Discoidin domain receptor 2 is an important modulator of BMP signaling during heterotopic bone formation
Abstract Bone morphogenetic proteins are essential for bone regeneration/fracture healing but can also induce heterotopic ossification (HO). Understanding accessory factors modulating BMP signaling would provide both a means of enhancing BMP-dependent regeneration while preventing HO. This study foc...
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| Format: | Article |
| Language: | English |
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Nature Publishing Group
2025-01-01
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| Series: | Bone Research |
| Online Access: | https://doi.org/10.1038/s41413-024-00391-z |
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| author | Fashuai Wu Chunxi Ge Haichun Pan Yuanyuan Han Yuji Mishina Vesa Kaartinen Renny T. Franceschi |
| author_facet | Fashuai Wu Chunxi Ge Haichun Pan Yuanyuan Han Yuji Mishina Vesa Kaartinen Renny T. Franceschi |
| author_sort | Fashuai Wu |
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| description | Abstract Bone morphogenetic proteins are essential for bone regeneration/fracture healing but can also induce heterotopic ossification (HO). Understanding accessory factors modulating BMP signaling would provide both a means of enhancing BMP-dependent regeneration while preventing HO. This study focuses on the ability of the collagen receptor, discoidin domain receptor 2 (DDR2), to regulate BMP activity. As will be shown, induction of bone formation by subcutaneous BMP2 implants is severely compromised in Ddr2-deficient mice. In addition, Ddr2 deficiency attenuates HO in mice expressing the ACVR1 mutation associated with human fibrodysplasia ossificans progressiva. In cells migrating into BMP2 implants, DDR2 is co-expressed with GLI1, a skeletal stem cell marker, and DDR2/GLI1-positive cells participate in BMP2-induced bone formation where they contribute to chondrogenic and osteogenic lineages. Consistent with this distribution, conditional knockout of Ddr2 in Gli1-expressing cells inhibited bone formation to the same extent seen in globally Ddr2-deficient animals. This response was explained by selective inhibition of Gli1 + cell proliferation without changes in apoptosis. The basis for this DDR2 requirement was explored further using bone marrow stromal cells. Although Ddr2 deficiency inhibited BMP2-dependent chondrocyte and osteoblast differentiation and in vivo, bone formation, early BMP responses including SMAD phosphorylation remained largely intact. Instead, Ddr2 deficiency reduced the nuclear/cytoplasmic ratio of the Hippo pathway intermediates, YAP and TAZ. This suggests that DDR2 regulates Hippo pathway-mediated responses to the collagen matrix, which subsequently affect BMP responsiveness. In summary, DDR2 is an important modulator of BMP signaling and a potential therapeutic target both for enhancing regeneration and treating HO. |
| format | Article |
| id | doaj-art-702b08a45d4e4ab0a51ff7b7e21d94b9 |
| institution | Kabale University |
| issn | 2095-6231 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Bone Research |
| spelling | doaj-art-702b08a45d4e4ab0a51ff7b7e21d94b92025-01-05T12:11:10ZengNature Publishing GroupBone Research2095-62312025-01-0113111810.1038/s41413-024-00391-zDiscoidin domain receptor 2 is an important modulator of BMP signaling during heterotopic bone formationFashuai Wu0Chunxi Ge1Haichun Pan2Yuanyuan Han3Yuji Mishina4Vesa Kaartinen5Renny T. Franceschi6Department of Periodontics & Oral Medicine, University of Michigan School of DentistryDepartment of Periodontics & Oral Medicine, University of Michigan School of DentistryDepartment of Biologic and Materials Sciences, University of Michigan School of DentistryDepartment of Periodontics & Oral Medicine, University of Michigan School of DentistryDepartment of Biologic and Materials Sciences, University of Michigan School of DentistryDepartment of Biologic and Materials Sciences, University of Michigan School of DentistryDepartment of Periodontics & Oral Medicine, University of Michigan School of DentistryAbstract Bone morphogenetic proteins are essential for bone regeneration/fracture healing but can also induce heterotopic ossification (HO). Understanding accessory factors modulating BMP signaling would provide both a means of enhancing BMP-dependent regeneration while preventing HO. This study focuses on the ability of the collagen receptor, discoidin domain receptor 2 (DDR2), to regulate BMP activity. As will be shown, induction of bone formation by subcutaneous BMP2 implants is severely compromised in Ddr2-deficient mice. In addition, Ddr2 deficiency attenuates HO in mice expressing the ACVR1 mutation associated with human fibrodysplasia ossificans progressiva. In cells migrating into BMP2 implants, DDR2 is co-expressed with GLI1, a skeletal stem cell marker, and DDR2/GLI1-positive cells participate in BMP2-induced bone formation where they contribute to chondrogenic and osteogenic lineages. Consistent with this distribution, conditional knockout of Ddr2 in Gli1-expressing cells inhibited bone formation to the same extent seen in globally Ddr2-deficient animals. This response was explained by selective inhibition of Gli1 + cell proliferation without changes in apoptosis. The basis for this DDR2 requirement was explored further using bone marrow stromal cells. Although Ddr2 deficiency inhibited BMP2-dependent chondrocyte and osteoblast differentiation and in vivo, bone formation, early BMP responses including SMAD phosphorylation remained largely intact. Instead, Ddr2 deficiency reduced the nuclear/cytoplasmic ratio of the Hippo pathway intermediates, YAP and TAZ. This suggests that DDR2 regulates Hippo pathway-mediated responses to the collagen matrix, which subsequently affect BMP responsiveness. In summary, DDR2 is an important modulator of BMP signaling and a potential therapeutic target both for enhancing regeneration and treating HO.https://doi.org/10.1038/s41413-024-00391-z |
| spellingShingle | Fashuai Wu Chunxi Ge Haichun Pan Yuanyuan Han Yuji Mishina Vesa Kaartinen Renny T. Franceschi Discoidin domain receptor 2 is an important modulator of BMP signaling during heterotopic bone formation Bone Research |
| title | Discoidin domain receptor 2 is an important modulator of BMP signaling during heterotopic bone formation |
| title_full | Discoidin domain receptor 2 is an important modulator of BMP signaling during heterotopic bone formation |
| title_fullStr | Discoidin domain receptor 2 is an important modulator of BMP signaling during heterotopic bone formation |
| title_full_unstemmed | Discoidin domain receptor 2 is an important modulator of BMP signaling during heterotopic bone formation |
| title_short | Discoidin domain receptor 2 is an important modulator of BMP signaling during heterotopic bone formation |
| title_sort | discoidin domain receptor 2 is an important modulator of bmp signaling during heterotopic bone formation |
| url | https://doi.org/10.1038/s41413-024-00391-z |
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