Regulation of Human Bone Turnover by FSH

描述(申请人提供)：我们将研究两种性激素，促性腺激素和雌激素，在调节骨转换中的相互作用。我们的工作表明，FSH和雌激素受体都可以调节骨骼分化和活动。我们和其他人的发现表明，这些调控系统之间的串扰是由包括TNFa在内的二级信号介导的。我们将验证雌激素是合成代谢的假说，而促卵泡激素是分解代谢的假说。在更年期，雌激素水平下降到低水平，FSH水平上升到高水平，导致迅速的骨质流失。然而，FSH和雌激素受体在骨细胞分化过程中的表达之间的关系尚不清楚。我们将使用人类细胞作为主要模型来研究这一点。基因敲除的小鼠也将被用作细胞来源，并用于体内的长期研究。目的1研究人未转化成骨细胞和破骨细胞前体细胞分化过程中卵泡刺激素和雌激素反应的调控。这将研究FSH-R主要以选择性剪接形式在成骨细胞MSC前体和破骨细胞上表达的假设。相比之下，雌激素主要通过Era，被认为只在分化过程中影响破骨细胞，而Era在成骨细胞分化后期强烈表达，在成骨细胞分化中调节骨形成。目的2将确定性激素和FSH信号在成骨细胞和破骨细胞中相互作用的机制。这将包括量化FSH和雌激素对人类破骨细胞分化和存活的相对影响。细胞对卵泡刺激素的反应机制将被描述。人类骨细胞对卵泡刺激素的反应产生的TNFa，将被定义。此外，还将研究雌激素和促卵泡激素信号的潜在反向调节。将评估FSH对人成骨细胞分化和存活的影响，包括与雌激素的相互作用。最后，我们将使用基因敲除的小鼠模型将FSH-R从雌激素效应中分离出来，并确定其对骨形成的影响。FSH-R-/-动物将被用于比较卵巢切除动物和去卵巢动物的骨转换，作为动物年龄的函数，使用和不使用雌激素替代。这些研究将澄清对绝经后骨丢失的理解，提高监测治疗的能力，并可能改善性腺功能减退性骨病的长期管理。与公共卫生相关。更年期的女性有快速的骨质流失，但雌激素补充只能部分阻止这一点。我们发现，调节雌激素产生的脑下垂体激素FSH可能会直接导致骨质流失。我们将研究FSH在骨骼中的反应，为预防骨质疏松症提供新的见解。

DESCRIPTION (provided by applicant): We will study the interactions of two sex hormones, FSH and estrogen, in regulating bone turnover. Our work shows that both FSH and estrogen receptors modulate bone differentiation and activity. Our findings, and those of others, show that crosstalk between these regulatory systems is mediated by secondary signals including TNFa. We will test the hypothesis that estrogen is anabolic, and FSH catabolic, for bone mass. In the menopause, estrogen drops to low levels and FSH climbs to high levels, leading to rapid bone loss. However, the relationship of FSH and estrogen receptor expression during bone cell differentiation is poorly understood. We will study this using human cells as the primary model. Knockout mice will also be used as sources of cells, and for long-term studies in vivo. Aim 1 will establish how FSH and estrogen responses are regulated during differentiation of human nontransformed osteoblast and osteoclast precursor cells. This will study the hypothesis that FSH-R, mainly in an alternatively spliced form, is expressed on osteoblast MSC precursors and on osteoclasts. In contrast, estrogen, mainly via ERa, is believed to affect osteoclasts only during differentiation, while ERa is strongly expressed late in osteoblast differentiation, where it regulates bone formation. Aim 2 will determine mechanisms of interaction of sex steroids and FSH signaling in osteoblasts and in osteoclasts. This will include quantifying the relative effects of FSH and estrogen on human osteoclast differentiation and survival. Mechanisms of cell response to FSH will be characterized. The production of TNFa, in human bone cells in response to FSH will be defined. In addition, potential counter-regulation of estrogen and FSH signaling will be studied. Effects of FSH on differentiation and survival of human osteoblasts will be evaluated, including interaction with estrogen effects. Finally, we will use a knockout mouse model to uncouple FSH-R from estrogen effects, and determine the effects on bone formation. FSH-R-/- animals will be used for studies comparing bone turnover to ovariectomized animals, with and without estrogen replacement, as functions of animal age. These studies will clarify understanding of postmenopausal bone loss, improve the ability to monitor treatment, and may improve the long-term management of hypogonadal bone disease. PUBLIC HEALTH RELEVANCE. Women at the menopause have rapid bone loss, but estrogen replacement only partially prevents this. We discovered that the pituitary hormone FSH, which regulates estrogen production, may cause bone loss directly. We will study this FSH response in bone to provide new insights into prevention of osteoporosis.