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J. Biol. Chem., Vol. 278, Issue 52, 52240-52252, December 26, 2003

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Parathyroid Hormone-Smad3 Axis Exerts Anti-apoptotic Action and Augments Anabolic Action of Transforming Growth Factor in Osteoblasts^*

Hideaki Sowa, Hiroshi Kaji, Mei Fway Iu, Tatsuo Tsukamoto, Toshitsugu Sugimoto, and Kazuo Chihara

From the Division of Endocrinology/Metabolism, Neurology and Hematology/Oncology, Department of Clinical Molecular Medicine, Kobe University Graduate School of Medicine, 7-5-2 Kusunoki-cho, Chuo-ku, Kobe 650-0017, Japan

Although several studies indicated that parathyroid hormone (PTH) exerted anabolic action on bone, its precise mechanisms have been unknown. On the other hand, transforming growth factor (TGF-), abundantly stored in bone matrix, stimulates bone formation with a local injection in rodents. Although our previous study suggested that Smad3 is an important molecule for the stimulation of bone formation, no reports have been available about the effects of PTH on Smad3. In this present study, we examined the effects of PTH on Smad3 and the physiological significance in mouse osteoblastic cells. PTH promoted the expression of Smad3 mRNA within 10 min and the protein level in a dose-dependent manner in MC3T3-E1 and rat osteoblastic UMR-106 cells. Protein kinase A (PKA) activator as well as protein kinase C (PKC) activators increased Smad3 protein level, and both PKA and PKC inhibitors antagonized PTH-induced Smad3, indicating that PTH promotes the production of Smad3 through both PKA and PKC pathways. Next, we examined anti-apoptotic effects of PTH and Smad3 in these cells, employing trypan blue, transferase-mediated nick end labeling, and Hoechst staining. Pretreatment with PTH or overexpression of Smad3 decreased the number of apoptotic cells induced by dexamethasone and etoposide. Moreover, a dominant negative mutant, Smad3C, abrogated PTH-induced anti-apoptotic effects. On the other hand, PTH augmented TGF--induced transcriptional activity. Furthermore, PTH enhanced TGF--induced production of type I collagen, whereas it did not affect TGF--reduced proliferation in MC3T3-E1 cells. These observations indicated that PTH amplified the anabolic effects of TGF- by accelerating the transcriptional activity of Smad3. In conclusion, we first demonstrated that PTH-Smad3 axis exerts anti-apoptotic effects in osteoblasts and reinforces the anabolic action by TGF- in osteoblasts. Hence, PTH-Smad3 axis might be involved in the bone anabolic action of PTH.

Received for publication, March 13, 2003 , and in revised form, July 22, 2003.

^* This work was supported in part by a grant from Kanzawa Medical Research Foundation (to H. K.); Grants-in-aid 15590977 (to H. K.) and 14571064 (to T. S.) from the Ministry of Science, Education, and Culture of Japan; and a grant-in-aid from the Hormone Receptor Abnormality Research Committee Ministry of Health and Welfare of Japan (to T. S.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed. Tel.: 81-78-382-5885; Fax: 81-78-382-5899; E-mail: sugimot{at}med.kobe-u.ac.jp.

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