Gori Francesca, Zhu Eric D, Demay Marie B
Endocrine Unit, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
Dev Biol. 2009 May 1;329(1):36-43. doi: 10.1016/j.ydbio.2009.02.006. Epub 2009 Feb 13.
Wdr5 is developmentally expressed in osteoblasts and is required for osteoblast differentiation. Mice overexpressing Wdr5 under the control of the mouse alpha(1)I collagen promoter (Col I-Wdr5) display accelerated osteoblast differentiation as well as accelerated chondrocyte differentiation, suggesting that overexpression of Wdr5 in osteoblasts affects chondrocyte differentiation. To elucidate the molecular mechanism by which overexpression of Wdr5 in the perichondrium regulates chondrocyte differentiation, studies were undertaken using skeletal elements and cultured metatarsals isolated from wild-type and Col I-Wdr5 embryos. FGF18 mRNA levels were decreased in Col I-Wdr5 humeri. Furthermore, local delivery of FGF18 to the bone collar of ex vivo cultures of metatarsals attenuated the chondrocyte phenotype of the Col I-Wdr5 metatarsals. Impairing local FGF action in wild-type metatarsals resulted in a chondrocyte phenotype analogous to that of Col I-Wdr5 metatarsals implicating impaired FGF action as the cause of the phenotype observed. The expression of Twist-1, which regulates chondrocyte differentiation, was increased in Col I-Wdr5 humeri. Chromatin immunoprecipitation analyses demonstrated that Wdr5 is recruited to the Twist-1 promoter. These findings support a model in which overexpression of Wdr5 in the perichondrium promotes chondrocyte differentiation by modulating the expression of Twist-1 and FGF18.
Wdr5在成骨细胞中呈发育性表达，是成骨细胞分化所必需的。在小鼠α(1)I胶原蛋白启动子（Col I-Wdr5）控制下过表达Wdr5的小鼠表现出加速的成骨细胞分化以及加速的软骨细胞分化，这表明成骨细胞中Wdr5的过表达会影响软骨细胞分化。为了阐明骨膜中Wdr5过表达调节软骨细胞分化的分子机制，我们使用从野生型和Col I-Wdr5胚胎分离的骨骼元件和培养的跖骨进行了研究。Col I-Wdr5肱骨中FGF18 mRNA水平降低。此外，将FGF18局部递送至跖骨体外培养物的骨环可减弱Col I-Wdr5跖骨的软骨细胞表型。破坏野生型跖骨中的局部FGF作用会导致类似于Col I-Wdr5跖骨的软骨细胞表型，这表明FGF作用受损是观察到的表型的原因。调节软骨细胞分化的Twist-1在Col I-Wdr5肱骨中的表达增加。染色质免疫沉淀分析表明Wdr5被募集到Twist-1启动子上。这些发现支持了一个模型，即骨膜中Wdr5的过表达通过调节Twist-1和FGF18的表达来促进软骨细胞分化。
