Mitogenic action of calcium-sensing receptor on rat calvarial osteoblasts

被引:120
作者
Chattopadhyay, N
Yano, S
Tfelt-Hansen, J
Rooney, P
Kanuparthi, D
Bandyopadhyay, S
Ren, XH
Terwilliger, E
Brown, EM
机构
[1] Harvard Univ, Sch Med, Brigham & Womens Hosp, Dept Med,Div Endocrinol Diabet & Hypertens, Boston, MA 02115 USA
[2] Harvard Univ, Sch Med, Brigham & Womens Hosp, Membrane Biol Program, Boston, MA 02115 USA
[3] Harvard Univ, Inst Med, Beth Israel Deaconess Med Ctr, Div Expt Med, Boston, MA 02115 USA
[4] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Neurol,Genet & Aging Unit, Charlestown, MA 02129 USA
关键词
D O I
10.1210/en.2003-1127
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
The parathyroid calcium-sensing receptor (CaR) plays a nonredundant role in systemic calcium homeostasis. In bone, Ca-o(2+), 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 Ca-o(2+) 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 Ca-o(2+) did not, however, alter IGF-I expression, a mitogenic factor for OBs. The high Ca-o(2+)-dependent increase in the proliferation of OBs was attenuated after transduction with a dominant-negative CaR (R185Q), confirming that the effect of high Ca-o(2+) is CaR mediated. Stimulation of proliferation by the CaR involves the Jun-terminal kinase (JNK) pathway, as high Ca-o(2+) 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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页码:3451 / 3462
页数:12
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