Gori Francesca, Friedman Lauren G, Demay Marie B
Endocrine Unit, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
Dev Biol. 2006 Jul 15;295(2):498-506. doi: 10.1016/j.ydbio.2006.02.031. Epub 2006 May 30.
Wdr5 accelerates osteoblast and chondrocyte differentiation in vitro, and is developmentally expressed in osteoblasts as well as in proliferating and hypertrophic chondrocytes. To investigate the role of Wdr5 during endochondral bone development, transgenic mice overexpressing Wdr5 under the control of the 2.3-kb fragment of the mouse alpha(1) I collagen promoter were generated. The transgene was specifically expressed in the osteoblasts of transgene positive mice and was absent in the growth plate. Histological analyses at embryonic day 14.5 demonstrated that the humeri of transgene positive embryos were longer than those isolated from wild-type littermates largely due to an expansion of the hypertrophic chondrocyte layer. Acceleration of osteoblast differentiation was observed with greater and more extensive expression of type I collagen and more extensive mineral deposition in the bone collar of transgene positive embryos. Acceleration of vascular invasion was also observed in transgene positive mice. Postnatal analyses of transgenic mice confirmed persistent acceleration of osteoblast differentiation. Targeted expression of Wdr5 to osteoblasts resulted in earlier activation of the canonical Wnt signaling pathway in the bone collar as well as in primary calvarial osteoblast cultures. In addition, overexpression of Wdr5 increased the expression of OPG, a target of the canonical Wnt signaling pathway. Overall, our findings suggest that Wdr5 accelerates osteoblast differentiation in association with activation of the canonical Wnt pathway.
Wdr5在体外可加速成骨细胞和软骨细胞的分化，并且在成骨细胞以及增殖期和肥大期软骨细胞中呈发育性表达。为了研究Wdr5在软骨内骨发育过程中的作用，构建了在小鼠α(1)I型胶原启动子2.3 kb片段控制下过表达Wdr5的转基因小鼠。转基因在转基因阳性小鼠的成骨细胞中特异性表达，在生长板中则不存在。胚胎第14.5天的组织学分析表明，转基因阳性胚胎的肱骨比从野生型同窝仔鼠分离的肱骨更长，这主要是由于肥大软骨细胞层的扩展。在转基因阳性胚胎的骨环中观察到成骨细胞分化加速，I型胶原表达更强且更广泛，矿物质沉积也更广泛。在转基因阳性小鼠中还观察到血管侵入加速。对转基因小鼠的出生后分析证实成骨细胞分化持续加速。将Wdr5靶向表达于成骨细胞导致骨环以及原代颅骨成骨细胞培养物中经典Wnt信号通路更早激活。此外，Wdr5的过表达增加了经典Wnt信号通路靶点OPG的表达。总体而言，我们的研究结果表明，Wdr5与经典Wnt通路的激活相关联，加速了成骨细胞的分化。
