| First Author | Sun L | Year | 2013 |
| Journal | Proc Natl Acad Sci U S A | Volume | 110 |
| Issue | 24 | Pages | 9891-6 |
| PubMed ID | 23716650 | Mgi Jnum | J:197402 |
| Mgi Id | MGI:5492271 | Doi | 10.1073/pnas.1308336110 |
| Citation | Sun L, et al. (2013) Genetic confirmation for a central role for TNFalpha in the direct action of thyroid stimulating hormone on the skeleton. Proc Natl Acad Sci U S A 110(24):9891-6 |
| abstractText | 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 TNFalpha. Compound mouse mutants generated by genetically deleting the Tnfalpha 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 TNFalpha production from macrophages and osteoblasts, respectively. TNFalpha, in turn, stimulates osteoclastogenesis but also enhances the production in bone marrow of a variant TSHbeta. This locally produced TSH suppresses osteoclast formation in a negative feedback loop. We speculate that TNFalpha 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. |
