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

• Published in: Endocrinology (Philadelphia) 2016-09, Vol.157 (9), p.3658-3667
• Main Authors: Baliram, R, Latif, R, Morshed, S. A, Zaidi, M, Davies, T. F
• Format: Article
• Language: English
• Subjects: Alternative splicing; Animals; Biological effects; Biology; Bone and Bones - metabolism; Bone marrow; Cell Line; CHO Cells; Colony-stimulating factor; Cricetulus; Hormones; Humans; Hyperthyroidism; Leukocytes (mononuclear); Macrophage colony-stimulating factor; Macrophages; Macrophages - metabolism; Male; Mice, Inbred C57BL; Monocytes; mRNA; Original Research; Osteoblastogenesis; Peripheral blood mononuclear cells; Phenotypes; Physical characteristics; Protein folding; Protein Isoforms; Real time; Thyroid; Thyroid gland; Thyroid hormones; Thyroid-stimulating hormone; Thyrotropin, beta Subunit - metabolism; Thyroxine; Time dependence; Triiodothyronine; Triiodothyronine - metabolism
• ISSN: 0013-7227; 1945-7170
• DOI: 10.1210/en.2015-1974

TSH and thyroid hormones (T3 and T4) are intimately involved in bone biology. We have previously reported the presence of a murine TSH-β splice variant (TSH-βv) expressed specifically in bone marrow-derived macrophages and that exerted an osteoprotective effect by inducing osteoblastogenesis. To extend this observation and its relevance to human bone biology, we set out to identify and characterize a TSH-β variant in human macrophages. Real-time PCR analyses using human TSH-β-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-βv previously reported. We then examined TSH-βv 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 T3 showed a 14-fold induction of human TSH-βv mRNA and variant protein. Furthermore, these human TSH-βv-positive cells, induced by T3 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-βv, which may exert its local osteoprotective role via osteoblast and osteoclast TSH receptors.