TY - JOUR
T1 - Functional roles of the bone morphogenetic protein system in thyrotropin signaling in porcine thyroid cells
AU - Suzuki, Jiro
AU - Otsuka, Fumio
AU - Takeda, Masaya
AU - Inagaki, Kenichi
AU - Miyoshi, Tomoko
AU - Mimura, Yukari
AU - Ogura, Toshio
AU - Doihara, Hiroyoshi
AU - Makino, Hirofumi
N1 - Funding Information:
We thank Dr. R. Kelly Moore for helpful discussion and critical reading of the manuscript. We are grateful to Drs. Jeff Wrana, Kohei Miyazono, and Shunichi Shimasaki for providing the Xvent2-Luc, Tlx2-Luc, and 3TP-Luc plasmids. We also thank Yamasa Corp. for providing porcine thyroid cells. This work was supported in part by Grants-in-Aid for Scientific Research (No. 16790525), Uehara Memorial Foundation, Japan Research Foundation for Clinical Pharmacology, Yamaguchi Endocrine Research Association, and Kanzawa Medical Research Foundation.
PY - 2005/2/25
Y1 - 2005/2/25
N2 - 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-β1 exhibited a dose-dependent suppression of DNA synthesis by porcine thyrocytes. BMP-2, -4, -6, -7, and TGF-β1 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.
AB - 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-β1 exhibited a dose-dependent suppression of DNA synthesis by porcine thyrocytes. BMP-2, -4, -6, -7, and TGF-β1 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.
KW - Activin receptor-like kinase
KW - Bone morphogenetic protein
KW - Thyroid follicular adenoma
KW - Thyroid papillary carcinoma
KW - Thyrotropin
KW - Transforming growth factor-β
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UR - http://www.scopus.com/inward/citedby.url?scp=12344249682&partnerID=8YFLogxK
U2 - 10.1016/j.bbrc.2004.12.122
DO - 10.1016/j.bbrc.2004.12.122
M3 - Article
C2 - 15652513
AN - SCOPUS:12344249682
VL - 327
SP - 1124
EP - 1130
JO - Biochemical and Biophysical Research Communications
JF - Biochemical and Biophysical Research Communications
SN - 0006-291X
IS - 4
ER -