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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >TNFα mediates the skeletal effects of thyroid-stimulating hormone
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TNFα mediates the skeletal effects of thyroid-stimulating hormone

机译：TNFα介导促甲状腺激素的骨骼作用

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摘要

We have shown recently that by acting on the thyroid-stimulating hormone (TSH) receptor (TSHR), TSH negatively regulates oste-oclast differentiation. Both heterozygotic and homozygotic TSHR null mice are osteopenic with evidence of enhanced osteoclast differentiation. Here, we report that the accompanying elevation of TNFα, an osteoclastogenic cytokine, causes the increased osteoclast differentiation. This enhancement in TSHR~(-/-) and TSHR~(+/-) mice is abrogated in compound TSHR~(-/-)/TNFα~(-/-) and TSHR~(+/-)/TNFα~(+/-) mice, respectively. In parallel studies, we find that TSH directly inhibits TNFα production, reduces the number of TNFα-producing osteoclast precursors, and attenuates the induction of TNFα expression by IL-1, TNFα, and receptor activator of NF-κB ligand. TSH also suppresses osteoclast formation in murine mac-rophages and RAW-C3 cells. The suppression is more profound in cells that overexpress the TSHR than those transfected with empty vector. The overexpression of ligand-independent, constitutively active TSHR abrogates osteoclast formation even under basal conditions and in the absence of TSH. Finally, IL-1/TNFα and receptor activator of NF-κB ligand fail to stimulate AP-1 and NF-κB binding to DNA in cells transfected with TSHR or constitutively active TSHR. The results suggest that TNFα is the critical cytokine mediating the downstream antiresorptive effects of TSH on the skeleton.
机译：我们最近显示，通过作用于促甲状腺激素（TSH）受体（TSHR），TSH负调节了破骨细胞的分化。 TSHR null杂合子和纯合子小鼠均具有骨质减少性，并有破骨细胞分化增强的证据。在这里，我们报道伴随的TNFα（破骨细胞因子）的升高引起破骨细胞分化的增加。 TSHR〜（-/-）和TSHR〜（+/-）小鼠的这种增强在化合物TSHR〜（-/-）/TNFα〜（-/-）和TSHR〜（+/-）/TNFα〜（ +/-）只小鼠。在平行研究中，我们发现TSH直接抑制TNFα的产生，减少产生TNFα的破骨细胞前体的数量，并减弱IL-1，TNFα和NF-κB配体的受体激活剂对TNFα表达的诱导。 TSH还抑制鼠巨噬细胞和RAW-C3细胞中的破骨细胞形成。与用空载体转染的细胞相比，在过表达TSHR的细胞中抑制作用更为明显。配体非依赖性，组成型活性TSHR的过表达即使在基础条件下和没有TSH的情况下也能消除破骨细胞的形成。最后，IL-1 /TNFα和NF-κB配体的受体激活剂不能刺激AP-1和NF-κB与TSHR或组成型活性TSHR转染的细胞中的DNA结合。结果表明，TNFα是介导TSH对骨架的下游抗再吸收作用的关键细胞因子。

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