Kif1c regulates osteoclastic bone resorption as a downstream molecule of p130Cas
Kif1c regulates osteoclastic bone resorption as a downstream molecule of p130Cas
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DOI：
10.1002/cbf.3476
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发表时间：
2019-12-30
影响因子：
3.6
通讯作者：
Jimi, Eijiro
中科院分区：
文献类型：
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作者：
Kobayakawa, Miki;Matsubara, Takuma;Jimi, Eijiro
破骨细胞中的足状体形成是骨细胞骨吸收的重要起始步骤。缺乏c-Src（c-Src（-/-））的小鼠由于破骨细胞中缺乏足体形成而表现出骨硬化症。我们先前鉴定了p130 Cas（Crk相关底物[Cas]）作为c-Src的下游分子之一，并且破骨细胞特异性p130 Cas缺陷（p130 Cas（Delta OCL-/-））小鼠也表现出与c-Src（-/-）小鼠相似的表型，表明c-Src/p130 Cas在破骨细胞的骨吸收中起重要作用。在这项研究中，我们进行了cDNA微阵列和比较的基因谱的破骨细胞从c-Src（-/-）或p130 Cas（δ OCL-/-）小鼠与野生型（WT）破骨细胞，以确定下游分子的c-Src/p130 Cas参与骨吸收。在c-Src（-/-）和p130 Cas（Delta OCL-/-）破骨细胞中普遍下调的几个基因中，我们鉴定了驱动蛋白家族蛋白1c（Kif 1c），其调节细胞骨架组织。与WT破骨细胞相比，在c-Src（-/-）和p130 Cas（Delta OCL-/-）破骨细胞中观察到Kif 1c表达减少。Kif 1c表现出广泛的组织分布，包括破骨细胞。在WT破骨细胞中使用shRNA敲低Kif 1c表达抑制肌动蛋白环形成。Kif 1c过表达恢复了p130 Cas（Delta OCL-/-）破骨细胞中肌动蛋白环形成后的骨吸收，但没有c-Src（-/-）破骨细胞，表明Kif 1c调节p130 Cas下游的骨吸收。研究的意义我们先前表明c-Src/p130 Cas（Cas）在破骨细胞的骨吸收中起重要作用。在这项研究中，我们确定驱动蛋白家族蛋白1c（Kif 1c），调节细胞骨架的组织，作为下游分子的c-Src/p130 Cas轴，使用cDNA微阵列。在野生型破骨细胞中使用shRNAs敲低Kif 1c表达抑制肌动蛋白环的形成在破骨细胞特异性p130 Cas缺陷型（p130 Cas（Delta OCL-/-））破骨细胞中，Kif 1c过表达恢复了肌动蛋白环形成后的骨吸收，但c-Src（-/-）破骨细胞没有，表明Kif 1c调节p130 Cas下游的骨吸收。
Podosome formation in osteoclasts is an important initial step in osteoclastic bone resorption. Mice lacking c-Src (c-Src(-/-)) exhibited osteopetrosis due to a lack of podosome formation in osteoclasts. We previously identified p130Cas (Crk-associated substrate [Cas]) as one of c-Src downstream molecule and osteoclast-specific p130Cas-deficient (p130Cas(Delta OCL-/-)) mice also exhibited a similar phenotype to c-Src(-/-) mice, indicating that the c-Src/p130Cas plays an important role for bone resorption by osteoclasts. In this study, we performed a cDNA microarray and compared the gene profiles of osteoclasts from c-Src(-/-) or p130Cas(Delta OCL-/-) mice with wild-type (WT) osteoclasts to identify downstream molecules of c-Src/p130Cas involved in bone resorption. Among several genes that were commonly downregulated in both c-Src(-/-) and p130Cas(Delta OCL-/-) osteoclasts, we identified kinesin family protein 1c (Kif1c), which regulates the cytoskeletal organization. Reduced Kif1c expression was observed in both c-Src(-/-) and p130Cas(Delta OCL-/-) osteoclasts compared with WT osteoclasts. Kif1c exhibited a broad tissue distribution, including osteoclasts. Knockdown of Kif1c expression using shRNAs in WT osteoclasts suppressed actin ring formation. Kif1c overexpression restored bone resorption subsequent to actin ring formation in p130Cas(Delta OCL-/-) osteoclasts but not c-Src(-/-) osteoclasts, suggesting that Kif1c regulates osteoclastic bone resorption in the downstream of p130Cas (191 words). Significance of the study We previously showed that the c-Src/p130Cas (Cas) plays an important role for bone resorption by osteoclasts. In this study, we identified kinesin family protein 1c (Kif1c), which regulates the cytoskeletal organization, as a downstream molecule of c-Src/p130Cas axis, using cDNA microarray. Knockdown of Kif1c expression using shRNAs in wild-type osteoclasts suppressed actin ring formation. Kif1c overexpression restored bone resorption subsequent to actin ring formation in osteoclast-specific p130Cas-deficient (p130Cas(Delta OCL-/-)) osteoclasts but not c-Src(-/-) osteoclasts, suggesting that Kif1c regulates osteoclastic bone resorption in the downstream of p130Cas.