Yang Maobin, Kream Barbara E
Department of Medicine, MC-1850, University of Connecticut Health Center, 263 Farmington Avenue, Farmington 06030, CT, USA.
Endocrine. 2008 Jun;33(3):245-53. doi: 10.1007/s12020-008-9092-8.
The cAMP response element modulator gene (Crem) encodes a variety of transcriptional regulators including the inducible cAMP early repressor, ICER. We previously showed that Crem knockout mice, which are deficient in CREM and ICER factors, display slightly increased long bone mass and decreased osteoclast number. These data are consistent with the notion that Crem regulates bone mass in part through an effect on osteoclast formation and/or function. Since ICER is strongly induced by cAMP, we asked whether the calcium-regulating hormone calcitonin, which stimulates cAMP production and inhibits osteoclastic bone resorption, could induce ICER in osteoclasts. The monocytic cell line RAW264.7 was treated with receptor activator of NF-kappaB ligand (RANKL) to induce osteoclast formation. Calcitonin caused a time- and dose-dependent induction of ICER mRNA and an increase in ICER protein abundance in RANKL-treated RAW264.7 cells. Calcitonin also induced ICER mRNA and protein in osteoclasts derived from primary mouse bone marrow cell cultures. Calcitonin-treated osteoclasts showed immunoreactivity with an anti-CREM antibody. Calcitonin decreased the activity of wild-type and Crem knockout osteoclasts in vitro, and this inhibitory effect was greater in Crem knockout osteoclasts. Furthermore, calcitonin decreased calcitonin receptor mRNA expression in wildtype osteoclasts, but not in Crem knockout osteoclasts. These data suggest that calcitonin induction of ICER in osteoclasts might regulate osteoclast activity.
环磷酸腺苷反应元件调节因子基因（Crem）编码多种转录调节因子，包括诱导型环磷酸腺苷早期阻遏物ICER。我们之前发现，缺乏CREM和ICER因子的Crem基因敲除小鼠，其长骨量略有增加，破骨细胞数量减少。这些数据与Crem部分通过影响破骨细胞形成和/或功能来调节骨量的观点一致。由于ICER是由环磷酸腺苷强烈诱导产生的，我们推测刺激环磷酸腺苷生成并抑制破骨细胞骨吸收的钙调节激素降钙素是否能在破骨细胞中诱导ICER的产生。用核因子κB受体活化因子配体（RANKL）处理单核细胞系RAW264.7以诱导破骨细胞形成。降钙素在RANKL处理的RAW264.7细胞中引起ICER mRNA的时间和剂量依赖性诱导以及ICER蛋白丰度增加。降钙素还能在源自原代小鼠骨髓细胞培养物的破骨细胞中诱导ICER mRNA和蛋白的产生。经降钙素处理的破骨细胞与抗CREM抗体呈免疫反应。降钙素在体外降低野生型和Crem基因敲除破骨细胞的活性，且这种抑制作用在Crem基因敲除破骨细胞中更强。此外，降钙素降低野生型破骨细胞中降钙素受体mRNA的表达，但对Crem基因敲除破骨细胞没有影响。这些数据表明，降钙素在破骨细胞中诱导ICER可能调节破骨细胞活性。
