九州大学の自見英治郎先生、東京大学の廣川信隆先生との共同研究が論文になりました。 破骨細胞による骨吸収に分子モーターKIF1Cが関与している可能性を示唆したものです。 Cell Biochem Funct. 誌に掲載されました。
Cell Biochem Funct. 2019 Dec 30. doi: 10.1002/cbf.3476. [Epub ahead of print]
Kobayakawa M1,2,3, Matsubara T1, Mizokami A4, Hiura F3, Takakura N3, Kokabu S1, Matsuda M3, Yasuda H5, Nakamura I6, Takei Y7, Honda H8, Hosokawa R2, Jimi E1,3,4.
Kif1c regulates osteoclastic bone resorption as a downstream molecule of p130Cas.
1 Division of Molecular Signaling and Biochemistry, Department of Health Improvement, Kyushu Dental University, Kitakyushu, Japan.
2 Division of Oral Reconstruction and Rehabilitation, Department of Oral Functional Reconstruction, Kyushu Dental University, Kitakyushu, Japan.
3 Laboratory of Molecular and Cellular Biochemistry, Faculty of Dental Science, Kyushu University, Fukuoka, Japan.
4 Oral Health/Brain Health/Total Health Research Center, Faculty of Dental Science, Kyushu University, Fukuoka, Japan.
5 Nagahama Institute for Biochemical Science, Oriental Yeast Co., Ltd., Shiga, Japan.
6Faculty of Health and Medical Science, Teikyo Heisei University 2-51-4 Higashi-Ikebukuro, Tokyo, Japan.
7 Department of Anatomy and Neuroscience, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan.
8 Field of Human Disease Models, Major in Advanced Life Sciences and Medicine, Institute of Laboratory Animals, Tokyo Women’s Medical University, Tokyo, Japan.
Abstract
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 (p130CasΔOCL-/- ) 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 p130CasΔOCL-/- 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 p130CasΔOCL-/- osteoclasts, we identified kinesin family protein 1c (Kif1c), which regulates the cytoskeletal organization. Reduced Kif1c expression was observed in both c-Src-/- and p130CasΔOCL-/- 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 p130CasΔOCL-/- 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 (p130CasΔOCL-/- ) osteoclasts but not c-Src-/- osteoclasts, suggesting that Kif1c regulates osteoclastic bone resorption in the downstream of p130Cas.
