Postmenopausal osteoporosis, a global public health problem, has for decades been attributed solely to declining estrogen levels. Although FSH levels rise sharply in parallel, a direct effect of FSH on the skeleton has never been explored. We show that FSH is required for hypogonadal bone loss. Neither FSHbeta nor FSH receptor (FSHR) null mice have bone loss despite severe hypogonadism. Bone mass is increased and osteoclastic resorption is decreased in haploinsufficient FSHbeta+/- mice with normal ovarian function, suggesting that the skeletal action of FSH is estrogen independent. Osteoclasts and their precursors possess G(i2alpha)-coupled FSHRs that activate MEK/Erk, NF-kappaB, and Akt to result in enhanced osteoclast formation and function. We suggest that high circulating FSH causes hypogonadal bone loss.

The established function of thyroid stimulating hormone (TSH) is to promote thyroid follicle development and hormone secretion. The osteoporosis associated with hyperthyroidism is traditionally viewed as a secondary consequence of altered thyroid function. We provide evidence for direct effects of TSH on both components of skeletal remodeling, osteoblastic bone formation, and osteoclastic bone resorption, mediated via the TSH receptor (TSHR) found on osteoblast and osteoclast precursors. Even a 50% reduction in TSHR expression produces profound osteoporosis (bone loss) together with focal osteosclerosis (localized bone formation). TSH inhibits osteoclast formation and survival by attenuating JNK/c-jun and NFkappaB signaling triggered in response to RANK-L and TNFalpha. TSH also inhibits osteoblast differentiation and type 1 collagen expression in a Runx-2- and osterix-independent manner by downregulating Wnt (LRP-5) and VEGF (Flk) signaling. These studies define a role for TSH as a single molecular switch in the independent control of both bone formation and resorption.

We report that oxytocin (OT), a primitive neurohypophyseal hormone, hitherto thought solely to modulate lactation and social bonding, is a direct regulator of bone mass. Deletion of OT or the OT receptor (Oxtr) in male or female mice causes osteoporosis resulting from reduced bone formation. Consistent with low bone formation, OT stimulates the differentiation of osteoblasts to a mineralizing phenotype by causing the up-regulation of BMP-2, which in turn controls Schnurri-2 and 3, Osterix, and ATF-4 expression. In contrast, OT has dual effects on the osteoclast. It stimulates osteoclast formation both directly, by activating NF-B and MAP kinase signaling, and indirectly through the up-regulation of RANK-L. On the other hand, OT inhibits bone resorption by mature osteoclasts by triggering cytosolic Ca 2؉ release and NO synthesis. Together, the complementary genetic and pharmacologic approaches reveal OT as a novel anabolic regulator of bone mass, with potential implications for osteoporosis therapy.osteoblast ͉ osteoclast ͉ osteoporosis ͉ pituitary hormones ͉ bone density O xytocin (OT), a hypothalamic nanopeptide secreted into the circulation from the posterior pituitary, is indispensable for lactation. It acts on a G protein-coupled receptor (Oxtr), the expression of which in reproductive tissues is regulated by sex steroids and OT. In humans and rodents, plasma OT levels are elevated maximally during suckling (1, 2).Mice lacking OT or its receptor (Oxtr) are unable to lactate, despite unperturbed breast tissue and milk formation (3, 4). Most notably, newborn pups die shortly after birth in the absence of a foster mother postpartum. This effect of OT is exerted peripherally, as the i.p. administration of recombinant OT to OT Ϫ/Ϫ mice rescues milk ejection, allowing the newborn to feed normally. In contrast to the milk ejection defect, no deficits in copulation, gestation, fecundity, or parturition have been noted in either OT Ϫ/Ϫ or Oxtr Ϫ/Ϫ mice, suggesting that these mice are typically eugonadal (5). Furthermore, compound mutants with both the Oxtr and the prostaglandin F2␣ receptor deleted exhibit no defects in parturition, indicating significant redundancy in the birth process per se (5). However, in view of the established pharmacology of circulating OT on the uterine myometrium, the possibility of a physiological action of OT during childbirth cannot be excluded, even without a loss-of-function phenotype.Two other key actions of OT warrant mention: effects on social , behavior and on the regulation of food intake. Male OT Ϫ/Ϫ and Oxtr Ϫ/Ϫ mice show deficits in social recognition, without altered cognition or olfactory learning. That this social amnesia is a central rather than a peripheral action of OT is supported by the observation that recombinant OT injected directly into the amygdala rescues the defect (6). Compared with males, female OT or Oxtr null mice display anxiety and exaggerated stress responses, which are likewise mediated through central OT-ergic neurones (7). OT also is involved in the reg...

Menopause is associated with bone loss and enhanced visceral adiposity. We have shown previously that a polyclonal antibody (Ab) to the β-subunit of the pituitary hormone Fsh increases bone mass in mice. Here, we report that this Ab sharply reduces adipose tissue in wild type mice, phenocopying genetic Fshr haploinsufficiency. The Ab also causes profound beiging, increases cellular mitochondrial density, activates brown adipose tissue, and enhances thermogenesis. These actions result from the specific binding of Ab to Fshβ to block its action. Our studies uncover novel opportunities for co-treating obesity and osteoporosis.

In nonneuronopathic type 1 Gaucher disease (GD1), mutations in the glucocerebrosidase gene (GBA1) gene result in glucocerebrosidase deficiency and the accumulation of its substrate, glucocerebroside (GL-1), in the lysosomes of mononuclear phagocytes. This prevailing macrophage-centric view, however, does not explain emerging aspects of the disease, including malignancy, autoimmune disease, Parkinson disease, and osteoporosis. We conditionally deleted the GBA1 gene in hematopoietic and mesenchymal cell lineages using an Mx1 promoter. Although this mouse fully recapitulated human GD1, cytokine measurements, microarray analysis, and cellular immunophenotyping together revealed widespread dysfunction not only of macrophages, but also of thymic T cells, dendritic cells, and osteoblasts. The severe osteoporosis was caused by a defect in osteoblastic bone formation arising from an inhibitory effect of the accumulated lipids LysoGL-1 and GL-1 on protein kinase C. This study provides direct evidence for the involvement in GD1 of multiple cell lineages, suggesting that cells other than macrophages may be worthwhile therapeutic targets.

Declining estrogen production after menopause causes osteoporosis in which the resorption of bone exceeds the increase in bone formation. We recently found that mice deficient in the ␤-subunit of follicle-stimulating hormone (FSH␤) are protected from bone loss despite severe estrogen deficiency. Here we show that FSH␤-deficient mice have lowered TNF␣ levels. However, TNF␣-deficient mice are resistant to hypogonadal bone loss despite having elevated FSH, suggesting that TNF␣ is critical to the effect of FSH on bone mass. We find that FSH directly stimulates TNF␣ production from bone marrow granulocytes and macrophages. We also explore how TNF␣ up-regulation induces bone loss. By modeling the known actions of TNF␣, we attribute the high-turnover bone loss to an expanded osteoclast precursor pool, together with enhanced osteoblast formation. TNF␣ inhibits osteoblastogenesis in the presence of ascorbic acid in culture medium, but in its absence this effect becomes stimulatory; thus, ascorbic acid reverses the true action of TNF␣. Likewise, ascorbic acid blunts the effects of TNF␣ in stimulating osteoclast formation. We propose that hypogonadal bone loss is caused, at least in part, by enhanced FSH secretion, which in turn increases TNF␣ production to expand the number of bone marrow osteoclast precursors. Ascorbic acid may prevent FSH-induced hypogonadal bone loss by modulating the catabolic actions of TNF␣.postmenopausal osteoporosis ͉ TNF␣ ͉ bone ͉ ascorbic acid ͉ hypogonadal P ostmenopausal osteoporosis is a leading cause of morbidity and mortality in the increasingly aging population, with fracture rates exceeding the combined incidence of breast cancer, stroke, and heart attacks in postmenopausal women (1). Traditionally, this bone loss has been attributed solely to declining estrogen levels. However, we recently showed that the pituitary hormone folliclestimulating hormone (FSH), the secretion of which is under estrogenic feedback, directly enhances osteoclast formation and function. The deletion of its ␤-subunit (FSH␤) protects against bone loss despite severe hypogonadism (2). This finding indicates that FSH is a requirement for hypogonadal bone loss and, although awaiting definitive proof, suggests strongly that elevated FSH contributes to the genesis of postmenopausal osteoporosis.However, enhanced osteoclastogenesis, a consequence of the direct action of FSH on its G i -coupled receptor on osteoclast precursors, does not fully explain hypogonadal bone loss. There are accompanying alterations in bone and bone marrow, notably enhanced bone formation, increased T lymphocyte production, and macrophage activation. The alterations in immune function have been attributed to an increase in TNF␣ production that is thought to arise solely from estrogen deficiency. However, because TNF inhibits osteoblast differentiation in vitro, the increased bone formation has not been attributed to TNF␣. Thus, the genesis of enhanced bone formation, an essential component of the highturnover bone loss, has remained unclear.Ablat...

We report that adrenocorticotropic hormone (ACTH) protects against osteonecrosis of the femoral head induced by depot methylprednisolone acetate (depomedrol). This therapeutic response likely arises from enhanced osteoblastic support and the stimulation of VEGF by ACTH; the latter is largely responsible for maintaining the fine vascular network that surrounds highly remodeling bone. We suggest examining the efficacy of ACTH in preventing human osteonecrosis, a devastating complication of glucocorticoid therapy.osteoporosis | osteoclast | osteoblast T he use of glucocorticoids for medical conditions as diverse as asthma, ulcerative colitis, kidney diseases, and rheumatologic disorders causes not only a variety of metabolic and medical complications, including diabetes and osteoporosis, but also a painful debilitating condition, osteonecrosis, usually affecting the femoral head (1). Osteonecrosis almost invariably requires surgical debridement of dead bone and contributes to approximately 10% of the more than 500,000 hip replacements annually in the United States (2). In addition, 30-50% patients on long-term glucocorticoids sustain a hip fracture with a 2-to 2.5-fold increased risk (3).Osteocyte apoptosis is thought to be the key determinant of glucocorticoid-induced cortical bone loss (4). Reduced osteoblast function manifesting in attenuated bone formation has also been documented in trabecular bone in rodents and humans (5). In contrast to glucocorticoid-induced osteoporosis, the pathogenesis of glucocorticoid-induced osteonecrosis is unclear (6). It resembles the osteonecrosis caused by traumatic damage to the artery that supplies the femoral head, hence the name, avascular necrosis (3), but the necrosis actually begins as regional trabecular death (6), likely from osteoblast and osteocyte apoptosis. However, there is strong evidence for an ischemic component. For example, studies using a rat model of Legg-Calve-Perthe's disease suggest that the intracortical blockade of lateral epiphyseal arteries that supply approximately 80% of the femoral head (7) can, in part, be attributed to their anatomical predisposition. It is nonetheless unclear whether ischemia is the initiating event or is secondary to local cellular or vascular bed damage (8).It is further surprising that osteonecrosis is not a cardinal feature of adrenocorticotropic hormone (ACTH)-producing adenomas (9), where glucocorticoid excess is profound. A question therefore arises-does ACTH protect against glucocorticoid-induced osteonecrosis? Indeed, one of our groups has documented functional ACTH receptors (MC2Rs) on osteoblasts; their activation enhances cell proliferation (10). These data are consistent with the presence of receptors for other anterior pituitary hormones, FSH and TSH, on bone cells, as well as with the description of another pituitary-bone axis, in which these hormones bypass traditional endocrine targets to regulate bone mass directly (11-13).We were thus prompted to investigate whether glucocorticoidinduced osteonecrosis could, i...

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