Black Bear Parathyroid Hormone as an Anabolic Agent for Bone

描述（由申请人提供）：由于只有一种合成代谢疗法（重组人甲状旁腺激素）是市售的，因此临床上需要更好的骨质疏松症治疗。熊是唯一能够防止骨质流失在身体不活动（冬眠）通过保持平衡的骨重建;这一现象背后的生物学过程可能是由内源性甲状旁腺激素（PTH），因为血清PTH水平与骨形成标记物骨钙素在冬眠和活跃的熊。因此，我们的目标是研究与人PTH相比熊PTH的合成代谢作用，以帮助开发更有效的骨质疏松症合成代谢治疗方法。通过改变PTH的氨基酸序列，可以上调骨细胞中的合成代谢途径。与人PTH相比，熊PTH在其氨基酸序列中有11个差异。因此，熊甲状旁腺素可能通过改变基因表达减少成骨细胞凋亡和增加骨基质产生，促进骨中比人甲状旁腺素更大的合成代谢反应。我们建议重组生产熊PTH 1-84，并通过测量熊PTH对骨细胞（MC-3 T3成骨细胞）凋亡和基因表达的影响来测量其体外促进骨形成的能力。将细胞反应与重组人PTH 1-84的作用进行比较，以确定熊PTH的相对合成代谢潜力。我们还将通过每天皮下注射人PTH 1-84治疗大鼠并携带PTH 1-84。股骨强度将通过3点弯曲试验确定，椎骨强度将通过压缩试验确定。骨形成率将在钙黄绿素标记的骨组织中进行组织学定量，矿物质含量将通过灰化和几何形状（例如，横截面积）将通过图像分析技术定量。 公共卫生解放：需要改进药物治疗来治疗约4400万受骨质疏松症影响的美国人。熊在身体不活动（冬眠）期间通过甲状旁腺激素（PTH）调节的生物过程独特地预防骨质疏松症。目前，注射人PTH用于严重骨质疏松患者的骨重建，但由于其不同的蛋白质结构，熊PTH可能比人PTH引起更大的骨形成，因此可能是治疗人类骨质疏松症的更有效的方法。

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 increasing 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 osteoblastic 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 osteoporosis 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.