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 (FSHbeta) are protected from bone loss despite severe estrogen deficiency. Here we show that FSHbeta-deficient mice have lowered TNFalpha levels. However, TNFalpha-deficient mice are resistant to hypogonadal bone loss despite having elevated FSH, suggesting that TNFalpha is critical to the effect of FSH on bone mass. We find that FSH directly stimulates TNFalpha production from bone marrow granulocytes and macrophages. We also explore how TNFalpha up-regulation induces bone loss. By modeling the known actions of TNFalpha, we attribute the high-turnover bone loss to an expanded osteoclast precursor pool, together with enhanced osteoblast formation. TNFalpha 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 TNFalpha. Likewise, ascorbic acid blunts the effects of TNFalpha in stimulating osteoclast formation. We propose that hypogonadal bone loss is caused, at least in part, by enhanced FSH secretion, which in turn increases TNFalpha 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 TNFalpha.
Iqbal
Jameel
J
Mount Sinai Bone Program, Department of Medicine, Mount Sinai School of Medicine, New York, NY 10029, USA.
Sun
Li
L
Kumar
T Rajendra
TR
Blair
Harry C
HC
Zaidi
Mone
M
D000818:Animals; D001205:Ascorbic Acid / Q000494:pharmacology; D001854:Bone Marrow Cells / Q000378:metabolism*; D001862:Bone Resorption; D001842:Bone and Bones / Q000187:drug effects / Q000378:metabolism; D037201:Follicle Stimulating Hormone, beta Subunit / Q000172:deficiency / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008954:Models, Biological; D010006:Osteoblasts / Q000166:cytology* / Q000187:drug effects; D010010:Osteoclasts / Q000166:cytology* / Q000187:drug effects; D013234:Stem Cells / Q000166:cytology; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis*
D037201:Follicle Stimulating Hormone, beta Subunit; D014409:Tumor Necrosis Factor-alpha; D001205:Ascorbic Acid