title: DDR2 (discoidin domain receptor 2) suppresses osteoclastogenesis and is a potential therapeutic target in osteoporosis.
abstract: Osteoporosis is a disease characterized by abnormal skeletal fragility due to an imbalance in bone homeostasis. Finding therapeutic targets that promote bone formation is valuable for treating osteoporosis. Discoidin domain receptor 2 (DDR2) is a receptor tyrosine kinase that promotes the differentiation of bone-depositing cells, osteoblasts, and bone formation. We investigated the role of DDR2 in osteoclastogenesis, the formation of cells responsible for bone resorption. We found that, although differentiated osteoclasts had catalytically active DDR2, its abundance was decreased. Overexpression of DDR2 inhibited the expression of osteoclastic markers, osteoclast maturation, and osteoclast-mediated bone resorption in a culture model of bone matrix. Conversely, knocking down Ddr2 through RNA interference accelerated osteoclast differentiation and bone resorption in mice. Further, we identified the co-receptor Neuropilin-1 (Nrp1) as a DDR2-interacting protein. DDR2 facilitated the binding of Nrp1 and the co-receptor PlexinA1 by forming a DDR2-Nrp1-PlexinA1 complex, which blocked PlexinA1-mediated stimulation of osteoclastogenesis. DDR2 prevented PlexinA1 from interacting with the receptor TREM2 and the adaptor DAP12. Moreover, knocking down Nrp1 rescued the expression of osteoclastic markers observed in DDR2-overexpressing cells, whereas ectopic expression of Nrp1 in DDR2-silenced cells inhibited the induction of osteoclastogenesis. Nrp1 enhanced the function of DDR2 in promoting osteoblast differentiation and bone formation in mice. In an ovariectomized mouse model of osteoporosis, adenovirus-mediated delivery of DDR2 to the femur bone alleviated osteopenic phenotypes. Our results revealed that DDR2 functions as an inhibitor of osteoclastogenesis, as well as a promoter of osteoblastogenesis, suggesting that enhancing DDR2 may be therapeutic for patients with osteoporosis.
authors: Center for Translational Medicine, the First Affiliated Hospital of Xi'an Jiaotong University College of Medicine, Xi'an, Shaanxi 710061, People's Republic of China.
authors: Yan
authors: Y
authors: Zhang
authors: Department of Biochemistry and Molecular Biology, the Fourth Military Medical University, Xi'an, Shaanxi 710032, People's Republic of China.
authors: Jin
authors: J
authors: Su
authors: Center for Translational Medicine, the First Affiliated Hospital of Xi'an Jiaotong University College of Medicine, Xi'an, Shaanxi 710061, People's Republic of China.
authors: Shufang
authors: S
authors: Wu
authors: Center for Translational Medicine, the First Affiliated Hospital of Xi'an Jiaotong University College of Medicine, Xi'an, Shaanxi 710061, People's Republic of China.
authors: Yue
authors: Y
authors: Teng
authors: Department of Orthopaedics, the First Affiliated Hospital of Xi'an Jiaotong University College of Medicine, Xi'an, Shaanxi 710061, People's Republic of China.
authors: Zhanhai
authors: Z
authors: Yin
authors: Key Laboratory of Biomedical Information Engineering of Ministry of Education, and Institute of Molecular Genetics, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an, Shaanxi 710049, People's Republic of China.
authors: Yan
authors: Y
authors: Guo
authors: Center for Translational Medicine, the First Affiliated Hospital of Xi'an Jiaotong University College of Medicine, Xi'an, Shaanxi 710061, People's Republic of China.
authors: Jing
authors: J
authors: Li
authors: Clinical laboratory, ShanXi Mineral Hospital, Xi'an, Shaanxi 710014, People's Republic of China.
authors: Kun
authors: K
authors: Li
authors: Department of Biochemistry and Molecular Biology, the Fourth Military Medical University, Xi'an, Shaanxi 710032, People's Republic of China.
authors: Libo
authors: L
authors: Yao
authors: Center for Translational Medicine, the First Affiliated Hospital of Xi'an Jiaotong University College of Medicine, Xi'an, Shaanxi 710061, People's Republic of China. lixuxjtu@163.com.
authors: Xu
authors: X
authors: Li
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism; D000818:Animals; D015153:Blotting, Western; D002454:Cell Differentiation / Q000235:genetics; D002460:Cell Line; D002478:Cells, Cultured; D000070818:Discoidin Domain Receptors; D005260:Female; D020869:Gene Expression Profiling; D057809:HEK293 Cells; D006801:Humans; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D039942:Neuropilin-1 / Q000235:genetics / Q000378:metabolism; D010006:Osteoblasts / Q000378:metabolism*; D010010:Osteoclasts / Q000378:metabolism*; D010012:Osteogenesis / Q000235:genetics; D010024:Osteoporosis / Q000235:genetics / Q000378:metabolism*; D010052:Ovariectomy; D011485:Protein Binding; D034622:RNA Interference; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism; D011971:Receptors, Immunologic / Q000235:genetics / Q000378:metabolism; D011975:Receptors, Mitogen / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000235:genetics
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D008562:Membrane Glycoproteins; D009419:Nerve Tissue Proteins; C492114:Plxna1 protein, mouse; D011956:Receptors, Cell Surface; D011971:Receptors, Immunologic; D011975:Receptors, Mitogen; C498716:Trem2 protein, mouse; C484963:Tyrobp protein, mouse; D039942:Neuropilin-1; D000070818:Discoidin Domain Receptors; D020794:Receptor Protein-Tyrosine Kinases