(Verbatim from the Applicant): We have developed and characterized an in vitro culture system that facilitates the chondrogenic differentiation of mammalian mesenchymal progenitor cells. We now propose to use the system to explore the stage of chondrogenesis involving progression from condensation to expression of cartilage extracellular matrix molecules. Recent evidence suggests a role for the MAP kinase pathways in controlling progression. Furthermore, the effects of p38 MAPK are similar to those seen with Wnt/beta-catenin signaling during chondrogenesis. Wnt pathways may be linked to the MAP kinases, and these combine to regulate progression. Wnts are a family of secreted proteins that appear to have important roles in development. Wnt involvement in chondrogenesis has been implied but it is unclear which Wnts are important. Modulation of Wnt action by Frzbs, the Wnt binding proteins, may be another level of control for chondrogenic progression. The overall hypothesis is that a specific, coordinated and temporal regulation of condensation-related proteins is necessary for progression from condensation to matrix production during chondrogenesis.
The Specific Aims to test this hypothesis are: (1) to characterize ERK 1/2 and p38 MAPK signaling during progression; (2) to characterize the Wnt pathways that operate during progression; and (3) to determine the role of Frzb, the Wnt binding protein expressed during chondrogenesis. This work will further our understanding of chondrogenic differentiation from progenitor cells. This may be of benefit for designing new therapeutic strategies for cartilage-related problems.
