Serum response factor regulates bone formation via IGF-1 and Runx2 signals.

Abstract

Serum response factor (SRF) plays vital roles in numerous cellular processes; however, the physiological function of SRF in skeletal tissue remains unknown. In several organ systems, SRF regulates the expression of insulin-like growth factor-1 (IGF-1), which is crucial for normal development of mineralized skeleton and bone remodeling throughout life. Here, we show that conditional deletion of SRF in osteoblasts by osteocalcin-Cre generated viable mice with normal body size and body weight. Compared with normal siblings, osteoblast-specific SRF-deficient adult mice exhibited a marked decrease in bone mineral density and bone formation rate. Deletion of SRF in primary mouse calvarial osteoblasts reduced cell differentiation and mineralization in vitro. This was accompanied by a decrease in IGF-1 expression and secretion. Addition of IGF-1 in the culture media enhanced osteoblast differentiation in control cells and partially restored the mineralization defect of SRF-deficient cells, supporting an important role of SRF in regulating IGF-1 and IGF-1-mediated osteoblast differentiation. IGF-1-induced Akt activation was inhibited in SRF-deficient calvarial cells and enhanced in the SRF overexpressed cells. In addition, SRF deficiency decreased the transcriptional activity of Runx2, the key transcription factor for osteogenesis. Overexpression of SRF induced Runx2 transactivity in control cells and restored Runx2 transactivity in the SRF-deficient cells. Taken together, we conclude that SRF is important for IGF-1-induced osteoblast differentiation and mineralization via regulating IGF-1 expression and Runx2 transactivity.

• Authors: Jianfeng Chen, Kaiyu Yuan, Xia Mao, Joseph M Miano, Hui Wu, Yabing Chen
• Journal: Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research (J Bone Miner Res) Vol. 27 Issue 8 Pg. 1659-68 (Aug 2012) ISSN: 1523-4681 [Electronic] United States
• PMID: 22434656 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: Copyright © 2012 American Society for Bone and Mineral Research.

Chemical References

• Core Binding Factor Alpha 1 Subunit
• Runx2 protein, mouse
• Serum Response Factor
• insulin-like growth factor-1, mouse
• Insulin-Like Growth Factor I
• DNA

Topics

• Aging (metabolism)
• Animals
• Cell Differentiation (drug effects)
• Cells, Cultured
• Core Binding Factor Alpha 1 Subunit (genetics, metabolism)
• DNA (metabolism)
• Densitometry
• Female
• Gene Deletion
• Insulin-Like Growth Factor I (metabolism, pharmacology)
• Male
• Mice
• Organ Size (drug effects)
• Organ Specificity (drug effects)
• Osteoblasts (cytology, drug effects, metabolism)
• Osteogenesis (drug effects)
• Protein Binding (drug effects)
• Serum Response Factor (deficiency, metabolism)
• Signal Transduction (drug effects)
• Skull (cytology)
• Transcriptional Activation (drug effects, genetics)
• X-Ray Microtomography