Netrin-4 derived from murine vascular endothelial cells inhibits osteoclast differentiation in vitro and prevents bone loss in vivo.
Bone is a highly vascularized organ, thus angiogenesis is a vital process during bone remodeling. However, the role of vascular systems in bone remodeling is not well recognized. Here we show that netrin-4 inhibits osteoclast differentiation in vitro and in vivo. Co-cultures of bone marrow macrophages with vascular endothelial cells markedly inhibited osteoclast differentiation. Adding a neutralizing antibody, or RNA interference against netrin-4, restored in vitro osteoclast differentiation. Administration of netrin-4 prevented bone loss in an osteoporosis mouse model by decreasing the osteoclast number. We propose that vascular endothelial cells interact with bone in suppressing bone through netrin-4.
Department of Oral and Maxillofacial Surgery, Saitama Medical University, Saitama, Japan.
Yuichiro
Y
Enoki
Department of Oral and Maxillofacial Surgery, Saitama Medical University, Saitama, Japan. Electronic address: tsato@saitama-med.ac.jp.
Tsuyoshi
T
Sato
Department of Orthopedic Surgery, Saitama Medical University, Saitama, Japan.
Shinya
S
Tanaka
Institute of Advanced Biomedical Engineering and Science, Tokyo Women's Medical University, Tokyo, Japan.
Takanori
T
Iwata
Department of Periodontology, Kyushu Dental University, Fukuoka, Japan.
Michihiko
M
Usui
Department of Physiology and Cell Biology, Tokyo Medical and Dental University, Tokyo, Japan.
Shu
S
Takeda
Department of Oral and Maxillofacial Surgery, Saitama Medical University, Saitama, Japan.
Shoichiro
S
Kokabu
Division of Functional Genomics and Systems Medicine, Research Center for Genomic Medicine, Saitama Medical University, Saitama, Japan.
Masahito
M
Matsumoto
Department of Oral and Maxillofacial Surgery, Saitama Medical University, Saitama, Japan; Division of Functional Genomics and Systems Medicine, Research Center for Genomic Medicine, Saitama Medical University, Saitama, Japan.
Masahiko
M
Okubo
Department of Periodontology, Kyushu Dental University, Fukuoka, Japan.
Keisuke
K
Nakashima
Institute of Advanced Biomedical Engineering and Science, Tokyo Women's Medical University, Tokyo, Japan.
Masayuki
M
Yamato
Institute of Advanced Biomedical Engineering and Science, Tokyo Women's Medical University, Tokyo, Japan.
Teruo
T
Okano
Department of Physiology and Cell Biology, Tokyo Medical and Dental University, Tokyo, Japan.
Toru
T
Fukuda
Department of Oral and Maxillofacial Surgery, Saitama Medical University, Saitama, Japan.
Dai
D
Chida
Division of Integrative Pathophysiology, Proteo-Science Center, Ehime University, Ehime, Japan.
Yuuki
Y
Imai
Planning & Development, Bioindustry Division, Oriental Yeast Co., Ltd., Tokyo, Japan.
Hisataka
H
Yasuda
Division of Infections and Molecular Biology, Kyushu Dental University, Fukuoka, Japan.
Tatsuji
T
Nishihara
Division of Morphological Science, Saitama Medical University, Saitama, Japan.
Masumi
M
Akita
Department of Orthopedic Surgery, Saitama Medical University, Saitama, Japan.
Hiromi
H
Oda
Division of Functional Genomics and Systems Medicine, Research Center for Genomic Medicine, Saitama Medical University, Saitama, Japan.
Yasushi
Y
Okazaki
Division of Functional Genomics and Systems Medicine, Research Center for Genomic Medicine, Saitama Medical University, Saitama, Japan.
Tatsuo
T
Suda
Department of Oral and Maxillofacial Surgery, Saitama Medical University, Saitama, Japan.
Tetsuya
T
Yoda
D000818:Animals; D001862:Bone Resorption / Q000378:metabolism; D002454:Cell Differentiation; D002478:Cells, Cultured; D018920:Coculture Techniques; D042783:Endothelial Cells / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000473:pathology; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009414:Nerve Growth Factors / Q000502:physiology*; D000075385:Netrins; D010010:Osteoclasts / Q000502:physiology*; D010024:Osteoporosis / Q000139:chemically induced / Q000378:metabolism*; D053245:RANK Ligand
D009414:Nerve Growth Factors; D000075385:Netrins; C416214:Ntn4 protein, mouse; D053245:RANK Ligand
Inhibition; Netrin-4; Osteoclast; Vascular endothelial cell