GATA4 regulates osteoblastic differentiation and bone remodeling via p38-mediated signaling

Abstract

Osteoblasts play a major role in bone remodeling and are regulated by transcription factors. GATA4, a zinc finger transcription factor from the GATA family, has an unclear role in osteoblast differentiation. In this study, the role of GATA4 in osteoblast differentiation was studied both in vitro and in vivo by GATA4 knockdown. GATA4 expression increased during osteoblast differentiation. GATA4 knockdown in osteoblast precursor cells reduced alkaline phosphatase activity and decreased the formation of calcified nodule in an osteogenic-induced cell culture system. In vivo, micro-CT showed that local injection of lentivirus-delivered GATA4 shRNA caused reduced new bone formation during tooth movement. Histological analyses such as total collagen and Goldner's trichrome staining confirmed these results. In vivo immunohistochemical analysis showed reduced expression of osterix (OSX), osteopontin (OPN), and osteocalcin (OCN) in the shGATA4 group (P < 0.05). Consistently, both western blotting and quantitative reverse-transcription PCR proved that expression of osteogenesis-related genes, including OSX, OPN, and OCN, was significantly repressed in the shGATA4 group in vitro (P < 0.01). For further analysis of the pathways involved in this process, we examined the MAPK signaling pathway, and found knockdown of GATA4, downregulated p38 signaling pathways (P < 0.01). Collectively, these results imply GATA4 is a regulator of osteoblastic differentiation via the p38 signaling pathways.

Keywords: GATA4; Lentiviral; MAPK; Osteoblast differentiation; Tooth movement model.