Follicle-stimulating hormone stimulates TNF production from immune cells to enhance osteoblast and osteoclast formation
Follicle-stimulating hormone stimulates TNF production from immune cells to enhance osteoblast and osteoclast formation
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DOI：
10.1073/pnas.0606805103
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发表时间：
2006-10-03
影响因子：
11.1
通讯作者：
Zaidi, Mone
中科院分区：
文献类型：
--
作者：
Iqbal, Jameel;Li Sun;Zaidi, Mone
绝经后雌激素分泌减少会导致骨质疏松症，骨的吸收超过骨形成的增加。我们最近发现，尽管严重缺乏雌激素，但卵泡刺激素(FSH)β亚基缺陷的小鼠仍可防止骨质丢失。在这里，我们显示FSHβ缺陷小鼠降低了肿瘤坏死因子α水平。然而，尽管卵泡刺激素升高，肿瘤坏死因子α缺陷小鼠仍能抵抗性腺功能低下的骨丢失，这表明肿瘤坏死因子α在卵泡刺激素对骨量的影响中起关键作用。我们发现FSH能直接刺激骨髓粒细胞和巨噬细胞产生肿瘤坏死因子α。我们还探讨了肿瘤坏死因子α上调如何导致骨丢失。通过模拟已知的肿瘤坏死因子α的作用，我们将高周转率的骨丢失归因于扩大的破骨细胞前体池，以及增强的成骨细胞形成。在培养液中有抗坏血酸存在时，肿瘤坏死因子α抑制成骨细胞的形成，但在没有抗坏血酸的情况下，这一作用变为刺激作用；因此，抗坏血酸逆转了肿瘤坏死因子α的真实作用。同样，抗坏血酸减弱了TNFa刺激破骨细胞形成的作用。我们认为，性腺下部骨质丢失至少部分是由于FSH分泌增加，进而增加了肿瘤坏死因子α的产生，从而扩大了骨髓破骨细胞前体的数量。抗坏血酸可能通过调节肿瘤坏死因子α的分解代谢作用来预防FSH诱导的性腺下腺骨质丢失。
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.