Endochondral bone formation is complex and requires the coordination of several signals. Members of the Transforming Growth Factor-beta superfamily are secreted growth factors that regulate many aspects of growth and differentiation. TGF-betas signal through heterodimeric type I and type II serine/threonine kinase receptors and genetic epistatic analysis in Drosophila and C. Elegans has identified the Smads family of proteins as important transducers of TGF-beta signaling. The current model is that Smads are phosphorylated by the TGF-beta type I receptor, translocate to the nucleus, and act as transcription factors. Transgenic mice expressing a dominant-negative form of the TGF-beta type II receptor have increased terminal chondrocyte differentiation, defects in closure of the sternum, and osteoarthritis, suggesting TGF-betas act to regulate chondrocyte differentiation in vivo. It has been proposed that Indian Hedgehog and Parathyroid Hormone-related Peptide (PTHrP) form a negative feedback loop that provides a mechanism for sensing and regulating the rate of cartilage differentiation. In the receptor- deficient mice, Indian hedgehog expression is increased and persistent, leading the investigator to suggest that TGF-beta signaling is required for Indian hedgehog inhibition of chondrocyte differentiation. Coupled with evidence that Dpp, a Drosophila TGF-beta-like protein, mediates hedgehog signaling during imaginal disc differentiation and TGF-betal stimulates PTHrP in cartilage organ cultures, the investigator proposes that TGF-betal acts as a signal relay between Indian hedgehog and PTHrP to regulate chondrocyte differentiation. To test this hypothesis, the investigator proposes to use an organ culture model of mouse metatarsal development. The investigator also proposes to test whether Smad proteins are required for the inhibition of chondrocyte differentiation and whether the Smads proteins directly regulate the PTHrP promoter.
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