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.
Highlights
During skeletal development, the majority of the bones in the body are established by the endochondral bone formation process, which is initiated by mesenchymal cell condensation and subsequent mesenchymal cell differentiation into chondrocytes and surrounding perichondrial cells
Our studies demonstrate that deletion of only Bmp2 or both Bmp2 and Bmp4 genes led to severe defects in chondrocyte proliferation and maturation during endochondral bone development
Deletion of Bmp2 and Bmp4 or Bmp2 alone impairs skeletal development To investigate the role of endogenous Bmp2 and Bmp4 genes in growth plate chondrocyte maturation and skeletal development, pregnant mice with embryos at E12.5 were injected with TM
Summary
The majority of the bones in the body are established by the endochondral bone formation process, which is initiated by mesenchymal cell condensation and subsequent mesenchymal cell differentiation into chondrocytes and surrounding perichondrial cells. The local vasculature, perichondrial osteoblasts and various other types of cells invade the calcified cartilage, replacing the terminally mature chondrocytes with marrow components and trabecular bone matrix. Chondrocyte maturation and the endochondral bone development process is tightly regulated by a series of growth factors and transcription factors, including bone morphogenetic proteins (BMPs), fibroblast growth factors (FGFs), indian hedgehog (Ihh), parathyroid hormone-related protein (PTHrP), Wnt signaling proteins and Runt-related transcription factor 2 (Runx2) (Yoon and Lyons, 2004; Ornitz, 2005; Kronenberg, 2003; Komori, 2003; Kolpakova and Olsen, 2005)
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