulate terminal differentiation of chondrocytes. Although several growth factors have been indentified which regulate chondrocyte maturation, it remains unclear how these factors interact to coordinate the process leading to bone elongation and endochondral ossification. In this issue, Grismud and colleagues propose a role for bone morphogenetic protein-6 (BMP-6) as a positive regulator of chondrocyte maturation. Their report also provides insight into how parathyroid hormone-related protein (PTHrP) and indian hedgehog, other growth factors known to modulate chondrocyte hypertrophy, may interact with BMP-6 in the growth plate. BMPs belong to the transforming growth factor-b (TGFb) superfamily of secreted growth and differentiation polypeptides, which also includes activins, growth and differentiation factors, and Mullerian inhibiting substance. For over 30 years, it has been known that BMPs are capable of inducing the formation of new cartilage and bone when implanted extraskeletally. However, it was not until 1988 that three of the proteins involved (BMP2–4) were cloned. Although their name stresses their critical impact on the skeletal system, more than 20 members of the BMP family have been identified and determined to have a broader biological impact than just skeletogenesis. This impact includes establishment of basic embryonic patterning and growth and differentiation of nearly all body systems including the cardiovascular, gastrointestinal, respiratory, nervous, and urogenital systems and the integument (see review by Hogan). As their name implies, most BMPs can initiate new cartilage and bone formation in a cascade of events reminiscent of endochondral bone formation. BMP-2, BMP-4, BMP-5, and BMP-7 have all been shown to possess the ability to promote bone formation in vivo. Additional evidence with cultured cells also point to considerable overlap in BMP function; recombinant BMP-2, BMP-4, BMP-6, and BMP-7 have all been shown to induce both hypertrophy in cultured chondrocytes and osteogenesis from mesenchymal stem cells. However, information derived from BMP localization studies and null mutations in mice suggests more specific roles for individual BMPs in normal development. The temporal and spatial patterns of expression of BMPs in embryonic mouse forelimbs support roles for BMP-2, BMP-4, BMP-6, and BMP-7 in skeletal formation, and multiple BMPs, including BMP-2, BMP-4, BMP-6, and BMP-7, are produced by chondrocytes undergoing endochondral ossification. Recent detailed analysis of expression patterns for BMPs in the embryonic mouse humerus by Solloway et al. show that BMP-7 is expressed in both proliferating chondrocytes and the perichondrum, BMP-4 is found in chondrocytes of the transition zone immediately adjacent to the mature hypertrophic chondro-