The expression of Fn14 via mechanical stress-activated JNK contributes to apoptosis induction in osteoblasts [Cell Biology]

January 20th, 2014 by Matsui, H., Fukuno, N., Kanda, Y., Kantoh, Y., Chida, T., Nagaura, Y., Suzuki, O., Nishitoh, H., Takeda, K., Ichijo, H., Sawada, Y., Sasaki, K., Kobayashi, T., Tamura, S.

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, while 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 Ca2+ influx which activated ROS generation in MC3T3-E1 osteoblasts. ROS then activated ASK1-JNK/p38 pathways. The activated JNK lead 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, ASK1-p38 pathway induced expression of monocyte chemoattractant protein-3 (MCP-3) gene, which promoted chemotaxis of pre-osteoclasts. 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 of mechanical stretch-loaded cells. The enhanced expressions of Fn14 and MCP-3 by 12% stretch and those 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.