The TGFβ type i receptor TGFβRI functions as an inhibitor of BMP signaling in cartilage

Abstract

The type I TGFβ receptor TGFβRI (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 TGFβ receptor or SMADs 2 and 3 the intracellular mediators of canonical TGFβ signaling. However we detected elevated BMP activity in Tgfbr1Col2 mice. As previous studies showed that TGFβRI 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 TGFβRI 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 TGFβRI in cartilage is not to transduce TGFβ signaling but rather to antagonize BMP signaling mediated by ACVRL1.