Regulation of Human Bone Turnover by FSH

FSH 对人体骨转换的调节

• 批准号: 7846783
• 负责人: Harry C. Blair
• 金额: $ 33万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-07-03 至 2013-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7846783
• 关键词: Affect; Age; Animals; Biological Assay; Bone Diseases; Bone Resorption; Cell Communication; Cell Differentiation process; Cell Lineage; Cells; Drops; Endocrine; Equilibrium; Estradiol; Estrogen Receptors; Estrogen Replacements; Estrogens; Evolution; Family; Follicle Stimulating Hormone Receptor; Genes; Glycoproteins; Gonadal Steroid Hormones; Green Fluorescent Proteins; Hormones; Human; Immune; In Vitro; Knock-out; Knockout Mice; Ligands; Longitudinal Studies; Macrophage Colony-Stimulating Factor; Mediating; Menopause; Mesenchymal Stem Cells; Minerals; Modeling; Monitor; Mus; Organ; Osteoblasts; Osteoclasts; Osteogenesis; Osteoporosis prevention; Ovarian; Pattern; Physiologic calcification; Pituitary Gland; Pituitary Hormones; Postmenopausal Osteoporosis; Production; Protein Isoforms; RNA Splicing; Regulation; Relative (related person); Reproduction; Signal Transduction; Skeleton; Source; Steroid Receptors; Steroids; System; TNFSF11 gene; Testing; Thyroid Hormones; Thyrotropin Receptor; Ursidae Family; Variant; Woman; Work; bone; bone cell; bone loss; bone mass; bone turnover; hydrocortisone receptor; improved; in vivo; insight; interest; knockout animal; mouse model; osteoblast differentiation; precursor cell; prevent; public health relevance; receptor; receptor expression; response; species difference; stem cell differentiation

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.

描述（由申请人提供）：我们将研究两种性激素（FSH 和雌激素）在调节骨转换方面的相互作用。我们的工作表明 FSH 和雌激素受体均可调节骨分化和活性。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。我们将检验以下假设：雌激素对于骨量而言是合成代谢的，FSH 是分解代谢的。在更年期，雌激素下降到低水平，FSH 上升到高水平，导致骨质快速流失。然而，人们对骨细胞分化过程中 FSH 和雌激素受体表达的关系知之甚少。我们将使用人体细胞作为主要模型来研究这一点。基因敲除小鼠也将用作细胞来源，并用于体内长期研究。目标 1 将确定在人类未转化的成骨细胞和破骨细胞前体细胞分化过程中如何调节 FSH 和雌激素反应。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。目标 2 将确定成骨细胞和破骨细胞中性类固醇与 FSH 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。将表征细胞对 FSH 的反应机制。人体骨细胞响应 FSH 产生 TNFa 的过程将被定义。此外，还将研究雌激素和 FSH 信号传导的潜在反调节。将评估 FSH 对人类成骨细胞分化和存活的影响，包括与雌激素作用的相互作用。最后，我们将使用基因敲除小鼠模型将 FSH-R 与雌激素效应分开，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（有或没有雌激素替代）作为动物年龄函数的研究。这些研究将澄清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减退性骨病的长期治疗。公共卫生相关性。更年期的女性骨质流失很快，但补充雌激素只能部分预防这种情况。我们发现调节雌激素产生的垂体激素 FSH 可能直接导致骨质流失。我们将研究骨中的 FSH 反应，为预防骨质疏松症提供新见解。