HORMONAL CONTROL OF PERIOSTEAL EXPANSION

描述(申请人提供)：骨膜现在被广泛认为是性激素和间歇性甲状旁腺激素(PTH)作用的动态平衡和治疗靶点。在一些实验模型中，雄激素和甲状旁腺素刺激骨膜扩张，而雌激素抑制骨膜扩张。然而，低浓度的雌激素也可能通过直接作用或通过允许雄激素或机械刺激的刺激作用间接促进骨膜扩张。性激素和甲状旁腺素影响这一关键骨骼包膜的机制尚不清楚。我们发现性激素和甲状旁腺激素在保护骨膜成骨细胞免受凋亡方面具有共同的特性。与之形成鲜明对比的是，与雄激素相比，雌激素和甲状旁腺素在调节早期骨膜成骨细胞前体细胞的募集方面具有相反的作用。雌激素受体(ER)本身具有重要的作用，既是作为配体雌激素相互作用的部位，也是作为独立的调节器。结合型内质网抑制骨膜成骨细胞的分化，而未被占用的内质网则促进骨膜成骨细胞的分化。我们假设性类固醇和甲状旁腺素促进成熟骨膜成骨细胞的存活。同时，雌激素抑制早期成骨细胞的增殖和分化，而雄激素、间歇性甲状旁腺激素和去连接内质网通过对早期成骨细胞的增殖和分化起相反作用促进骨膜扩张。雌激素和甲状旁腺素联合作用于骨膜表面，反映了成骨细胞存活时间的延长和甲状旁腺素和雌激素对骨膜成骨细胞增殖和分化的相反作用之间的相对平衡。为了验证这些假设，我们将检验雌激素和雄激素、甲状旁腺激素和去连接雌激素是否对不同群体的骨膜成骨细胞前体细胞的分化和增殖有不同的调节作用。性激素、间歇性甲状旁腺激素以及甲状旁腺激素和雌激素的联合作用对骨膜扩张的促进作用将在体内进行研究。最后，我们将在体内证实雌激素对骨膜骨量的影响与成骨细胞的特异性作用有关。了解性激素和甲状旁腺素相互作用或相互作用以调节骨膜的保存或扩张的细胞和分子机制，可能会导致治疗骨质疏松症的新的治疗方法。公共卫生相关性：骨膜现在被广泛认为是性激素和间歇性甲状旁腺激素(PTH)作用的动态平衡和治疗靶点。在一些实验模型中，雄激素和甲状旁腺素刺激骨膜扩张，而雌激素抑制骨膜扩张。我们假设性类固醇和甲状旁腺素促进成熟骨膜成骨细胞的存活。同时，雌激素抑制早期成骨细胞的增殖和分化，而雄激素、间歇性甲状旁腺激素和去连接内质网通过对早期成骨细胞的增殖和分化起相反作用促进骨膜扩张。

DESCRIPTION (provided by applicant): The periosteum is now widely recognized as a homeostatic and therapeutic target for actions of sex steroids and intermittent parathyroid hormone (PTH) administration. Androgens and PTH stimulate while estrogens suppress periosteal expansion in a number of experimental models. However, low estrogen concentrations may also promote periosteal expansion by direct actions or indirectly by permitting the stimulatory effects of androgens or mechanical stimulation. The mechanisms by which sex steroids and PTH influence this key skeletal envelope are not known. We have found that sex steroids and PTH have common properties in protecting periosteal osteoblasts from apoptosis. In sharp contrast, estrogens as compared to androgens and PTH have opposing actions to regulate the recruitment of early periosteal osteoblast progenitors. The estrogen receptor (ER) itself has important actions both as a site for liganded estrogen interaction and as an independent modulator. The liganded ER attenuates periosteal osteoblast differentiation while in its unoccupied configuration, it potentiates periosteal osteoblast differentiation. We hypothesize that sex steroids and PTH promote the survival of mature periosteal osteoblasts. In parallel, estrogens suppress whereas androgens, intermittent PTH, and the unliganded ER promote periosteal expansion by exerting opposite actions on the proliferation and differentiation of early periosteal osteoblast progenitors. The effect of combined estrogen and PTH administration to the periosteal surface reflects the relative balance between prolongation of osteoblast survival, an action shared by both hormones, and opposing actions of PTH and estrogens on proliferation and differentiation of progenitor periosteal osteoblasts. To test these hypotheses, we will examine whether estrogens versus androgens, PTH and unliganded ER differentially regulate differentiation and proliferation of distinct populations of periosteal osteoblast precursors. The contribution of pro-differentiating versus anti-apoptotic actions of sex steroids, intermittent PTH and the combination of PTH and estrogens to the periosteal expansion that occurs with skeletal maturity will be investigated in vivo. Finally, we will establish in vivo that the osteoblast-specific actions of estrogens account for their effects on periosteal bone mass. Understanding the cellular and molecular mechanisms by which sex steroids and PTH act and interact to regulate periosteal preservation or expansion, could lead to new therapeutic approaches to the treatment of osteoporosis. PUBLIC HEALTH RELEVANCE: The periosteum is now widely recognized as a homeostatic and therapeutic target for actions of sex steroids and intermittent parathyroid hormone (PTH) administration. Androgens and PTH stimulate while estrogens suppress periosteal expansion in a number of experimental models. We hypothesize that sex steroids and PTH promote the survival of mature periosteal osteoblasts. In parallel, estrogens suppress whereas androgens, intermittent PTH, and the unliganded ER promote periosteal expansion by exerting opposite actions on the proliferation and differentiation of early periosteal osteoblast progenitors.