Article

BMP-9-induced osteogenic differentiation of mesenchymal progenitors requires functional canonical Wnt/beta-catenin signalling.

The Second Affiliated Hospital and the Key Laboratory of Diagnostic Medicine designated by the Chinese Ministry of Education, Chongqing Medical University, Chongqing, China.
Journal of Cellular and Molecular Medicine (impact factor: 4.13). 12/2008; 13(8B):2448-64. DOI:10.1111/j.1582-4934.2008.00569.x pp.2448-64
Source: PubMed

ABSTRACT Bone morphogenetic protein 9 (BMP-9) is a member of the transforming growth factor (TGF)-beta/BMP superfamily, and we have demonstrated that it is one of the most potent BMPs to induce osteoblast differentiation of mesenchymal stem cells (MSCs). Here, we sought to investigate if canonical Wnt/beta-catenin signalling plays an important role in BMP-9-induced osteogenic differentiation of MSCs. Wnt3A and BMP-9 enhanced each other's ability to induce alkaline phosphatase (ALP) in MSCs and mouse embryonic fibroblasts (MEFs). Wnt antagonist FrzB was shown to inhibit BMP-9-induced ALP activity more effectively than Dkk1, whereas a secreted form of LPR-5 or low-density lipoprotein receptor-related protein (LRP)-6 exerted no inhibitory effect on BMP-9-induced ALP activity. beta-Catenin knockdown in MSCs and MEFs diminished BMP-9-induced ALP activity, and led to a decrease in BMP-9-induced osteocalcin reporter activity and BMP-9-induced expression of late osteogenic markers. Furthermore, beta-catenin knockdown or FrzB overexpression inhibited BMP-9-induced mineralization in vitro and ectopic bone formation in vivo, resulting in immature osteogenesis and the formation of chondrogenic matrix. Chromatin immunoprecipitation (ChIP) analysis indicated that BMP-9 induced recruitment of both Runx2 and beta-catenin to the osteocalcin promoter. Thus, we have demonstrated that canonical Wnt signalling, possibly through interactions between beta-catenin and Runx2, plays an important role in BMP-9-induced osteogenic differentiation of MSCs.

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Keywords

beta-catenin knockdown
 
BMP-9 induced recruitment
 
BMP-9-induced ALP activity
 
BMP-9-induced expression
 
BMP-9-induced osteocalcin reporter activity
 
BMP-9-induced osteogenic differentiation
 
Bone morphogenetic protein 9
 
canonical Wnt signalling
 
canonical Wnt/beta-catenin signalling
 
Chromatin immunoprecipitation
 
ectopic bone formation
 
induce alkaline phosphatase
 
induce osteoblast differentiation
 
low-density lipoprotein receptor-related protein
 
mouse embryonic fibroblasts
 
other's ability
 
potent BMPs
 
TGF)-beta/BMP superfamily
 
transforming growth factor
 
Wnt antagonist FrzB
 

Ni Tang