Follicle-stimulating hormone stimulates TNF production from immune cells to enhance osteoblast and osteoclast formation

Abstract

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...

Pituitary-bone connection in skeletal regulation

“…We discovered that FSH directly stimulates bone resorption by osteoclasts [8,9]. Several studies have confirmed direct effects of FSH on the skeleton in rodents and humans.…”

“…In a separate study, FSHR activation was shown to enhance RANK receptor expression [20]. In addition, FSH indirectly stimulates osteoclast formation by releasing osteoclastogenic cytokines, namely interleukin 1β (IL-1β), tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) in proportion to the surface expression of FSHRs [9,21]. In a study of 36 women between the ages of 20 and 50 years, serum FSH concentrations correlated with circulating cytokine concentrations [21,22].…”

Epitope-specific monoclonal antibodies to FSHβ increase bone mass

“…In addition to its action on bone and fat cells, we found previously that FSH directly upregulates the production of the inflammatory cytokine TNFα (27). Mice genetically deficient in FSHβ thus showed reduced TNFα production from bone marrow macrophages (27).…”

Blocking antibody to the β-subunit of FSH prevents bone loss by inhibiting bone resorption and stimulating bone synthesis

“…Wu et al independently show that FSH stimulates osteoclastogenesis, which is abolished in mice lacking immunoreceptor tyrosine-based activation motif (ITAM) adapter signaling molecules (11). FSHR activation also enhances receptor activator of nuclear factor kappa-B (RANK) receptor expression (29), and indirectly stimulates osteoclast formation by releasing IL-1β, TNF-α, and IL-6 (30,31). Serum FSH levels thus correlate with circulating cytokine concentrations (32).…”