Dataset Information

The TGF? type I receptor TGF?RI functions as an inhibitor of BMP signaling in cartilage.

ABSTRACT: The type I TGF? receptor TGF?RI (encoded by Tgfbr1) was ablated in cartilage. The resulting Tgfbr1 ^Col2 mice exhibited lethal chondrodysplasia. Similar defects were not seen in mice lacking the type II TGF? receptor or SMADs 2 and 3, the intracellular mediators of canonical TGF? signaling. However, we detected elevated BMP activity in Tgfbr1 ^Col2 mice. As previous studies showed that TGF?RI can physically interact with ACVRL1, a type I BMP receptor, we generated cartilage-specific Acvrl1 (Acvrl1 ^Col2 ) and Acvrl1/Tgfbr1 (Acvrl1/Tgfbr1 ^Col2 ) knockouts. Loss of ACVRL1 alone had no effect, but Acvrl1/Tgfbr1 ^Col2 mice exhibited a striking reversal of the chondrodysplasia seen in Tgfbr1 ^Col2 mice. Loss of TGF?RI 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 TGF?RI in cartilage is not to transduce TGF? signaling, but rather to antagonize BMP signaling mediated by ACVRL1.

SUBMITTER: Wang W

PROVIDER: S-EPMC6681752 | biostudies-literature | 2019 Jul

REPOSITORIES: biostudies-literature

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

Wang Weiguang W Chun Hyelim H Baek Jongseung J Sadik Joshua Elyahu JE Shirazyan Anna A Razavi Peyman P Lopez Noah N Lyons Karen M KM

Proceedings of the National Academy of Sciences of the United States of America 20190716 31

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 r ...[more]

PMID: 31311865

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Project description:Articular cartilage plays an essential role in health and mobility, but is frequently damaged or lost in millions of people that develop arthritis. The molecular mechanisms that create and maintain this thin layer of cartilage that covers the surface of bones in joint regions are poorly understood, in part because tools to manipulate gene expression specifically in this tissue have not been available. Here we use regulatory information from the mouse Gdf5 gene (a bone morphogenetic protein [BMP] family member) to develop new mouse lines that can be used to either activate or inactivate genes specifically in developing joints. Expression of Cre recombinase from Gdf5 bacterial artificial chromosome clones leads to specific activation or inactivation of floxed target genes in developing joints, including early joint interzones, adult articular cartilage, and the joint capsule. We have used this system to test the role of BMP receptor signaling in joint development. Mice with null mutations in Bmpr1a are known to die early in embryogenesis with multiple defects. However, combining a floxed Bmpr1a allele with the Gdf5-Cre driver bypasses this embryonic lethality, and leads to birth and postnatal development of mice missing the Bmpr1a gene in articular regions. Most joints in the body form normally in the absence of Bmpr1a receptor function. However, articular cartilage within the joints gradually wears away in receptor-deficient mice after birth in a process resembling human osteoarthritis. Gdf5-Cre mice provide a general system that can be used to test the role of genes in articular regions. BMP receptor signaling is required not only for early development and creation of multiple tissues, but also for ongoing maintenance of articular cartilage after birth. Genetic variation in the strength of BMP receptor signaling may be an important risk factor in human osteoarthritis, and treatments that mimic or augment BMP receptor signaling should be investigated as a possible therapeutic strategy for maintaining the health of joint linings.

Dataset Information

The TGF? type I receptor TGF?RI functions as an inhibitor of BMP signaling in cartilage.

Publications

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

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