Regulation of spontaneous glutamate release activity in osteoblastic cells and its role in differentiation and survival: evidence for intrinsic glutamatergic signaling in bone

被引:62
作者
Genever, PG [1 ]
Skerry, TM [1 ]
机构
[1] Univ York, Dept Biol, York YO10 5YW, N Yorkshire, England
关键词
intercellular communication; osteoblasts; osteoclasts;
D O I
10.1096/fj.00-0594fje
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Maintenance of bone mass depends on numerous osteoblast-derived autocrine and paracrine signaling factors that ensure the coupled resorptive and formative activity of osteoclasts and osteoblasts. Here, we provide the first evidence that osteoblasts actively secrete glutamate, an amino acid neurotransmitter found at excitatory synapses in the central nervous system, complementing previous reports of functional glutamate receptor expression by bone cells, Several osteoblastic cell-types spontaneously released between 2-7 nmoles glutamate per mg protein, equivalent to or greater than reported levels of glutamate release from depolarized neurons. Osteoblastic glutamate exocytosis appeared dependent on an AMPA-type glutamate autoreceptor, and addition of depolarizing concentrations of KCl caused significant calcium-dependent inhibition of glutamate release. Levels of exocytosed and intracellular free glutamate, and susceptibility to depolarization-induced inhibition of glutamate release, increased during osteoblastic differentiation of MC3T3-E1 cells. Pharmacological inhibition of glutamate release with riluzole (1-25 muM) significantly inhibited differentiation and induced morphological and biochemical characteristics of apoptosis in osteoblastic cells. Exogenous glutamate application increased survival rates of osteoblasts grown in serum-free medium, and proinflammatory cytokines (tumor necrosis factor-alpha and interferon-gamma) significantly inhibited osteoblastic glutamate release. These findings provide evidence for an intrinsic synaptic-like glutamatergic signaling network in bone that is essential for in vitro osteoblast differentiation and survival.
引用
收藏
页码:1586 / +
页数:29
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