The TGFß type I receptor TGFßRI functions as an inhibitor of BMP signaling in cartilage.

ABSTRACT

The type I TGFß receptor TGFßRI (encoded by Tgfbr1) was ablated in cartilage. The resulting Tgfbr1Col2 mice exhibited lethal chondrodysplasia. Similar defects were not seen in mice lacking the type II TGFß receptor or SMADs 2 and 3, the intracellular mediators of canonical TGFß signaling. However, we detected elevated BMP activity in Tgfbr1Col2 mice. As previous studies showed that TGFßRI can physically interact with ACVRL1, a type I BMP receptor, we generated cartilage-specific Acvrl1 (Acvrl1Col2 ) and Acvrl1/Tgfbr1 (Acvrl1/Tgfbr1Col2) knockouts. Loss of ACVRL1 alone had no effect, but Acvrl1/Tgfbr1Col2 mice exhibited a striking reversal of the chondrodysplasia seen in Tgfbr1Col2 mice. Loss of TGFßRI led to a redistribution of the type II receptor ACTRIIB into ACVRL1/ACTRIIB complexes, which have high affinity for BMP9. Although BMP9 is not produced in cartilage, we detected BMP9 in the growth plate, most likely derived from the circulation. These findings demonstrate that the major function of TGFßRI in cartilage is not to transduce TGFß signaling, but rather to antagonize BMP signaling mediated by ACVRL1.