The expression of Fn14 via mechanical stress-activated JNK contributes to apoptosis induction in osteoblasts.
Bone mass is maintained by the balance between the activities of bone-forming osteoblasts and bone-resorbing osteoclasts. It is well known that adequate mechanical stress is essential for the maintenance of bone mass, whereas excess mechanical stress induces bone resorption. However, it has not been clarified how osteoblasts respond to different magnitudes of mechanical stress. Here we report that large-magnitude (12%) cyclic stretch induced Ca(2+) influx, which activated reactive oxygen species generation in MC3T3-E1 osteoblasts. Reactive oxygen species then activated the ASK1-JNK/p38 pathways. The activated JNK led to transiently enhanced expression of FGF-inducible 14 (Fn14, a member of the TNF receptor superfamily) gene. Cells with enhanced expression of Fn14 subsequently acquired sensitivity to the ligand of Fn14, TNF-related weak inducer of apoptosis, and underwent apoptosis. On the other hand, the ASK1-p38 pathway induced expression of the monocyte chemoattractant protein 3 (MCP-3) gene, which promoted chemotaxis of preosteoclasts. In contrast, the ERK pathway was activated by small-magnitude stretching (1%) and induced expression of two osteogenic genes, collagen Ia (Col1a) and osteopontin (OPN). Moreover, activated JNK suppressed Col1a and OPN induction in large-magnitude mechanical stretch-loaded cells. The enhanced expression of Fn14 and MCP-3 by 12% stretch and the enhanced expression of Col1a and OPN by 1% stretch were also observed in mouse primary osteoblasts. These results suggest that differences in the response of osteoblasts to varying magnitudes of mechanical stress play a key role in switching the mode of bone metabolism between formation and resorption.
Department of Biochemistry, Institute of Development, Aging and Cancer, Tohoku University, 4-1 Seiryo-machi, Sendai 980-8575, Japan; Department of Advanced Prosthetic Dentistry, Tohoku University, 4-1 Seiryo-machi, Sendai 980-8575, Japan; Laboratory for Mechanical Medicine, Locomotive Syndrome Research Institute, Nadogaya Hospital, Nadogaya 687-4, Kashiwa 277-0032, Japan.
Hiroyuki
H
Matsui
Department of Biochemistry, Institute of Development, Aging and Cancer, Tohoku University, 4-1 Seiryo-machi, Sendai 980-8575, Japan; Department of Advanced Prosthetic Dentistry, Tohoku University, 4-1 Seiryo-machi, Sendai 980-8575, Japan.
Naoto
N
Fukuno
Department of Advanced Prosthetic Dentistry, Tohoku University, 4-1 Seiryo-machi, Sendai 980-8575, Japan.
Yoshiaki
Y
Kanda
Department of Biochemistry, Institute of Development, Aging and Cancer, Tohoku University, 4-1 Seiryo-machi, Sendai 980-8575, Japan; Department of Advanced Prosthetic Dentistry, Tohoku University, 4-1 Seiryo-machi, Sendai 980-8575, Japan.
Yusuke
Y
Kantoh
Department of Biochemistry, Institute of Development, Aging and Cancer, Tohoku University, 4-1 Seiryo-machi, Sendai 980-8575, Japan.
Toko
T
Chida
Department of Biochemistry, Institute of Development, Aging and Cancer, Tohoku University, 4-1 Seiryo-machi, Sendai 980-8575, Japan.
Yuko
Y
Nagaura
Division of Craniofacial Function Engineering, Graduate School of Dentistry, Tohoku University, 4-1 Seiryo-machi, Sendai 980-8575, Japan.
Osamu
O
Suzuki
Division of Biochemistry and Molecular Biology, Department of Medical Sciences, University of Miyazaki, 5200 Kihara, Kiyotake, 889-1692 Japan.
Hideki
H
Nishitoh
Division of Cell Regulation, Graduate School of Biomedical Sciences, Nagasaki University, 1-14 Bunkyo-machi, Nagasaki 852-8521, Japan.
Kohsuke
K
Takeda
Laboratory of Cell Signaling, Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
Hidenori
H
Ichijo
Laboratory for Mechanical Medicine, Locomotive Syndrome Research Institute, Nadogaya Hospital, Nadogaya 687-4, Kashiwa 277-0032, Japan; Mechanobiology Institute, National University of Singapore, 5A Engineering Drive 1, 117411 Singapore.
Yasuhiro
Y
Sawada
Department of Advanced Prosthetic Dentistry, Tohoku University, 4-1 Seiryo-machi, Sendai 980-8575, Japan.
Keiichi
K
Sasaki
Department of Biochemistry, Institute of Development, Aging and Cancer, Tohoku University, 4-1 Seiryo-machi, Sendai 980-8575, Japan.
Takayasu
T
Kobayashi
Department of Biochemistry, Institute of Development, Aging and Cancer, Tohoku University, 4-1 Seiryo-machi, Sendai 980-8575, Japan. Electronic address: tamura@idac.tohoku.ac.jp.
Shinri
S
Tamura
D016475:3T3 Cells; D000818:Animals; D017209:Apoptosis; D005786:Gene Expression Regulation; D048848:MAP Kinase Kinase Kinase 5 / Q000378:metabolism*; D020935:MAP Kinase Signaling System; D051379:Mice; D048055:Mitogen-Activated Protein Kinase 8 / Q000378:metabolism*; D048056:Mitogen-Activated Protein Kinase 9 / Q000378:metabolism*; D010006:Osteoblasts / Q000378:metabolism / Q000502:physiology*; D018124:Receptors, Tumor Necrosis Factor / Q000235:genetics*; D013314:Stress, Mechanical; D000074050:TWEAK Receptor
D018124:Receptors, Tumor Necrosis Factor; D000074050:TWEAK Receptor; C000613299:Tnfrsf12a protein, mouse; D048056:Mitogen-Activated Protein Kinase 9; D048055:Mitogen-Activated Protein Kinase 8; D048848:MAP Kinase Kinase Kinase 5; C482859:Map3k5 protein, mouse
Apoptosis; Fn14; Jun N-terminal Kinase (JNK); Mechanotransduction; Osteoblasts; p38 MAPK