EGR1 plays an important role in BMP9‐mediated osteoblast differentiation by promoting SMAD1/5 phosphorylation

• Published in: FEBS letters Vol. 596; no. 13; pp. 1720 - 1732
• Main Authors: Chiba, Norika, Noguchi, Yukie, Seong, Chang Hwan, Ohnishi, Tomokazu, Matsuguchi, Tetsuya
• Format: Journal Article
• Language: English
• Published: England 01.07.2022
• Subjects: BMP; bone formation; differentiation; EGR1; genetic markers; homeostasis; mineralization; osteoblast; osteoblasts; phosphorylation; precipitin tests; protein synthesis; signal transduction; SMAD; transcription (genetics); transcriptional activation; EGR1; differentiation; SMAD; osteoblast; BMP; signal transduction
• ISSN: 0014-5793; 1873-3468; 1873-3468
• DOI: 10.1002/1873-3468.14407

Bone morphogenetic proteins (BMPs) are essential regulators of skeletal homeostasis, and BMP9 is the most potently osteogenic among them. Here, we found that BMP9 and BMP2 rapidly induced early growth response 1 (EGR1) protein expression in osteoblasts through MEK/ERK pathway‐dependent transcriptional activation. Knock‐down of EGR1 using siRNA significantly inhibited BMP9‐induced matrix mineralization and osteogenic marker gene expression in osteoblasts. Knock‐down of EGR1 significantly reduced SMAD1/5 phosphorylation and inhibited the expression of their transcriptional targets in osteoblasts stimulated by BMP9. In contrast, forced EGR1 overexpression in osteoblasts enhanced BMP9‐mediated osteoblast differentiation and SMAD1/5 phosphorylation. An intracellular association between EGR1 and SMAD1/5 was identified using immunoprecipitation assays. These results indicated that EGR1 plays an important role in BMP9‐stimulated osteoblast differentiation by enhancing SMAD1/5 phosphorylation. This study identifies the role of the protein early growth response 1 (EGR1) in bone morphogenetic protein 9 (BMP9) signalling in osteoblasts. EGR1 expression in osteoblasts was rapidly induced by BMP9 through ERK activation. An intracellular EGR1–SMAD1/5 complex was detected. Knock‐down and overexpression experiments showed that BMP9‐induced EGR1 expression promoted BMP9‐induced SMAD1/5 phosphorylation and osteogenic marker gene expression.