title: Functional roles of the bone morphogenetic protein system in thyrotropin signaling in porcine thyroid cells.
abstract: We uncovered a new regulation of thyrocyte function by bone morphogenetic protein (BMP) under the influence of thyrotropin (TSH) using primary culture of porcine thyrocytes. The BMP type I receptors, ALK-2 (ActRIA), -3 (BMPRIA), and -6 (BMPRIB), were expressed in porcine thyrocytes, while ALK-6 was not detected in human thyroid. Treatment with BMP-2, -4, -6, -7, and TGF-beta1 exhibited a dose-dependent suppression of DNA synthesis by porcine thyrocytes. BMP-2, -4, -6, -7, and TGF-beta1 suppressed TSH receptor mRNA expression on thyrocytes, which was consistent with their suppressive effect on TSH-induced cAMP synthesis and TSH-induced insulin-like growth factor-1 expression. Activin exhibited minimal suppression of thyrocyte DNA synthesis and did not exhibit suppressive effects on TSH receptor mRNA expression. Phosphorylated Smad1/5/8 was detected in the lysates of porcine thyrocytes treated with BMP-2, -4, -6, and -7. However, in the presence of TSH, BMP-6 and -7 failed to activate Smad1/5/8 phosphorylation and 3TP-reporter activity, whereas BMP-2 and -4 maintained clear activation of the BMP signaling regardless of the presence of TSH. This diverged regulation of thyroid BMP system by TSH is most likely due to the reduction of ALK-6 expression caused by TSH. Thus, the thyroid BMP system is functionally linked to TSH actions through modulating TSH receptor expression and TSH, in turn, selectively inhibits BMP signaling. Given that BMP system is present in human thyroid and the expression pattern of ALK-2 and BMPRII is different between follicular adenomas and normal thyroid tissues, the endogenous BMP system may be involved in regulating thyrocyte growth and TSH sensitivity of human thyroid adenomas.
authors.affiliation: Department of Medicine and Clinical Science, Okayama University Graduate School of Medicine and Dentistry, 2-5-1 Shikata-cho, Okayama City 700-8558, Japan.
authors.forename: Jiro
authors.initials: J
authors.lastname: Suzuki
authors.forename: Fumio
authors.initials: F
authors.lastname: Otsuka
authors.forename: Masaya
authors.initials: M
authors.lastname: Takeda
authors.forename: Kenichi
authors.initials: K
authors.lastname: Inagaki
authors.forename: Tomoko
authors.initials: T
authors.lastname: Miyoshi
authors.forename: Yukari
authors.initials: Y
authors.lastname: Mimura
authors.forename: Toshio
authors.initials: T
authors.lastname: Ogura
authors.forename: Hiroyoshi
authors.initials: H
authors.lastname: Doihara
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Makino
mesh_terms: D000328:Adult; D000818:Animals; D052004:Bone Morphogenetic Protein Receptors; D019485:Bone Morphogenetic Proteins / Q000378:metabolism* / Q000494:pharmacology; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000378:metabolism; D004247:DNA / Q000096:biosynthesis; D005260:Female; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000235:genetics; D008297:Male; D008875:Middle Aged; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D017978:Receptors, Growth Factor / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D013552:Swine; D013961:Thyroid Gland / Q000166:cytology* / Q000187:drug effects* / Q000378:metabolism; D013972:Thyrotropin / Q000494:pharmacology*
chemical_list: D019485:Bone Morphogenetic Proteins; D012333:RNA, Messenger; D017978:Receptors, Growth Factor; D007334:Insulin-Like Growth Factor I; D013972:Thyrotropin; D004247:DNA; D000242:Cyclic AMP; D052004:Bone Morphogenetic Protein Receptors