Thyroid hormone excess rather than thyrotropin deficiency induces osteoporosis in hyperthyroidism
Thyroid hormone excess rather than thyrotropin deficiency induces osteoporosis in hyperthyroidism
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DOI：
10.1210/me.2007-0033
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发表时间：
2007-05-01
影响因子：
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通讯作者：
Williams, Graham R.
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文献类型：
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作者：
Bassett, J. H. Duncan;O'Shea, Patrick J.;Williams, Graham R.
甲状腺机能亢进症是骨质疏松症的一个重要但尚未被认识到的原因。最近，促甲状腺激素缺乏，而不是甲状腺激素过多，被认为是根本原因。为了研究甲状腺疾病中骨质疏松症的分子机制，我们对缺乏甲状腺激素受体α或β(trα(0/0)，trβ(-/-))的小鼠的骨骼进行了表征。值得注意的是，在循环甲状腺激素和TSH浓度正常的情况下，成年trα(0/0)小鼠出现骨硬化并伴有破骨细胞性骨吸收减少，而幼年小鼠软骨内成骨延迟，骨矿沉积减少。相比之下，TSH和甲状腺激素水平升高的成年trβ(-/-)小鼠骨质疏松，有证据表明骨吸收增加，而青少年有晚期骨化，骨矿沉积增加。对T-3靶基因表达的分析显示，在trα(0/0)小鼠中存在骨骼甲状腺功能减退，而在trβ(-/-)小鼠中存在骨骼甲状腺毒性。这些研究表明，甲状腺功能亢进症的骨丢失不依赖于循环中的TSH水平，并且主要由trα介导，从而证实trα是预防和治疗骨质疏松症的新的药物靶点。
Thyrotoxicosis is an important but under recognized cause of osteoporosis. Recently, TSH deficiency, rather than thyroid hormone excess, has been suggested as the underlying cause. To investigate the molecular mechanism of osteoporosis in thyroid disease, we characterized the skeleton in mice lacking either thyroid hormone receptor alpha or beta (TR alpha(0/0), TR beta(-/-)). Remarkably, in the presence of normal circulating thyroid hormone and TSH concentrations, adult TR alpha(0/0) mice had osteosclerosis accompanied by reduced osteoclastic bone resorption, whereas juveniles had delayed endochondral ossification with reduced bone mineral deposition. By contrast, adult TR beta(-/-) mice with elevated TSH and thyroid hormone levels were osteoporotic with evidence of increased bone resorption, whereas juveniles had advanced ossification with increased bone mineral deposition. Analysis of T-3 target gene expression revealed skeletal hypothyroidism in TR alpha(0/0) mice, but skeletal thyrotoxicosis in TR beta(-/-) mice. These studies demonstrate that bone loss in thyrotoxicosis is independent of circulating TSH levels and mediated predominantly by TR alpha, thus identifying TR alpha as a novel drug target in the prevention and treatment of osteoporosis.