Abstract:
: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 the Tnfα 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 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.
journal_name
Proc Natl Acad Sci U S Aauthors
Sun L,Zhu LL,Lu P,Yuen T,Li J,Ma R,Baliram R,Moonga SS,Liu P,Zallone A,New MI,Davies TF,Zaidi Mdoi
10.1073/pnas.1308336110subject
Has Abstractpub_date
2013-06-11 00:00:00pages
9891-6issue
24eissn
0027-8424issn
1091-6490pii
1308336110journal_volume
110pub_type
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