HORMONAL CONTROL OF PERIOSTEAL EXPANSION

描述（由申请人提供）：骨膜现在被广泛认为是性类固醇和间歇性甲状旁腺激素（PTH）给药的稳态和治疗靶点。在一些实验模型中，雄激素和甲状旁腺激素刺激骨膜扩张，而雌激素抑制骨膜扩张。然而，低雌激素浓度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。性类固醇和甲状旁腺激素影响这一关键骨骼包膜的机制尚不清楚。我们发现性类固醇和甲状旁腺激素在保护骨膜成骨细胞免于凋亡方面具有共同的特性。与之形成鲜明对比的是，与雄激素和甲状旁腺激素相比，雌激素在调节早期骨膜成骨细胞祖细胞募集方面具有相反的作用。雌激素受体（ER）本身作为配体雌激素相互作用的位点和作为独立的调节剂具有重要的作用。配位的内质网减弱骨膜成骨细胞的分化，而在其未被占用的结构中，它增强骨膜成骨细胞的分化。我们假设性类固醇和甲状旁腺激素促进成熟骨膜成骨细胞的存活。与此同时，雌激素抑制骨膜扩张，而雄激素、间歇性PTH和未配体内质网通过对早期骨膜成骨细胞祖细胞的增殖和分化施加相反的作用来促进骨膜扩张。雌激素和PTH联合给药对骨膜表面的影响反映了两种激素共同作用的成骨细胞存活延长与PTH和雌激素对祖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，我们将研究雌激素与雄激素、甲状旁腺激素和未配体内质网是否对不同种群的骨膜成骨细胞前体的分化和增殖有差异调节。我们将在体内研究性类固醇、间歇性甲状旁腺激素以及甲状旁腺激素和雌激素联合作用对骨骼成熟过程中骨膜扩张的促进分化和抗凋亡作用。最后，我们将在体内建立雌激素的成骨特异性作用，说明它们对骨膜骨量的影响。了解性类固醇和甲状旁腺激素作用和相互作用调节骨膜保存或扩张的细胞和分子机制，可以为治疗骨质疏松症提供新的治疗方法。公共卫生相关性：骨膜现在被广泛认为是性类固醇和间歇性甲状旁腺激素（PTH）给药的稳态和治疗靶点。在一些实验模型中，雄激素和甲状旁腺激素刺激骨膜扩张，而雌激素抑制骨膜扩张。我们假设性类固醇和甲状旁腺激素促进成熟骨膜成骨细胞的存活。与此同时，雌激素抑制骨膜扩张，而雄激素、间歇性PTH和未配体内质网通过对早期骨膜成骨细胞祖细胞的增殖和分化施加相反的作用来促进骨膜扩张。

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.