Bmpr1a and Bmpr1b have overlapping functions and are essential for chondrogenesis in vivo.
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.
Yoon
Byeong S
BS
Department of Molecular, Cell, and Developmental Biology, University of California, Los Angeles, CA 90095, USA.
Ovchinnikov
Dmitry A
DA
Yoshii
Isaac
I
Mishina
Yuji
Y
Behringer
Richard R
RR
Lyons
Karen M
KM
D000818:Animals; D052005:Bone Morphogenetic Protein Receptors, Type I; D002454:Cell Differentiation; D019902:Chondrocytes / Q000378:metabolism / Q000473:pathology; D020219:Chondrogenesis / Q000235:genetics / Q000502:physiology*; D004268:DNA-Binding Proteins / Q000378:metabolism; D005109:Extracellular Matrix / Q000378:metabolism / Q000473:pathology; D018507:Gene Expression Regulation, Developmental; D006609:High Mobility Group Proteins / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009687:Nuclear Proteins / Q000378:metabolism; D010009:Osteochondrodysplasias / Q000196:embryology / Q000235:genetics; D010641:Phenotype; D017346:Protein Serine-Threonine Kinases / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D017978:Receptors, Growth Factor / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D055758:SOX9 Transcription Factor; D055755:SOXD Transcription Factors; D015398:Signal Transduction; D014157:Transcription Factors / Q000378:metabolism
D004268:DNA-Binding Proteins; D006609:High Mobility Group Proteins; D009687:Nuclear Proteins; D017978:Receptors, Growth Factor; D055758:SOX9 Transcription Factor; D055755:SOXD Transcription Factors; C089186:Sox5 protein, mouse; C095939:Sox6 protein, mouse; C527933:Sox9 protein, mouse; D014157:Transcription Factors; D017346:Protein Serine-Threonine Kinases; C498212:Bmpr1a protein, mouse; C498215:Bmpr1b protein, mouse; D052005:Bone Morphogenetic Protein Receptors, Type I