BMP2, but not BMP4, is crucial for chondrocyte proliferation and maturation during endochondral bone development
- 15 October 2011
- journal article
- Published by The Company of Biologists in Journal of Cell Science
- Vol. 124 (20), 3428-3440
- https://doi.org/10.1242/jcs.083659
Abstract
The BMP signaling pathway has a crucial role in chondrocyte proliferation and maturation during endochondral bone development. To investigate the specific function of the Bmp2 and Bmp4 genes in growth plate chondrocytes during cartilage development, we generated chondrocyte-specific Bmp2 and Bmp4 conditional knockout (cKO) mice and Bmp2,Bmp4 double knockout (dKO) mice. We found that deletion of Bmp2 and Bmp4 genes or the Bmp2 gene alone results in a severe chondrodysplasia phenotype, whereas deletion of the Bmp4 gene alone produces a minor cartilage phenotype. Both dKO and Bmp2 cKO mice exhibit severe disorganization of chondrocytes within the growth plate region and display profound defects in chondrocyte proliferation, differentiation and apoptosis. To understand the mechanism by which BMP2 regulates these processes, we explored the specific relationship between BMP2 and Runx2, a key regulator of chondrocyte differentiation. We found that BMP2 induces Runx2 expression at both the transcriptional and post-transcriptional levels. BMP2 enhances Runx2 protein levels through inhibition of CDK4 and subsequent prevention of Runx2 ubiquitylation and proteasomal degradation. Our studies provide novel insights into the genetic control and molecular mechanism of BMP signaling during cartilage development.Keywords
This publication has 60 references indexed in Scilit:
- New roles and mechanism of action of BMP4 in postnatal tooth cytodifferentiationBone, 2010
- Smad3 Prevents β-Catenin Degradation and Facilitates β-Catenin Nuclear Translocation in ChondrocytesJournal of Biological Chemistry, 2010
- Prostaglandin E2 inhibits BMP signaling and delays chondrocyte maturationJournal of Orthopaedic Research, 2009
- Hypertrophy is induced during the in vitro chondrogenic differentiation of human mesenchymal stem cells by bone morphogenetic protein-2 and bone morphogenetic protein-4 gene transferArthritis Research & Therapy, 2009
- Influences of Reduced Expression of Maternal Bone Morphogenetic Protein 2 on Mouse Embryonic DevelopmentSexual Development, 2008
- Autogenous regulation of a network of bone morphogenetic proteins (BMPs) mediates the osteogenic differentiation in murine marrow stromal cellsBone, 2007
- Bone Morphogenetic Protein 2 Activates Smad6 Gene Transcription through Bone-specific Transcription Factor Runx2Online Journal of Public Health Informatics, 2007
- Generation of a transgenic mouse model with chondrocyte‐specific and tamoxifen‐inducible expression of Cre recombinasegenesis, 2007
- Cyclin D1-Cdk4 Induce Runx2 Ubiquitination and DegradationOnline Journal of Public Health Informatics, 2006
- Developmental regulation of the growth plateNature, 2003