Role of Ca^<2+>-sensing receptor in the pathogenesis of arteriosclerosis and osteoporosis

我们克隆了人肾钙敏感受体（CaSR）cDNA，并在一个家族性低尿钙高钙血症的家系中发现了该基因的一个突变，从钙代谢的角度来看，衰老可以部分地被认为是体内钙重新分布的结果。也就是说，钙从骨骼转移到动脉壁。因此，可以推测这种钙代谢异常导致动脉硬化和骨质疏松症。本研究探讨了CaSR是否参与动脉硬化和骨质疏松症的发病机制。1）A7 r5是大鼠主动脉平滑肌细胞来源的细胞系。CaSR mRNA存在于细胞中。当用PDGF（50 ng/ml）、TGF-β 1（3 ng/ml）、IL-1 α（5 ng/ml）、IGF-1（10 ng/ml）、17 β-雌二醇（10 μ M）刺激细胞<-8>12 h时，CaSR的mRNA水平没有变化。我们检测到细胞中的CaSR mRNA。因此，我们假设CaSR参与骨生成。用1，25（OH）_2维生素D_3（10 μ M-10 μ M）刺激UMR-106<-6><-8>细胞6- 24小时，CaSR mRNA的表达无明显变化。当细胞在无Ca^2+的培养基中培养36 h后，再加入2 mM的Ca^2+，再培养6或12 h，CaSR mRNA的表达量下降到对照组的一半。当加入17 β-雌二醇（10 μ <-8>M）、TGE-beta1（3 ng/ml）、PDGF（50 ng/ml）、IL-1 α（5 ng/ml）、IGF-1（10 ng/ml）、视黄酸（10 <-6>μ M）、大鼠PTH（10 μ <-8>M）24小时后，其mRNA的表达水平没有改变。

We have cloned the human kidney Ca^<2+>-sensing receptor (CaSR) cDNA and identified a mutation in the gene in a family of familial hypocalciuric hypercalcemia.From the point of view of calcium metabolism, aging can be assumed in part to result from redistribution of calcium in the body. That is, calcium is transferred from the bone to the arterial walls. It can, therefore, be presumed that this abnormality in calcium metabolism results in arteriosclerosis and osteoporosis.In this study, we investigated if CaSR is involved in the pathogenesis of arteriosclerosis and osteoporosis.1) A7r5 is a cell line derived form rat aortic smooth muscle cells. CaSR mRNA is present in the cells. When the cells were stimulated with PDGF (50ng/ml), TGF-beta1 (3ng/ml), IL-1alpha (5ng/ml), IGF-1 (10ng/ml), 17beta-estradiol (10^<-8>M) for 12h, the mRNA levels for CaSR did not changed.2) UMR-106 is a cell line derived from rat osteosarcoma. We detected the CaSR mRNA in the cells. Therefore, we assumed that the CaSR is involved in osteogenesis. Then, UMR-106 cells were stimulated with 1,25 (OH)_2 vitamin D3 (10^<-6>-10^<-8>M) for 6-24hr, the expression of the CaSR mRNA did not changed. When the cells were cultured in Ca^<2+>-free medium for 36h and then Ca^<2+> was added to 2mM for additional 6 or 12h, the CaSR mRNAs were decreased to the half levels of that of the control. When 17beta-estradiol (10^<-8>M), TGE-beta1 (3ng/ml), PDGF (50ng/ml), IL-1alpha (5ng/ml), IGF-1 (10ng/ml), retinoic acid (10^<-6>M), rat PTH(10^<-8>M) were added for 24h, the expression levels of the mRNA did not altered.From these studies, although CaSR is expressed in the aortic smooth muscles and osteoblastic cells, contribution of CaSR to the pathogenesis of arteriosclerosis and osteoporosis is, if any, very little.