During early embryogenesis the cranial base (chondrocranium), the mandibular condyle and other dental support tissue are composed of cartilage. With further development, however, most of the cartilage (""""""""transient"""""""" cartilage) is replaced by bone via endochondral ossification. The remaining cartilage (""""""""permanent"""""""" cartilage) does not undergo endochondral ossification and persists throughout life at specific skeletal sites such as underneath the fibrous covering of the condyle. The mechanisms regulating the divergent behavior and fate of transient and permanent cartilage are-largely unknown. Recent studies from this and other laboratories have indicated that basic fibroblast growth factor (bFGF) and its 120-140 kDa high affinity cell surface receptor (bFGF-R) may play a major role in detemining chondrocyte development. Our hypothesis is that the development of hypertrophic chondrocytes during endochondral ossification and their replacement by bone cells require a significant decrease in autocrine stimulation by bFGF. Our second hypothesis is that, in contrast, continuous autocrine stimulation is needed in permanent chondrocytes to prevent endochondral ossification, maintain a stable phenotype, and allow the cells to persist throughout postnatal life. To test these hypotheses, we will determine the nature of the bFGF-R(s) in transient and permanent chondrocytes, the regulation of their expression, the relationship between gene expression of bFGF and bFGF-R, the mechansims of interaction of bFGF with bFGF-R, and the specific roles these proteins play in regulating the chondrocyte phenotype. This information is of obvious relevance to oral-facial and skeletal development, a poorly understood process probably involving complex regulatory mechanisms. This project will also generate insights into the pathogenesis of cranio-facial and skeletal defects involving abnormal cartilage development; these abnormal processes could be associated with aberrant expression of bFGF and bFGF-R.
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