Regulation of chondrocyte gene expression.

Extracellular influences known to affect the regulation of chondrocyte biosynthetic and catabolic activity have been shown to include soluble factors, extracellular matrix and mechanical stress. A balance of these numerous extracellular influences is required for normal function of articular cartilage. It is likely that OA is the result of an imbalance of regulatory influences, ultimately resulting in deleterious changes in gene expression, altered extracellular matrix (ECM) and tissue degeneration. Molecular signaling via soluble mediators has been shown to be crucial to cartilage homeostasis. A number of vitamins, hormones, growth/differentiation factors and cytokines have been implicated in chondrocyte differentiation and cartilage metabolism. During normal maintenance, as well as in aging and pathology, these soluble factors can significantly influence the physical properties and the function of cartilage. Chondrocytes, like cells in other tissues, exist within an information-rich extracellular environment consisting of ECM molecules, a milieu which interacts with and modulates the activity of growth factors, hormones and ECM remodeling enzymes. Cell surface matrix receptors, including a family of proteins known as integrins, connect structural information in the ECM to a complex cellular response mechanism in the cell's interior. Integrins on cell surfaces detect and transduce signals in a cooperative manner with other adhesion receptor classes and/or growth factor receptors. The effects of mechanical stress upon a number of chondrocyte biological parameters has been examined in several laboratories. Other investigations have addressed the mechanism by which mechanical force affects biochemical and biosynthetic processes in chondrocytes, in particular synthesis of aggrecan, a major component of the cartilage ECM. Each of these extracellular influences upon chondrocyte metabolism may affect regulation of chondrocyte ECM biosynthesis at many levels, including mRNA transcription, RNA splicing, nuclear transport, protein translation, post-translational modification, intracellular vesicular transport, and protein secretion. Transcriptional regulation of some of the major protein and proteoglycan components of the cartilage ECM has been examined in a number of species, and promoters have been characterized for aggrecan, link protein and collagen type II genes. There is evidence that gene expression may be altered in OA cartilage, providing clues as to which subsets of genes expressed in chondrocytes may be considered relevant to OA pathophysiology.