Hepatocyte growth factor-induced BMP-2 expression is mediated by c-Met receptor, FAK, JNK, Runx2, and p300 pathways in human osteoblasts

Abstract

Hepatocyte growth factor (HGF) has been demonstrated to stimulate osteoblast proliferation and participated bone remodeling. Bone morphogenetic protein-2 (BMP-2) is a crucial mediator in bone formation during fracture healing. However, the effects of HGF in BMP-2 expression in human osteoblasts are large unknown. Here we found that HGF induced BMP-2 expression in human osteoblasts dose-dependently. HGF-mediated BMP-2 production was attenuated by c-Met inhibitor or siRNA. Pretreatment with FAK inhibitor or JNK inhibitor (SP600125) also blocked the potentiating action of HGF. Stimulation of osteoblasts with HGF enhanced FAK phosphorylation, JNK phosphorylation, and RunX2 translocation from cytosol to the nucleus. HGF-mediated Runx2 binding to BMP-2 promoter was inhibited by c-Met inhibitor, FAK inhibitor, and SP600125. The binding of Runx2 to the BMP-2 promoter, as well as the recruitment of p300 and the enhancement of histones H3 and H4 acetylation on the BMP-2 promoter was enhanced by HGF. Our results suggest that HGF increased BMP-2 production in human osteoblasts via the c-Met receptor/FAK/JNK/Runx2 and p300 signaling pathways.