Involvement of p38MAPK/NF-κB Signaling Pathways in Osteoblasts Differentiation in Response to Mechanical Stretch

Bone morphogenetic proteins (BMPs) are known to be important in osteoblasts' response to mechanical stimuli. BMPs/Smad signaling pathway has been demonstrated to play a regulatory role in the mechanical signal transduction in osteoblasts. However, little is currently known about the Smad independent pathway in osteoblasts differentiation in mechanical loading. In this study, MC3T3-E1 cells were subjected to mechanical stretch of 2000 micro-stain (mu I mu) at 0.5 Hz, in order to investigate the involvement of p38MAPK and NF-kappa B signaling pathways in mechanical response in osteoblasts. We found BMP-2/BMP-4 were up-regulated by mechanical stretch via the earlier activation of p38MAPK and NF-kappa B signaling pathways, which enhanced osteogenic gene expressions including alkaline phosphatase (ALP), collagen type I (Col I) and osteocalcin (OCN), and the expressions of these osteogenic genes were remarkably decreased with Noggin (an inhibitor for BMPs signals) pretreatment. Furthermore, BMP-2/BMP-4 expressions were suppressed by PDTC, an inhibitor of NF-kappa B pathway and SB203580, an inhibitor of p38MAPK pathway, respectively, leading to the declined levels of ALP, Col I and OCN. Interestingly, blocking in p38MAPK pathway can also cause the inactivation of NF-kappa B pathway in mechanical stretch. Collectively, the results indicate during mechanical stretch p38MAPK and NF-kappa B signaling pathways are activated first, and then up-regulate BMP-2/BMP-4 to enhance osteogenic gene expressions. Moreover, p38MAPK and NF-kappa B signals have cross-talk in regulation of BMP-2/BMP-4 in mechanical response.