(Taken from the application): Cell proliferation is critical for tissue homeostasis and repair. Progressive hypocellularity of articular cartilage is a well recognized age-related phenomenon. This is associated with a reduced proliferative capacity in articular chondrocytes in older individuals. Chondrocyte loss is also a feature of osteoarthritis. These observations indicate that articular chondrocytes lack the requisite proliferative capability to effectively maintain cell numbers in response to age-related of pathological changes. However, articular chondrocytes are capable of considerable proliferative activity when isolated from cartilage matrix and cultured under appropriate in vitro conditions. The working hypothesis that follows from these observations is as follows: Specific factors within the articular cartilage milieu actively repress articular chondrocyte proliferative activity. This proposal addresses the issue of cell cycle control in articular chondrocytes by focusing on the expression and regulation of factors that intrinsically control proliferative activity during the G1 phase of the cell cycle. The critical cell cycle regulatory factors expressed by articular chondrocytes will be identified in experiments detailed in Specific Aim 1. Cell: matrix interactions significantly influence proliferative activity.
In Specific Aim 2, the changes in expression of cell cycle regulatory factors and the consequent effects on proliferative activity will be investigated in an in vitro model of cartilage formation. TGF-beta1 is of particular relevance to the hypothesis under investigation. It has potent anti-proliferative activities in a wide range of cell types and is present in comparatively high concentrations in cartilage. The experiments detailed in Specific Aim 3 will characterize the expression, secretion and bioactivity of TGF-beta1 in an in vitro model of cartilage formation. The effects of TGF-beta1 administration and sequestration on articular chondrocyte proliferation and on the expression of intrinsic cell cycle regulatory factors in this model will also be determined. The experiments described in this proposal will provide the conceptual and methodological bases for a comprehensive understanding of the molecular mechanisms of cell cycle regulation in articular chondrocytes. The long-term goal of this project is to identify critical regulatory factors that can be targeted to therapeutically modulate the intrinsic proliferative activity of articular chondrocyte in vivo.
|Stewart, Matthew C; Kadlcek, Renata M; Robbins, Paul D et al. (2004) Expression and activity of the CDK inhibitor p57Kip2 in chondrocytes undergoing hypertrophic differentiation. J Bone Miner Res 19:123-32|