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

Abstract

The type I TGFβ receptor TGFβRI (encoded by <i>Tgfbr1</i>) was ablated in cartilage. The resulting <i>Tgfbr1</i>^<i>Col2</i> 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 <i>Tgfbr1</i>^<i>Col2</i> mice. As previous studies showed that TGFβRI can physically interact with ACVRL1, a type I BMP receptor, we generated cartilage-specific <i>Acvrl1</i> (<i>Acvrl1</i>^<i>Col2</i> ) and <i>Acvrl1/Tgfbr1 (Acvrl1/Tgfbr1</i>^<i>Col2</i><i>)</i> knockouts. Loss of ACVRL1 alone had no effect, but <i>Acvrl1/Tgfbr1</i>^<i>Col2</i> mice exhibited a striking reversal of the chondrodysplasia seen in <i>Tgfbr1</i>^<i>Col2</i> 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.