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

我们利用基因靶向小鼠、PTH/PTHrP受体突变的转基因细胞和PTHrP过表达的骨转移瘤小鼠，对成纤维细胞生长因子受体III(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。2004年，我们培育了FGFR3^&lt；-/-&gt；/PTHrP^&lt；-/-&gt；小鼠，并检测了骨骼和软骨的畸形。结果表明，PTHrP主要影响软骨细胞的增殖，而不是FGFR3。但FGFR3可影响软骨细胞进入肥大表型后的凋亡和血管内皮生长因子的表达。2005年，我们曾报道PTHrP以自分泌/旁分泌的方式刺激成骨细胞的增殖和存活。此外，我们还提供了突变的PTH/PTHrP受体蛋白在内质网积聚并随后泄漏到细胞质区域的可能性，这些突变导致Jansen型和Blomstrand型软骨发育不良。因此，突变受体通常不会以细胞膜为靶点。此外，我们还对PTHrP过表达肿瘤的转移灶进行了形态观察。因此，我们评估了FGFR3和/或PTHrP基因突变和异常表达所导致的骨骼病理特征。

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.