Genetic confirmation for a central role for TNFα in the direct action of thyroid stimulating hormone on the skeleton

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 alpha. Compound mouse mutants generated by genetically deleting the Tnf alpha 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 alpha production from macrophages and osteoblasts, respectively. TNF alpha, 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 alpha 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.