Regulation of Human Bone Turnover by FSH

描述（由申请人提供）：我们将研究FSH和雌激素两种性激素在调节骨转换中的相互作用。我们的研究表明FSH和雌激素受体都能调节骨的分化和活性。我们和其他人的研究结果表明，这些调节系统之间的串扰是由包括TNFa在内的次级信号介导的。我们将测试雌激素是合成代谢，FSH是分解代谢，骨量的假设。在更年期，雌激素下降到低水平，FSH上升到高水平，导致骨质迅速流失。然而，骨细胞分化过程中卵泡刺激素与雌激素受体表达的关系尚不清楚。我们将以人类细胞为主要模型进行研究。基因敲除小鼠也将被用作细胞来源，并在体内进行长期研究。目的1将确定在人类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被调节的。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。相反，雌激素，主要通过ERa，被认为仅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，调节骨形成。目的2将确定成骨细胞和破骨细胞中性类固醇和卵泡刺激素信号相互作用的机制。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FSH反应的机制将被描述。人类骨细胞对FSH的反应中TNFa的产生将被定义。此外，雌激素和卵泡刺激素信号的潜在反调控也将被研究。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，我们将使用敲除小鼠模型将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-/-动物将用于研究比较骨转换与卵巢切除动物，有无雌激素替代，作为动物年龄的功能。这些研究将阐明对绝经后骨质流失的认识，提高监测治疗的能力，并可能改善性腺功能低下骨病的长期管理。公共卫生相关性。绝经期的女性骨质流失迅速，但雌激素替代只能部分防止这种情况。我们发现调节雌激素分泌的垂体激素FSH可能直接导致骨质流失。我们将研究FSH在骨中的反应，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.