Mechanical stress modulates bone remodeling signals

Mechanical stress plays an essential role in bone homeostasis. Although mechanotransduction-induced de novo gene expression is required for bone remodeling, the molecular mechanism of intracellular signaling, which leads to regulation of gene expression, is not fully understood. Here, we show that JNK and p38 [two stress-responsible mitogen-activated protein kinases (MAPKs)] are activated via ASK1 (a stress-responsible MAPK kinase) in mechanical stretch loaded MC3T3-E1 preosteoblasts. Using pharmaceutical and RNAi approaches, we demonstrated that ASK1 is activated via Ca2+ influx-induced reactive oxygen species generation. Furthermore, we observed that ASK1-activated JNK and p38 induced the expression of two bone remodeling related genes, Fn14 and MCP-3, respectively. These findings suggest that mechanical stress-activated JNK and p38 induce cytokine cross-talks between osteoblasts and bone marrow-derived monocytes and macrophages, which may play key roles in bone remodeling.