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Mitogenic action of calcium-sensing receptor on rat calvarial osteoblasts

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

The parathyroid calcium-sensing receptor (CaR) plays a nonredundant role in systemic calcium homeostasis. In bone, Ca2+ o, a maj or 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.

OriginalsprogEngelsk
TidsskriftEndocrinology
Vol/bind145
Udgave nummer7
Sider (fra-til)3451-3462
Antal sider12
ISSN0013-7227
DOI
StatusUdgivet - 1 jul. 2004
Eksternt udgivetJa

ID: 203877547