The main goal of this multifacted proposal is to continue research on the mechanisms by which parathyroid hormone, PTH, paradoxically considered a catabolic hormone for bone, can stimulate bone growth in vivo. We have developed a reproducible in vivo model by giving intermittent synthetic human PTH 1-34 to young rats to increase bone mass and bone forming surfaces. A specific goal is to determine how factors associated with growth, such as growth hormone (GH), GH-dependent insulin-like growth factor (IGF-I) and nutrition regulate the PTH-induced anabolic response in young and aging rats. New models proposed include hypophysectomised rats, the use of somatostatin analog suppress GH and mice with genetic growth defects. A second specific goal is to use a new in vivo-in vivo protocol of the PTH-induced anabolic response to determine if PTH stimulates the secretion of local growth factors, specifically IGF-I and TGFbeta. Immunocytochemistry is being developed to localise sites of IGF-I and TGFbeta secretion in histologic bone sections. The third specific goal is to investigate bone cell kinetics to determine the effect of anabolic doses of PTH on osteoblast differentiation and osteoblast precursor replication. The techniques described include established and new in vivo and new in vivo-in vitro approaches, using chemical, biochemical, computer-assisted morphometric and autoradiographic methods I developed to assess changes in bone mass and growth, and applying recent developments in bone growth factor research. A new in vivo model to study the direct effects of PTH and local bone growth factors is proposed, using intra-arterial infusion of a rat hindlimb. Knowledge of the mechanisms and mediators regulating the anabolic effect of PTH would provide a more rational basis to justify the current use of PTH in the treatment of osteoporosis and might suggest new approaches to therapies to stimulate bone growth in a wide variety of patients with bone diseases.
