Bmpr1a and Bmpr1b have overlapping functions and are essential for chondrogenesis in vivo

doi:10.1073/pnas.0500031102

Bmpr1a and Bmpr1b have overlapping functions and are essential for chondrogenesis in vivo

Departments of ^*Molecular, Cell, and Developmental Biology, ^§Orthopaedic Surgery, and ^¶Biological Chemistry, University of California, Los Angeles, CA 90095; ^†Department of Molecular Genetics, University of Texas M. D. Anderson Cancer Center, Houston, TX 77030; and ^‡Laboratory of Reproductive and Developmental Toxicology, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709

Edited by Kathryn V. Anderson, Sloan–Kettering Institute, New York, NY, and approved February 24, 2005 (received for review January 3, 2005)

Abstract

Previous studies have demonstrated the ability of bone morphogenetic proteins (BMPs) to promote chondrogenic differentiation in vitro. However, the in vivo role of BMP signaling during chondrogenesis has been unclear. We report here that BMP signaling is essential for multiple aspects of early chondrogenesis. Whereas mice deficient in type 1 receptors Bmpr1a or Bmpr1b in cartilage are able to form intact cartilaginous elements, double mutants develop a severe generalized chondrodysplasia. The majority of skeletal elements that form through endochondral ossification are absent, and the ones that form are rudimentary. The few cartilage condensations that form in double mutants are delayed in the prechondrocytic state and never form an organized growth plate. The reduced size of mutant condensations results from increased apoptosis and decreased proliferation. Moreover, the expression of cartilage-specific extracellular matrix proteins is severely reduced in mutant elements. We demonstrate that this defect in chondrocytic differentiation can be attributed to lack of Sox9, L-Sox5, and Sox6 expression in precartilaginous condensations in double mutants. In summary, our study demonstrates that BMPR1A and BMPR1B are functionally redundant during early chondrogenesis and that BMP signaling is required for chondrocyte proliferation, survival, and differentiation in vivo.

Footnotes

↵ ∥ To whom correspondence should be addressed at: 2641 MacDonald Research Laboratories, University of California, 675 Charles E. Young Drive South, Los Angeles, CA 90095. E-mail: klyons{at}mednet.ucla.edu.
Author contributions: B.S.Y. and K.M.L. designed research; B.S.Y. and I.Y. performed research; D.A.O., Y.M., and R.R.B. contributed new reagents/analytic tools; B.S.Y. and K.M.L. analyzed data; and B.S.Y. wrote the paper.
This paper was submitted directly (Track II) to the PNAS office.
Abbreviations: BMP, bone morphogenetic protein; BMPR1A, BMP receptor type 1A; BMPR1B, BMP receptor type 1B; ActR1, activin receptor type 1; ECM, extracellular matrix; DN, dominant negative; CKO, conditional knockout; IHC, immunohistochemistry; PCNA, proliferating cell nuclear antigen; En, embyronic day n.