TSH, Hyperthyroidism, and Bone Mass.

Thyrotropin, traditionally seen as a pituitary hormone that regulates thyroid glands, has additional roles in physiology including skeletal remodeling. Population-based observations in subjects with euthyroidism or subclinical hyperthyroidism indicated a negative association between bone mass and low-normalTSH. The findings of correlative studies were supported by small intervention trials using recombinant human TSH (rhTSH) injection, and genetic and case-based evidence. Genetically-modified mouse models, which disrupt the reciprocal relationship between TSH and thyroid hormone, have allowed us to examine an independent role of TSH. Since the first description of osteoporotic phenotype in haploinsufficient Tshr  +/- mice with normal thyroid hormone levels, the anti-osteoclastic effect of TSH has been documented in in vitro and in vivo studies. Further studies showed that increased osteoclastogenesis in Tshr-deficient mice was mediated by TNFα. Low TSH not only increased osteoclastogenesis, but also decreased osteoblastogenesis in bone marrow-derived primary osteoblast cultures. However, later in vivo studies using small and intermittent dose of rhTSH showed pro-anabolic effect, which suggests that its action might be dose- and frequency-dependent. TSHR was shown to interact with IGF1R, and VEGF and Wnt pathway might play a role in TSH effect on osteoblasts. The expression and direct skeletal effect of a biologically active splice variant of TSHβ subunit (TSHβv) in bone-marrow-derived macrophage and other immune cells suggest local skeletal effect of TSHR. Further studies of how locally secreted TSHβv and systemic TSHβ interact in skeletal remodeling through the endocrine, immune and skeletal system will help us better understand the hyperthyroidism-induced bone disease.