Genetic confirmation for a central role for TNF* in the direct action of thyroid stimulating hormone on the skeleton.
Genetic confirmation for a central role for TNF* in the direct action of thyroid stimulating hormone on the skeleton.
复制标题
基因证实 TNF* 在促甲状腺激素对骨骼的直接作用中发挥核心作用。
DOI：
10.1073/pnas.1308336110
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发表时间：
2013
影响因子：
11.1
通讯作者：
Zaidi,Mone
中科院分区：
文献类型：
--
作者：
Sun,Li;Zhu,Ling-Ling;Lu,Ping;Yuen,Tony;Li,Jianhua;Ma,Risheng;Baliram,Ramkumarie;Baliram,Ramkumari;Moonga,SurinderS;Liu,Peng;Zallone,Alberta;New,MariaI;Davies,TerryF;Zaidi,Mone
Clinical data showing correlations between low thyroid-stimulating hormone (TSH) levels and high bone turnover markers, low bone mineral density, and an increased risk of osteoporosis-related fractures are buttressed by mouse genetic and pharmacological studies identifying a direct action of TSH on the skeleton. Here we show that the skeletal actions of TSH deficiency are mediated, in part, through TNFα. Compound mouse mutants generated by genetically deleting theTnfαgene on aTshr−/−(homozygote) orTshr+/−(heterozygote) background resulted in full rescue of the osteoporosis, low bone formation, and hyperresorption that accompany TSH deficiency. Studies using ex vivo bone marrow cell cultures showed that TSH inhibits and stimulates TNFα production from macrophages and osteoblasts, respectively. TNFα, in turn, stimulates osteoclastogenesis but also enhances the production in bone marrow of a variant TSHβ. This locally produced TSH suppresses osteoclast formation in a negative feedback loop. We speculate that TNFα elevations due to low TSH signaling in human hyperthyroidism contribute to the bone loss that has traditionally been attributed solely to high thyroid hormone levels.
