The authors have no conflict of interest
Hepatocyte Growth Factor Contributes to Fracture Repair by Upregulating the Expression of BMP Receptors†
Article first published online: 20 JUN 2005
Copyright © 2005 ASBMR
Journal of Bone and Mineral Research
Volume 20, Issue 10, pages 1723–1730, October 2005
How to Cite
Imai, Y., Terai, H., Nomura-Furuwatari, C., Mizuno, S., Matsumoto, K., Nakamura, T. and Takaoka, K. (2005), Hepatocyte Growth Factor Contributes to Fracture Repair by Upregulating the Expression of BMP Receptors. J Bone Miner Res, 20: 1723–1730. doi: 10.1359/JBMR.050607
- Issue published online: 4 DEC 2009
- Article first published online: 20 JUN 2005
- Manuscript Accepted: 16 JUN 2005
- Manuscript Revised: 5 JUN 2005
- Manuscript Received: 15 FEB 2005
- BMP receptors;
- hepatocyte growth factor;
Hepatocyte growth factor (HGF) is activated and the expression of BMP receptors (BMPRs) is induced around the fracture site during the early phase of fracture repair. HGF facilitates the expression of BMPRs in mesenchymal cells. This study suggests that HGF contributes to fracture repair by inducing the expression of BMPRs.
Introduction: The precise mechanisms that control the upregulation of BMP, BMPRs, and other molecules involved in bone repair are not completely understood. In this study, we hypothesized that HGF, activated through the action of thrombin on the HGF activator, may enhance BMP action through the local induction of BMP or BMPRs.
Materials and Methods: Callus samples from tibial fractures in mice were harvested for immunohistochemical analysis of HGF and phosphorylated c-Met, for in situ hybridization of BMPRs, and for real-time RT-PCR analysis for the expression of HGF, c-Met, and BMPRs. To study the changes in gene expression of BMPRs in response to HGF, C3H10T1/2 cells were cultured with or without HGF and harvested for real-time RT-PCR and for Western blot analysis. To evaluate the contribution of HGF to the biological action of BMP2, C3H10T1/2 cells and primary muscle-derived mesenchymal cells were precultured with HGF and cultured with BMP2. In addition, the expression of the luciferase gene linked to the Id1 promoter containing the BMP responsive element and alkaline phosphatase (ALP) activity were assayed.
Results: Positive immunostaining of HGF and phosphorylated c-Met was detected around the fracture site at 1 day after the fracture was made. mRNA expression of BMPRs was increased 1 day after fracture and localized in mesenchymal cells at the fracture site. From an in vitro study, the expression of mRNA for BMPRs was elevated by treatment with HGF, but the expression of BMP4 did not change. Western blot analysis also showed the upregulation of BMPR2 by HGF treatment. The results from the luciferase and ALP assays indicated increased responsiveness to BMPs by treating with HGF.
Conclusions: This study indicates that HGF is activated and expressed at the fracture site and that HGF induces the upregulation of BMPRs in mesenchymal cells. Furthermore, HGF may facilitate BMP signaling without altering the expression of BMP molecules.