Black Bear Parathyroid Hormone as an Anabolic Agent for Bone

DESCRIPTION (provided by applicant): A clinical need exists for better osteoporosis treatments since only one anabolic therapy (recombinant human parathyroid hormone) is commercially available. Bears are uniquely able to prevent bone loss during physical inactivity (hibernation) by maintaining balanced bone remodeling; the biological processes behind this phenomenon are likely governed by endogenous parathyroid hormone (PTH), since serum PTH levels are correlated with the bone formation marker osteocalcin in hibernating and active bears. Thus, our goal is to investigate the anabolic effects of bear PTH in comparison to human PTH to aid in the development of a more effective anabolic treatment for osteoporosis. It is possible to upregulate anabolic pathways in bone cells by changing PTH's amino acid sequence. Bear PTH has eleven differences in its amino acid sequence compared to human PTH. Thus, bear PTH may promote a greater anabolic response in bone than human PTH by decreasing osteoblast apoptosis and incr easing bone matrix production by altering gene expression. We propose to recombinantly produce bear PTH 1-84 and measure its ability to promote bone formation in vitro by measuring bear PTH's effects on apoptosis and gene expression in bone cells (MC-3T3 o steoblastic cells). The cellular responses will be compared with the effects of recombinant human PTH 1-84 to determine the relative anabolic potential of bear PTH. We will also treat rats with daily subcutaneous injections of human PTH 1-84 and bear PTH 1 -84. Femoral bone strength will be determined by 3-point bending tests and vertebral bone strength by compression tests. Bone formation rate will be quantified histologically in calcein labeled bone tissue, mineral content will be determined by ashing, and geometry (e.g., cross- sectional area) will be quantified by image analysis techniques. PUBLIC HEALTH RELEVENCE: Improved drug therapies are needed to treat the approximately 44 million Americans affected by osteoporosis. Bears uniquely prevent osteoporo sis during physical inactivity (hibernation) through biological processes regulated by parathyroid hormone (PTH). Injections of human PTH are currently used to rebuild bone in severely osteoporotic patients, but due to its different protein structure, bear PTH may cause greater bone formation than human PTH, and therefore may be a more effective treatment for human osteoporosis.