T3 Regulates a Human Macrophage-Derived TSH-β Splice Variant: Implications for Human Bone Biology

TSH and thyroid hormones (T-3 and T-4) are intimately involved in bone biology. We have previously reported the presence of a murine TSH-beta splice variant (TSH-beta v) expressed specifically in bone marrow-derived macrophages and that exerted an osteoprotective effect by inducing osteoblas-togenesis. To extend this observation and its relevance to human bone biology, we set out to identify and characterize a TSH-beta variant in human macrophages. Real-time PCR analyses using human TSH-beta-specific primers identified a 364-bp product in macrophages, bone marrow, and peripheral blood mononuclear cells that was sequence verified and was homologous to a human TSH-beta v previously reported. We then examined TSH-beta v regulation using the THP-1 human monocyte cell line matured into macrophages. After 4 days, 46.1% of the THP-1 cells expressed the macrophage markers CD-14 and macrophage colony-stimulating factor and exhibited typical morphological characteristics of macrophages. Real-time PCR analyses of these cells treated in a dose-dependent manner with T-3 showed a 14-fold induction of human TSH-beta v mRNA and variant protein. Furthermore, these human TSH-beta v-positive cells, induced by T-3 exposure, had categorized into both M1 and M2 macrophage phenotypes as evidenced by the expression of macrophage colony-stimulating factor for M1 and CCL-22 for M2. These data indicate that in hyperthyroidism, bone marrow resident macrophages have the potential to exert enhanced osteoprotective effects by oversecreting human TSH-beta v, which may exert its local osteoprotective role via osteoblast and osteoclast TSH receptors.