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

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 beta-subunit of follicle-stimulating hormone (FSH beta) are protected from bone loss despite severe estrogen deficiency. Here we show that FSH beta-deficient mice have lowered TNF alpha levels. However, TNF alpha-deficient mice are resistant to hypogonadal bone loss despite having elevated FSH, suggesting that TNF alpha is critical to the effect of FSH on bone mass. We find that FSH directly stimulates TNF alpha production from bone marrow granulocytes and macrophages. We also explore how TNF alpha up-regulation induces bone loss. By modeling the known actions of TNF alpha, we attribute the high-turnover bone loss to an expanded osteoclast precursor pool, together with enhanced osteoblast formation. TNF alpha 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 alpha. Likewise, ascorbic acid blunts the effects of TNFa 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 alpha 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 alpha.