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Mitogenic Action of Calcium-Sensing Receptor on Rat Calvarial Osteoblasts

Division of Endocrinology, Diabetes and Hypertension (N.C., S.Y., J.T.-H., P.R., D.K., E.M.B.), Department of Medicine and Membrane Biology Program, Brigham and Women’s Hospital, Harvard Medical School, and Division of Experimental Medicine (X.R., E.T.), Beth Israel Deaconess Medical Center, Harvard Institutes of Medicine, Boston, Massachusetts 02115; and Genetics and Aging Unit (S.B.), Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts 02129

Address all correspondence and requests for reprints to: Naibedya Chattopadhyay, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, 221 Longwood Avenue, Boston, Massachusetts 02115. E-mail: Naibedya{at}rics.bwh.harvard.edu.

The parathyroid calcium-sensing receptor (CaR) plays a nonredundant role in systemic calcium homeostasis. In bone, Ca²⁺_o, a major extracellular factor in the bone microenvironment during bone remodeling, could potentially serve as an extracellular first messenger, acting via the CaR, that stimulates the proliferation of preosteoblasts and their differentiation to osteoblasts (OBs). Primary digests of rat calvarial OBs express the CaR as assessed by RT-PCR, Northern, and Western blot analysis, and immunocolocalization of the CaR with the OB marker cbfa-1. Real-time PCR revealed a significant increase in CaR mRNA in 5- and 7-d cultures compared with 3-d cultures post harvesting. High Ca²⁺_o did not affect the expression of CaR mRNA during this time but up-regulated cyclin D (D1, D2, and D3) genes, which are involved in transition from the G1 to the S phase of the cell cycle, as well as the early oncogenes, c-fos and early growth response-1; high Ca²⁺_o did not, however, alter IGF-I expression, a mitogenic factor for OBs. The high Ca²⁺_o-dependent increase in the proliferation of OBs was attenuated after transduction with a dominant-negative CaR (R185Q), confirming that the effect of high Ca²⁺_o is CaR mediated. Stimulation of proliferation by the CaR involves the Jun-terminal kinase (JNK) pathway, as high Ca²⁺_o stimulated the phosphorylation of JNK in a CaR-mediated manner, and the JNK inhibitor SP600125 abolished CaR-induced proliferation. Our data, therefore, show that the parathyroid/kidney CaR expressed in rat calvarial OBs exerts a mitogenic effect that involves activation of the JNK pathway and up-regulation of several mitogenic genes.

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