Role of FSH in Osreoclast Formation and Function

FSH 在破骨细胞形成和功能中的作用

• 批准号: 7914737
• 负责人: Mone Zaidi
• 金额: $ 21.13万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-15 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7914737
• 关键词: A Mouse; Affect; American; Anterior Pituitary Hormones; Apoptosis; Attenuated; Bone Resorption; Cells; Cessation of life; Coupled; Dominant-Negative Mutation; Endocrine Glands; Estrogen Receptors; Estrogens; Excision; Follicle Stimulating Hormone; Follicle Stimulating Hormone Receptor; Fracture; GTP-Binding Proteins; Goals; Heart; Hip region structure; Human; Hypogonadism; In Vitro; Incidence; Mediating; Menopause; Monoclonal Antibodies; Mus; Osteoclasts; Osteoporosis; Ovarian; Ovariectomy; Ovary; Phosphatidylinositide 3-Kinase Inhibitor; Phosphotransferases; Pituitary Hormones; Postmenopausal Osteoporosis; Public Health; Recombinant Follicle Stimulating Hormone; Role; Serum; Skeleton; Spinal Fractures; Stroke; Testing; Transgenic Organisms; Woman; Work; bone; bone loss; bone mass; cytokine; disability; human data; in vivo; malignant breast neoplasm; osteoclastogenesis; prevent; receptor; reconstitution; skeletal

DESCRIPTION (provided by applicant): Post-menopausal osteoporosis, a global public health problem, has for decades been attributed solely to declining estrogen levels, and although follicle stimulating hormone (FSH) levels rise sharply in parallel, a direct effect of FSH on the skeleton has never been explored. The only ascribed function of FSH is ovarian estrogen secretion. We speculate that, in addition to declining estrogen, FSH drives the decreases in bone mass during the early menopause by stimulating the osteoclast, the cell that resorbs bone. Mice devoid of FSH or its receptor do not display hyper-resorption or bone loss despite being severely hypogonadal. That FSH is pro-resorptive is supported by in vitro evidence for a G-protein coupled FSH receptor (FSHR) on the osteoclast. FSH also enhances the release of the osteoclastogenic cytokine TNFa from osteoclast precursors, and additionally, promotes osteoclast survival. The hypothesis emerging from our study, supported by the tight correlations between bone mass and serum FSH in humans, is that circulating FSH directly stimulates osteoclastic bone resorption. We will therefore investigate in Specific Aim 1 whether FSH causes bone loss in vivo independently of lowered estrogen. For this, we will administer or over-express FSH in mice lacking the two estrogen receptors, ER??-/-, as well as GnRH-deficient hpg mice. We will also examine whether selective FSHR deletion in the osteoclast will prevent ovariectomy-induced bone loss, and whether transgenic reconstitution of the FSHR in FSHR-/- osteoclasts will restore resorptive activity. In Specific Aim 2 we determine the mechanism of the FSH effect. We will first study the mechanism of FSH-induced TNFa expression, and then, using TNFa-/- mice, elucidate if the entire effect of FSH is TNFa-dependent. Finally, using Akt-deficient cells, we will also determine whether the pro-survival action of FSH is Akt-mediated. If FSH is proven to be pro-resorptive in vivo, we envisage attenuating FSH in humans to a skeletal advantage without compromising ovarian function, for example by a monoclonal antibody. The latter premise arises from our observation that FSH haploinsufficiency in mice increases bone mass, while sparing the ovaries. The significance of this work thus lies not only in our challenging an archetypal paradigm, estrogen deficiency, as being the full explanation for menopausal bone loss, but also in establishing that pituitary hormones, such as FSH, act beyond traditional target endocrine organs.

描述（由申请人提供）：绝经后骨质疏松症是一个全球性的公共卫生问题，几十年来一直被仅仅归因于雌激素水平下降，尽管促卵泡激素（FSH）水平同时急剧上升，但从未探讨过 FSH 对骨骼的直接影响。 FSH 的唯一固有功能是卵巢雌激素分泌。我们推测，除了雌激素下降外，促卵泡激素还通过刺激破骨细胞（骨再吸收细胞），导致绝经早期骨量减少。缺乏 FSH 或其受体的小鼠尽管性腺严重功能减退，但不会表现出过度吸收或骨质流失。破骨细胞上存在 G 蛋白偶联 FSH 受体 (FSHR) 的体外证据支持 FSH 具有促吸收作用。 FSH 还增强破骨细胞前体细胞中破骨细胞因子 TNFa 的释放，此外还促进破骨细胞存活。我们的研究得出的假设是，循环中的 FSH 直接刺激破骨细胞的骨吸收，这一假设得到了人类骨量和血清 FSH 之间紧密相关性的支持。因此，我们将在具体目标 1 中研究 FSH 是否会独立于雌激素降低而导致体内骨质流失。为此，我们将在缺乏两种雌激素受体ERα-/-的小鼠以及GnRH缺陷的hpg小鼠中施用或过度表达FSH。我们还将研究破骨细胞中选择性 FSHR 缺失是否会防止卵巢切除引起的骨质流失，以及 FSHR-/- 破骨细胞中 FSHR 的转基因重建是否会恢复再吸收活性。在具体目标 2 中，我们确定了 FSH 效应的机制。我们将首先研究 FSH 诱导 TNFa 表达的机制，然后使用 TNFa-/- 小鼠，阐明 FSH 的整个作用是否依赖于 TNFa。最后，使用 Akt 缺陷细胞，我们还将确定 FSH 的促生存作用是否是 Akt 介导的。如果 FSH 被证明在体内具有促吸收作用，我们设想通过例如单克隆抗体，在不损害卵巢功能的情况下，将人类的 FSH 减弱到骨骼优势。后一个前提源于我们的观察，即小鼠的 FSH 单倍体不足会增加骨量，同时不影响卵巢。因此，这项工作的意义不仅在于我们挑战了雌激素缺乏这一原型范式，将其作为更年期骨质流失的完整解释，而且还在于确定垂体激素（例如 FSH）的作用超出了传统的目标内分泌器官。