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Parathyroid Hormone Increases ß-Catenin Levels through Smad3 in Mouse Osteoblastic Cells

Division of Endocrinology/Metabolism, Neurology, and Hematology/Oncology, Department of Clinical Molecular Medicine, Kobe University Graduate School of Medicine (T.T., H.K., H.S., J.N., K.C.), Kobe 650-0017, Japan; Departments of Medicine, Physiology, and Human Genetics, McGill University, and Calcium Research Laboratory and Hormones and Cancer Research Unit, Royal Victoria Hospital (L.C., G.N.H.), Montréal, Québec, Canada H3A 1A1; and Department of Endocrinology, Metabolism, and Hematological Oncology, Shimane University School of Medicine (T.S.), Shimane 693-8501, Japan

Address all correspondence and requests for reprints to: Dr. Hiroshi Kaji, Division of Endocrinology/Metabolism, Neurology, and Hematology/Oncology, Department of Clinical Molecular Medicine, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe 650-0017, Japan. E-mail: hiroshik{at}med.kobe-u.ac.jp.

PTH, via the PTH/PTH-related protein receptor type 1 that couples to both protein kinase A (PKA) and protein kinase C (PKC) pathways, and the canonical Wnt-ß-catenin signaling pathway play important roles in bone formation. In the present study we have examined the interaction between the PTH and Wnt signaling pathways in mouse osteoblastic MC3T3-E1 cells. PTH dose- and time-dependently increased the concentrations of ß-catenin. The PKA activator, forskolin, and the PKC activator, phorbol 12-myristate-13-acetate, as well as the PTH analog, [Nle^8,18,Tyr³⁴]human PTH-(3–34)amide, all increased ß-catenin levels. Both H-89, a specific PKA inhibitor, and PKC inhibitors, staurosporine and calphostin C, antagonized PTH stimulation of ß-catenin levels. TGF-ß as well as transfection of the TGF-ß-signaling molecule, Smad3, enhanced ß-catenin levels, and this was antagonized by transfection of a dominant-negative Smad3. The transcriptional activity of transfected dominant-active ß-catenin was enhanced by PTH, an effect that was antagonized by cotransfection of a dominant-negative Smad3. PTH as well as LiCl₂, which mimics the effects of the Wnt-ß-catenin pathway, rescued the dexamethasone- and etoposide-induced apoptosis of osteoblastic cells. In conclusion, the data demonstrate that PTH stimulates osteoblast ß-catenin levels via Smad3, and that both PKA and PKC pathways are involved. The canonical Wnt-ß-catenin pathway is likely to be involved in the antiapoptotic actions of PTH by acting through Smad3 in osteoblasts.

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