Regulation of Human Bone Turnover by FSH

描述（由申请人提供）：我们将研究两种性激素FSH和雌激素在调节骨转换中的相互作用。我们的工作表明，FSH和雌激素受体调节骨分化和活性。我们的发现和其他人的发现表明，这些调节系统之间的串扰是由包括TNF α在内的二级信号介导的。我们将检验雌激素是合成代谢，FSH是分解代谢，对骨量的假设。在绝经期，雌激素下降到低水平，FSH上升到高水平，导致快速骨质流失。然而，在骨细胞分化过程中FSH和雌激素受体表达的关系知之甚少。我们将使用人类细胞作为主要模型来研究这一点。敲除小鼠也将用作细胞来源，并用于长期体内研究。目的1将建立在人非转化成骨细胞和破骨细胞前体细胞分化过程中FSH和雌激素反应是如何调节的。这将研究的假设，FSH-R，主要是在一个选择性剪接的形式，表达成骨细胞MSC前体细胞和破骨细胞。相反，雌激素，主要通过ER α，被认为只在分化过程中影响破骨细胞，而ER α在成骨细胞分化后期强烈表达，在那里它调节骨形成。目的2将确定性类固醇激素和FSH信号在成骨细胞和破骨细胞中的相互作用机制。这将包括量化FSH和雌激素对人破骨细胞分化和存活的相对影响。细胞对FSH反应的机制将被描述。将定义人骨细胞中响应FSH的TNF α的产生。此外，还将研究雌激素和FSH信号传导的潜在反调节作用。将评价FSH对人成骨细胞分化和存活的影响，包括与雌激素效应的相互作用。最后，我们将使用基因敲除小鼠模型将FSH-R与雌激素效应分离，并确定其对骨形成的影响。FSH-R-/-动物将用于比较骨转换与卵巢切除动物（有和无雌激素替代）的研究，作为动物年龄的函数。这些研究将阐明对绝经后骨质流失的理解，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。公共卫生相关性。绝经期的妇女骨质流失迅速，但雌激素替代只能部分防止这种情况。我们发现，垂体激素FSH，调节雌激素的产生，可能会直接导致骨质流失。我们将研究骨中FSH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.