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This version published online on April 7, 2004
Endocrinology, doi:10.1210/en.2003-1127
A more recent version of this article appeared on July 1, 2004
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Submitted on August 27, 2003
Accepted on March 30, 2004

Mitogenic Action of Calcium-sensing Receptor on Rat Calvarial Osteoblasts

Naibedya Chattopadhyay*, Shozo Yano, Jacob Tfelt-Hansen, Paul Rooney, Deepthi Kanuparthi, Sanghamitra Bandyopadhyay, Xianghui Ren, Ernest Terwilliger, and Edward M. Brown

Division of Endocrinology, Diabetes and Hypertension, Department of Medicine and Membrane Biology Program, Brigham and Women's Hospital, Harvard Medical School, 221 Longwood Avenue, Boston, MA, 02115; Division of Experimental Medicine, Beth Israel Deaconess Medical Center, Harvard Institutes of Medicine, 4 Blackfan Circle, Boston, MA 02115; Genetics and Aging Unit, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, 02129

* To whom correspondence should be addressed. 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 immuno-colocalization of the CaR with the OB marker cbfa-1. Real-time PCR revealed a significant increase in CaR mRNA in 5 and 7-day cultures compared with 3-day cultures post-harvesting. High Ca2+o did not affect the expression of CaR mRNA during this time but upregulated 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 egr-1; high Ca2+o did not, however, alter IGF-1 expression, a mitogenic factor for OBs. The high Ca2+o-dependent increase in the proliferation of OBs was attenuated following 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 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.
Key words: Proliferation • c-fos • Egr-1 • cyclin D • JNK • parathyroid




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