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

Author:

Shu Bing12,Zhang Ming1,Xie Rong1,Wang Meina1,Jin Hongting3,Hou Wei2,Tang Dezhi2,Harris Stephen E.4,Mishina Yuji5,O'Keefe Regis J.1,Hilton Matthew J.1,Wang Yongjun2,Chen Di1

Affiliation:

1. Department of Orthopaedics and Rehabilitation, Center for Musculoskeletal Research, University of Rochester School of Medicine, Rochester, NY 14642, USA

2. Spine Research Institute, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China

3. Institute of Orthopaedics and Traumatology, Zhejiang Chinese Medical University, Hangzhou, Zhejiang Province, China

4. Department of Periodontics, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA

5. Department of Biologic and Materials Sciences, School of Dentistry, University of Michigan, Ann Arbor, MI 48109, USA

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.

Publisher

The Company of Biologists

Subject

Cell Biology

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