期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2013
卷号：110
期号：24
页码：9891-9896
DOI：10.1073/pnas.1308336110
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：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 TNF. Compound mouse mutants generated by genetically deleting the Tnf gene on a Tshr-/- (homozygote) or Tshr+/- (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 TNF production from macrophages and osteoblasts, respectively. TNF, in turn, stimulates osteoclastogenesis but also enhances the production in bone marrow of a variant TSH{beta}. This locally produced TSH suppresses osteoclast formation in a negative feedback loop. We speculate that TNF 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.
关键词：bone metabolism ; thyroid disease ; bone density
