Discoidin domain receptor 2 is an important modulator of BMP signaling during heterotopic bone formation  

作　　者：Fashuai Wu Chunxi Ge Haichun Pan Yuanyuan Han Yuji Mishina Vesa Kaartinen Renny T.Franceschi 

机构地区：[1]Department of Periodontics&Oral Medicine,University of Michigan School of Dentistry,Ann Arbor,MI,USA [2]Department of Orthopaedics,Union Hospital,Tongji Medical College,Huazhong University of Science and Technology,Wuhan,China [3]Department of Biologic and Materials Sciences,University of Michigan School of Dentistry,Ann Arbor,MI,USA

出　　处：《Bone Research》2025年第1期121-138,共18页骨研究(英文版)

基　　金：Scientific Research Training Program for Young Talents of Union Hospital,Tongji Medical College,Huazhong University of Science and Technology(F.W.),NIH/NIDCR grants DE029012 and DE029465;Department of Defense Grant PR190899(R.T.F.);Michigan Musculoskeletal Health Core Center(NIH/NIAMS P30 AR069620)。

摘　　要：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.

关 键 词：inhibited HEALING MODULATOR 

分 类 号：R73[医药卫生—肿瘤]