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

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.bone morphogenetic protein ͉ cartilage ͉ endochondral ossification ͉ Sox proteins ͉ skeletal development D uring endochondral ossification, mesenchymal cells condense and differentiate into chondrocytes. The chondrocytes undergo a highly organized differentiation program, forming the template for bone formation (1, 2). Bone morphogenetic proteins (BMPs) were identified by their ability to promote ectopic cartilage and bone formation (3). BMPs are members of the TGF␤ superfamily and transduce signals by binding to heteromeric complexes of type 1 and type 2 serine͞threonine kinase receptors. The binding of BMPs to the receptor complex results in the phosphorylation of intracellular Smads, which then translocate to the nucleus, where they regulate transcription (4). The differential affinities of distinct BMP ligands for the three type 1 receptors, BMPR1A (BMP receptor type 1A), BMPR1B (BMP receptor type 1B), and ActR1 (activin receptor type 1), are thought to contribute to the diversity of actions during development. Several lines of evidence suggest that Bmpr1a, Bmpr1b, and ActR1 have distinct roles during chondrogenesis. In the chick, Bmpr1a is expressed at low levels throughout the limb bud mesenchyme, whereas Bmpr1b is expressed in precartilaginous condensations, suggesting that these receptors have different roles in chondrogenesis. Furthermore, whereas constitutively active forms of either BMPR1A or BMPR1B promote chondrogenesis, only the overexpression of dominant negative (DN)-BMPR1B, and not DN-BMPR1A or DN-ActR1, blocks these events, suggesting that BMPR1B is the major transducer of BMP signals in limb condensations (5-8). However, Bmpr1b null mic...

In vitro stage‐specific chondrogenesis of mesenchymal stem cells committed to chondrocytes

“…Of particular importance, the Smads mediated by the TGF␤ genes activated the receptor TGF␤R1, which plays an essential role in promoting MSCs to chondroprogenitors and chondrogenic differentiation, especially Smad1. Alternatively, the BMP signaling molecules collectively controlled the activation of transcription factor SOX9, through receptors BMPR1A and BMPR1B (45,46).…”

AP2γ regulates neural and epidermal development downstream of the BMP pathway at early stages of ectodermal patterning

“…Here, we identified AP2γ as a novel BMP downstream target that is directly regulated by BMP4 through Smad1 binding to the AP2γ promoter (Figure 7). BMPR1a-knockout mice die at E8.0 while BMPR1b-null mice are viable [71,72], implying that BMPR1a was the possible receptor mediating BMP functions during ectodermal patterning. In the early chick embryo, cAP2γ can be ectopically induced by BMP4 and suppressed by chordin (Figure 6), suggesting that clearance of AP2γ transcripts from the medial epiblast might be elicited by BMP antagonists secreted from the organizer with gradually enhanced expression [63,73].…”

Mechanisms of digit formation: Human malformation syndromes tell the story

“…Chondrogenesis in the limb is dependent on BMP signaling, since its inhibition in the chicken limb by implantation of Noggin beads, or retroviral overexpression of dominant-negative BMP receptors, equally interfere with chondrogenesis (Zou et al, 1997;Merino et al, 1998). In the mouse ablation of both type I receptors (BmpR1a and BmpR1b) causes a severe generalized chondrodysplasia in which most skeletal elements that form through endochondroal ossification are absent or rudimentary (Yoon et al, 2005;Ovchinnikov et al, 2006). Homozygous inactivation of BmpR1b alone leads to severe brachydactyly in the mouse with hypoplasia/aplasia of the proximal and medial phalanges (Baur et al, 2000;Yi et al, 2000).…”