The analyses on bone and cartilage diseases caused by mutations of FGFR3/PTHrP genes

我们对成纤维细胞生长因子受体III型（FGFR3）和甲状旁腺激素相关肽（PTHrP）的生物学功能进行了广泛的分析，通过基因靶向小鼠，PTH/PTHrP受体突变的细胞转基因和PTHrP过表达肿瘤的骨转移小鼠。2004年，我们生成了FGFR3^<-/->/PTHrP^<-/->小鼠，并检查了骨和软骨的骨骼畸形。结果表明，PTHrP主导影响软骨细胞增殖，而不是FGFR3。然而，FGFR3可以影响软骨细胞进入肥厚表型后的凋亡和VEGF表达。2005年，我们报道了PTHrP以自分泌/旁分泌的方式刺激成骨细胞增殖和存活。此外，我们还提出了突变的PTH/PTHrP受体的蛋白质在内质网中积累，并随后渗漏到细胞质区，从而诱导Jansen型和Blomstrand型软骨发育不良的可能性很大。因此，突变受体通常不会靶向细胞膜。此外，我们通过过表达pthrp的肿瘤对转移性病变进行了形态学检查。因此，我们评估了由FGFR3和/或PTHrP基因突变和异常表达引起的骨骼病理特征。

We conducted the broad analyses on the biological function of fibroblast growth factor receptor type III (FGFR3) and parathyroid hormone-related peptide (PTHrP), by employing gene targeted mice, cells transgenes with mutated PTH/PTHrP receptors and bone metastatic mice with PTHrP-overexpressing tumors. In 2004, we have generated FGFR3^<-/->/PTHrP^<-/-> mice, and examined the skeletal deformities on bone and cartilage. As a results, PTHrP dominantly affected on the chondrocyte proliferation, rather than FGFR3. However, FGFR3 could influence the apoptosis and VEGF expression in chondrocytes after their entry to hypertrophic phenotype. In 2005, we have reported that PTHrP stimulated osteoblastic proliferation and survival in an autocrine/paracrine manner. Also, we provided the strong possibility that proteins of mutated PTH/PTHrP receptors, inducing Jansen type and Blomstrand type chondrodysplasia, would be accumulated in endoplasmic reticulum, and subsequent be leaked into the cytoplasmic region. Therefore, the mutant receptors would not be normally targeted to the cell membranes. In addition, we have morphologically examined the metastastic lesion by PTHrP-overexpressing tumors. Thus, we assessed the skeletal pathological features caused by the mutations and abnormal expression of FGFR3 and/or PTHrP genes.