Prostaglandins (PGs) have both stimulatory and inhibitory effects on bone formation and resorption. These effects are likely to be important in regulation of bone turnover by mechanical forces, in bone loss associated with inflammation and in the pathogenesis of osteoporosis. This proposal is focused on the effects of PGs on bone formation. The applicants will test the following hypotheses: (1) The stimulatory (anabolic) effect of PGs is due to an increase in replication and differentiation of osteoblast precursors. One of the receptors involved is of the EP2 class which stimulates cyclic AMP production. The response involves increased production or activation of endogenous growth factors. (2) The inhibitory (catabolic) effect is on differentiated osteoblasts. It involves activation of an FP receptor and inhibition of collagen gene transcription, mediated via a protein kinase C (PKC) pathway. (3) PGs can induce prostaglandin G/H synthase (PGHS) mRNA in bone. This autoamplification can produce sustained increases in endogenous PG levels after transient perturbations. The responses might be either anabolic or catabolic depending on the cells affected and the PGs produced. To test these hypotheses the investigators will study the effects of exogenous and endogenous PGs on cultured primary calvarial cells, rodent and human bone cell lines and transgenic mice bearing collagen promoter- chloramphenicol acetyl transferase reporter constructs. They will determine the role of growth factors and define transcriptional regulatory elements for collagen. Autoamplification of PGHS will be studied in cell culture and in vivo and its structure-activity relations, signal transduction mechanisms and transcriptional regulation examined. These studies should improve understanding of the role of PGs in physiology and pathology and might also lead to development of new anabolic agents for the skeleton.
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