CHEMOATTRACTANTS & GROWTH FACTORS IN MINERALIZED TISSUES

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This project seeks to define two important classes of biologically active proteins in mineralized tissues: chemoattractants and growth factors. The chemoattractant work focuses on bone and dentin matrix proteins, particularly osteocalcin and its constituent peptides which are active on monocytes in vitro. Chromatographic separation and quantitation of total bone chemoattractant activity by screening with a fluorescence assay for membrane potential changes will determine the contribution of osteocalcin and will reveal other significant molecular species which will be purified and characterized. Using 125I-osteocalcin the monocyte osteocalcin receptor will be covalently labeled and identified. Defining the receptor's affinity for osteocalcin and related synthetic peptides is prerequisite information for developing biochemical strategies to control mineralized tissue resorption in humans. Growth factors of at least four classes (PDGF, aFGF, cFGF, and TGF-beta) have previously been purified and characterized from bone matrix, utilizing heparin affinity chromatography as a central method. All of these factors are active mitogens for osteoblasts and undoubtedly modulate the development, growth, and remodelling of bone. Three other mineralized tissues of critical importance to the oral cavity (dentin, enamel, and cementum) will be subjected to the same analysis to assess the relevance of growth factors in the formation of teeth and their attachment to bone. Biosynthesis studies with rat osteoblasts, odontoblasts, and the enamel organ of developing incisors will help to identify the sources of the matrix-bound growth factors. Determination of the actual biological functions of chemoattractants and growth factors in mineralized tissues must await their exact chemical description which is the principal objective of this project. This knowledge should yield direct benefits for the treatment and/or prevention of pathological conditions, including osteoporosis, osteopetrosis, Paget's disease, and oral problems involving localized bone loss, alveolar ridge resorption, and tooth root resorption during orthodontic tooth movement.