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

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 Tnf α 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.

Pituitary-bone connection in skeletal regulation

“…TNFα production is expectedly upregulated in osteoporotic TSHR -/-mice [37], and the genetic deletion of TNFα in these mice reverses the osteoporosis, as well as the bone formation and resorption defects, proving that the TSHR -/-phenotype is mediated by TNFα, at least in part [64,76]. The osteoporosis, low bone formation, and hyperresorption that accompany TSH deficiency were fully rescued in compound mouse mutants in which TNFα is genetically deleted on a homozygote TSHR -/-or heterozygote TSHR +/-background [76]. Studies using ex vivo bone marrow cell cultures show that TSH inhibits and stimulates TNFα production from macrophages and osteoblasts, respectively [76].…”

“…The effect of TSH on TNFα synthesis is mediated transcriptionally by binding of two high mobility group box proteins, HMGB1 and HMGB2, to TNFα gene promoter [75]. TNFα production is expectedly upregulated in osteoporotic TSHR -/-mice [37], and the genetic deletion of TNFα in these mice reverses the osteoporosis, as well as the bone formation and resorption defects, proving that the TSHR -/-phenotype is mediated by TNFα, at least in part [64,76]. The osteoporosis, low bone formation, and hyperresorption that accompany TSH deficiency were fully rescued in compound mouse mutants in which TNFα is genetically deleted on a homozygote TSHR -/-or heterozygote TSHR +/-background [76].…”

“…The osteoporosis, low bone formation, and hyperresorption that accompany TSH deficiency were fully rescued in compound mouse mutants in which TNFα is genetically deleted on a homozygote TSHR -/-or heterozygote TSHR +/-background [76]. Studies using ex vivo bone marrow cell cultures show that TSH inhibits and stimulates TNFα production from macrophages and osteoblasts, respectively [76]. TNFα, in turn, not only stimulates osteoclastogenesis but also enhances the production in bone marrow of a variant TSHβ [76,77].…”

“…Studies using ex vivo bone marrow cell cultures show that TSH inhibits and stimulates TNFα production from macrophages and osteoblasts, respectively [76]. TNFα, in turn, not only stimulates osteoclastogenesis but also enhances the production in bone marrow of a variant TSHβ [76,77]. This locally produced TSH suppresses osteoclast formation in a negative feedback loop.…”

Enhancement of Osteogenic Differentiation by Combination Treatment with 5-azacytidine and Thyroid-Stimulating Hormone in Human Osteoblast Cells

“…9) Since the genetic deletion of TNFα in these mice ameliorated low bone mass, as well as the bone formation and resorption defects, it is reasonable to deduce that the low bone mass phenotype of Tshr −/− mice is mediated by TNFα, at least in part. 10,11) However, the role of TSH in osteoblast regulation is still undetermined. While it inhibits osteoblastic differentiations in bone marrow-derived mesenchymal stromal cell cultures, TSH stimulates differentiation and mineralization in murine cell cultures via a Wnt5a-dependent manner.…”