华人科学家彭原振：PNAS上发表甲状腺素研究的最新成果

生物谷

        在最新一期的《美国科学院院刊》（8月22日）上，来自美国纽约西奈山医学院的华人学者彭原振（Yuanzhen  Peng）、刘兰英（Lanying  Liu）、孙莉（Li  Sun）等人和同事公布了他们有关甲状腺激素研究的最新成果。

        在之前的研究中，这个研究组已经证实，通过影响甲状腺刺激激素（TSH）受体（TSHR），甲状腺激素能够负向调控破骨细胞的分化。研究人员发现杂合和纯合TSHR小鼠其破骨细胞分化增加了。

        在这项新的研究中，研究人员发现TNFα的水平也同时上升。TNFα是一种破骨细胞激素，它的水平的上升导致破骨细胞分化的加剧。TSHR–/–和  TSHR+/–小鼠中这种分化水平的增加在TSHR–/–/TNF  –/–和TSHR+/–/TNF  +/小鼠中消失了。

        在平行研究中，研究人员发现TSH能直接抑制TNFα的制造，并减少产TNFα的破骨细胞前体的数目，而且能够利用IL-1、TNFα和NF-B配基受体活化因子来减弱TNFα表达的诱导。

        TSH还能抑制小鼠巨噬细胞和RAW-C3细胞中破骨细胞的形成。这种抑制作用对过度表达TSHR的细胞比对那些用空载体转染的细胞会产生更深远的影响。

        这种与配基无关的活性TSHR的过度表达能阻止破骨细胞的形成，即使是在缺少TSH的情况下。最终，IL-1/TNFα和NF-B配基受体活化因子不能活化AP-1。这项研究的结果表明TNFα是关键的细胞激素，它接到TSH对骨骼的下游抗再吸收效应。

部分英文原文；

TNF mediates the skeletal effects of thyroid-stimulating hormone

We have shown recently that by acting on the thyroid-stimulating hormone (TSH) receptor (TSHR), TSH negatively regulates osteoclast differentiation. Both heterozygotic and homozygotic TSHR null mice are osteopenic with evidence of enhanced osteoclast differentiation. Here, we report that the accompanying elevation of TNF {alpha} , an osteoclastogenic cytokine, causes the increased osteoclast differentiation. This enhancement in TSHR-/- and TSHR+/- mice is abrogated in compound TSHR-/-/TNF {alpha} -/- and TSHR+/-/TNF {alpha} +/- mice, respectively. In parallel studies, we find that TSH directly inhibits TNF {alpha} production, reduces the number of TNF {alpha} -producing osteoclast precursors, and attenuates the induction of TNF {alpha} expression by IL-1, TNF {alpha} , and receptor activator of NF- {kappa} B ligand. TSH also suppresses osteoclast formation in murine macrophages 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/TNF {alpha} and receptor activator of NF- {kappa} B ligand fail to stimulate AP-1 and NF- {kappa} B binding to DNA in cells transfected with TSHR or constitutively active TSHR. The results suggest that TNF {alpha} is the critical cytokine mediating the downstream antiresorptive effects of TSH on the skeleton.