Calcium in the regulation of osteoclast formation

绝经后骨质疏松症是一个全球公共健康问题，几十年来一直被完全归因于 雌激素水平下降，尽管卵泡刺激素(FSH)水平同时大幅上升，但 卵泡刺激素对骨骼的直接影响从未被研究过。卵泡刺激素的唯一功能是卵巢 雌激素分泌。我们推测，除了雌激素的减少，卵泡刺激素还会导致骨量的减少。 在绝经早期，通过刺激破骨细胞(吸收骨的细胞)而引起的肿块。小鼠缺乏 尽管有严重的性腺功能减退，但FSH或其受体不会表现出高吸收或骨丢失。那 FSH是促吸收的，体外证据支持G蛋白偶联的FSH受体(FSHR)在 破骨细胞。FSH还能促进破骨细胞释放破骨细胞因子TNFa 前体，此外，促进破骨细胞存活。从我们的研究中得出的假设是， 在人类骨量和血清FSH之间的紧密相关性的支持下，循环FSH 直接刺激破骨细胞性骨吸收。因此，我们将在具体目标1中调查 卵泡刺激素在体内导致骨丢失，而不依赖于雌激素水平的降低。为此，我们将管理或超过- 在缺乏两种雌激素受体Erap“7”的小鼠以及GnRH缺乏的HPG小鼠中表达FSH。我们 我还将检查破骨细胞中选择性的FSHR缺失是否会阻止卵巢切除诱导的骨 FSHR‘7“破骨细胞中FSHR的转基因重组是否会恢复吸收活性。 在特定的目标2中，我们确定了FSH效应的机制。我们将首先研究FSH的机制- 诱导TNFa的表达，然后用TNFa7“小鼠，阐明FSH的整个作用是否是TNFa- 依附的。最后，利用Akt缺陷细胞，我们还将确定FSH的促生存作用是否 AKT介导的。如果FSH在体内被证实是促吸收的，我们设想将人类的FSH减弱到 在不损害卵巢功能的情况下具有骨骼优势，例如通过单抗。后者 前提是我们观察到小鼠的FSH单倍性不足会增加骨量，而不会 卵巢。因此，这项工作的意义不仅在于我们挑战了一个原型范式， 雌激素缺乏，这是绝经期骨质丢失的完全解释，但也是建立在 脑下垂体激素，如促卵泡刺激素，其作用超出了传统的内分泌器官。

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, ERap"7", 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'7" 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 TNFa7" 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.