BMP2, but not BMP4, is crucial for chondrocyte proliferation and maturation during endochondral bone development

Abstract

SummaryThe 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.Key words: Bmp2, Bmp4, Chondrocyte, Endochondral bone formation Introduction 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. The committed chondrocytes proliferate rapidly forming the cartilage growth plate where cells are arranged in columns of proliferating, differentiating and terminally hypertrophic chondrocytes. Chondrocytes near the center of the cartilage elements exit the cell cycle initiating the process of hypertrophic differentiation to generate a calcified cartilage matrix. Eventually, 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. Primary ossification occurs with osteoblast-mediated bone formation, which initially occurs on the calcified cartilage template. 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),

Shox2regulates progression through chondrogenesis in the mouse proximal limb

“…Therefore, we examined the humeral expression pattern of Bmp4 using ISH. In accordance with earlier reports of Bmp4 expression in the growth plate (Isshiki et al, 2011;Shu et al, 2011), we found that Bmp4 is expressed weakly in the prehypertrophic zone and more strongly in the hypertrophic region of the E13.5 humerus (Fig. 3E).…”

Fibroblast Growth Factor-1 Is a Mesenchymal Stromal Cell-Secreted Factor Stimulating Proliferation of Osteoarthritic Chondrocytes in Co-Culture

“…BMP-2's contribution to matrix formation, there are a few reports studying its function in chondrocyte proliferation [34,38]. However, qPCR data from the xenogenic co-culture model indicated that expression of BMP-2 appeared to be increased predominantly in hPCs but not in MSCs.…”

“…Among these genes, BMP-2 and FGF-1 stood out, as their functions in chondrocyte proliferation and matrix formation had been previously demonstrated [32][33][34]. For a long time, BMP-2 has been used as a strong stimulator for osteogenic differentiation of stem cells [35].…”

Bmp2 gene in osteoblasts of periosteum and trabecular bone links bone formation to vascularization and mesenchymal stem cells

“…Selected polymorphisms in the BMP2 gene are associated with increased fracture risk and osteoporosis (Styrkarsdottir et al, 2003). Deletion of other BMP family members Bmp7 and Bmp4 suggests that they play minor roles in bone and cartilage development in the embryo or postnatally, whereas Bmp2 is critical for chondrocyte function and endochondral bone development Shu et al, 2011;Tsuji et al, 2008). Removal of Bmp2 in mouse mesenchymal precursor cells in 10 d.p.c.…”