During skeletal tissue development, a common stem cell gives rise to both chondrocytes and osteoblasts. Osteoblasts are defined by their ability to synthesize a specialized extracellular matrix (ECM) that undergoes mineralization and is capable of being resorbed. However, chondrocytes are defined by two phenotypes: articular cartilage at joint surfaces that remain unmineralized; and growth cartilage that undergoes hypertrophic differentiation, which does mineralize and is resorbed. While both growth cartilage and bone are calcified and are resorbed, functional growth cartilage is a transient developmental tissue, and mineralized bone is involved in the homeostatic maintenance of systemic ion balance, and is remodeled over much longer periods. Both hypertrophic chondrocytes and osteoblasts express a subset of common genes which are believed to be involved in mediating mineralization and resorption. One of these genes, which shows an almost exclusive restriction of its expression to osteoblasts and hypertrophic chondrocytes, is bone sialoprotein (BSP). The hypothesis of this proposal is that there are common molecular mechanisms that regulate the basal activation of the BSP gene during skeletal cell lineage commitment, while unique molecular mechanisms quantitatively modulate this gene's expression within hypertrophic chondrocytes and osteoblasts. It is suggested that understanding the molecular mechanisms which activate this gene's expression in these different tissues, and differentially regulate BSP expression during these tissues' development, will provide insight into the developmental mechanisms that regulate skeletal cell lineage differentiation. A major focus of these studies will be the mechanisms by which the major systemic peptide hormone regulates calcium homeostasis (PTH), and the major developmental autocrine/paracrine factor (PTHrP) controls skeletal cell differentiation. A comparison of the mechanisms which control BSP expression in primary cell cultures of osteoblasts osteocytes, and hypertrophic chondrocytes, and in these different tissues during in vivo embryonic development, will be carried out using a combination of molecular endocrinology and molecular biological techniques.
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