Department of Oral Biology, School of Dental Medicine, State University of New York at Buffalo, Buffalo, NY 14214, USA.
Exp Cell Res. 2013 Mar 10;319(5):623-32. doi: 10.1016/j.yexcr.2012.12.028. Epub 2013 Jan 16.
Partial mutation of intraflagellar transport 80 (IFT80) in humans causes Jeune asphyxiating thoracic dystrophy (JATD) and short-rib polydactyly (SRP) syndrome type III. These diseases are autosomal recessive chondrodysplasias that share clinical similarities, including shortened long bones and constricted thoracic cage. However, the role and mechanism of IFT80 in the regulation of chondrocyte differentiation and function remain largely unknown. We hypothesize that IFT80 is required for the formation and function of cilia and plays a critical role in chondrogenic differentiation by regulating Hedgehog (Hh) and Wingless (Wnt) signaling pathways. To test this hypothesis, we first analyzed the IFT80 expression pattern and found that IFT80 was predominantly expressed in growth plate chondrocytes and during chondrogenic differentiation. Silencing IFT80 impaired cilia formation and chondrogenic differentiation in mouse bone marrow derived stromal cells (BMSCs), and decreased the expression of chondrocyte marker genes--collagen II and aggrecan. Additionally, silencing IFT80 down-regulated Hh signaling activity whereas up-regulated Wnt signaling activity. The overexpression of Gli2 in IFT80-silenced cells promoted chondrogenesis and recovered the chondrogenic deficiency from IFT80 silencing. Overall, our results demonstrate that IFT80 is essential for chondrocyte differentiation by regulating the Hh and Wnt signaling pathways.
IFT80 基因突变会导致人类 Jeune 型致死性先天性中胚层发育不良（JATD）和短肋多指（SRP）综合征 III 型。这些疾病是常染色体隐性遗传性软骨发育不良，具有相似的临床特征，包括长骨缩短和胸廓狭窄。然而，IFT80 在调节软骨细胞分化和功能中的作用和机制在很大程度上仍不清楚。我们假设 IFT80 对于纤毛的形成和功能是必需的，并通过调节 Hedgehog（Hh）和 Wingless（Wnt）信号通路在软骨生成分化中发挥关键作用。为了验证这一假设，我们首先分析了 IFT80 的表达模式，发现 IFT80 主要在生长板软骨细胞和软骨分化过程中表达。沉默 IFT80 会损害小鼠骨髓基质细胞（BMSCs）中的纤毛形成和软骨分化，并降低软骨细胞标志物基因——胶原 II 和聚集蛋白聚糖的表达。此外，沉默 IFT80 会降低 Hh 信号活性，而增加 Wnt 信号活性。IFT80 沉默细胞中 Gli2 的过表达促进了软骨生成，并从 IFT80 沉默中恢复了软骨生成的不足。总的来说，我们的结果表明，IFT80 通过调节 Hh 和 Wnt 信号通路对软骨细胞分化至关重要。
