title: IL-12p40 impairs mesenchymal stem cell-mediated bone regeneration via CD4+T cells.
abstract: Severe or prolonged inflammatory response caused by infection or biomaterials leads to delayed healing or bone repair failure. This study investigated the important roles of the proinflammatory cytokines of the interleukin-12 (IL-12) family, namely, IL-12 and IL-23, in the inflammation-mediated inhibition of bone formation in vivo. IL-12p40-/-mice lacking IL-12 and IL-23 exhibited enhanced bone formation. IL-12 and IL-23 indirectly inhibited bone marrow mesenchymal stem cell (BMMSC) differentiation by stimulating CD4+T cells to increase interferon γ (IFN-γ) and IL-17 levels. Mechanistically, IL-17 synergistically enhanced IFN-γ-induced BMMSC apoptosis. Moreover, INF-γ and IL-17 exerted proapoptotic effects by upregulating the expression levels of Fas and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), as well as by activating the caspase cascade in BMMSCs. IL-12p40 depletion in mice could promote ectopic bone formation. Thus, IL-12p40 is an attractive therapeutic target to overcome the inflammation-mediated inhibition of bone formation in vivo.
authors.affiliation: The Key Laboratory of Stem Cell Biology, Institute of Health Sciences, Shanghai Institutes for Biological Sciences (SIBS), Chinese Academy of Sciences (CAS); University of Chinese Academy of Sciences and Shanghai Jiao Tong University School of Medicine (SJTUSM), Shanghai 200031, China.
authors.forename: Jiajia
authors.identifier: 0000-0002-6084-2029
authors.initials: J
authors.lastname: Xu
authors.affiliation: The Key Laboratory of Stem Cell Biology, Institute of Health Sciences, Shanghai Institutes for Biological Sciences (SIBS), Chinese Academy of Sciences (CAS); University of Chinese Academy of Sciences and Shanghai Jiao Tong University School of Medicine (SJTUSM), Shanghai 200031, China.
authors.forename: Yiyun
authors.initials: Y
authors.lastname: Wang
authors.affiliation: The Key Laboratory of Stem Cell Biology, Institute of Health Sciences, Shanghai Institutes for Biological Sciences (SIBS), Chinese Academy of Sciences (CAS); University of Chinese Academy of Sciences and Shanghai Jiao Tong University School of Medicine (SJTUSM), Shanghai 200031, China.|Shanghai Key Laboratory of Orthopaedic Implant, Department of Orthopaedic Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine (SJTUSM), Shanghai 200011, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Li
authors.affiliation: The Key Laboratory of Stem Cell Biology, Institute of Health Sciences, Shanghai Institutes for Biological Sciences (SIBS), Chinese Academy of Sciences (CAS); University of Chinese Academy of Sciences and Shanghai Jiao Tong University School of Medicine (SJTUSM), Shanghai 200031, China.
authors.forename: Xudong
authors.initials: X
authors.lastname: Zhang
authors.affiliation: The Key Laboratory of Stem Cell Biology, Institute of Health Sciences, Shanghai Institutes for Biological Sciences (SIBS), Chinese Academy of Sciences (CAS); University of Chinese Academy of Sciences and Shanghai Jiao Tong University School of Medicine (SJTUSM), Shanghai 200031, China.
authors.forename: Yiyun
authors.initials: Y
authors.lastname: Geng
authors.affiliation: The Key Laboratory of Stem Cell Biology, Institute of Health Sciences, Shanghai Institutes for Biological Sciences (SIBS), Chinese Academy of Sciences (CAS); University of Chinese Academy of Sciences and Shanghai Jiao Tong University School of Medicine (SJTUSM), Shanghai 200031, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Huang
authors.affiliation: The Key Laboratory of Stem Cell Biology, Institute of Health Sciences, Shanghai Institutes for Biological Sciences (SIBS), Chinese Academy of Sciences (CAS); University of Chinese Academy of Sciences and Shanghai Jiao Tong University School of Medicine (SJTUSM), Shanghai 200031, China.|Shanghai Key Laboratory of Orthopaedic Implant, Department of Orthopaedic Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine (SJTUSM), Shanghai 200011, China.
authors.forename: Kerong
authors.initials: K
authors.lastname: Dai
authors.affiliation: The Key Laboratory of Stem Cell Biology, Institute of Health Sciences, Shanghai Institutes for Biological Sciences (SIBS), Chinese Academy of Sciences (CAS); University of Chinese Academy of Sciences and Shanghai Jiao Tong University School of Medicine (SJTUSM), Shanghai 200031, China.|Shanghai Key Laboratory of Orthopaedic Implant, Department of Orthopaedic Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine (SJTUSM), Shanghai 200011, China.
authors.forename: Xiaoling
authors.initials: X
authors.lastname: Zhang
mesh_terms: D000818:Animals; D017209:Apoptosis; D001854:Bone Marrow Cells / Q000166:cytology; D001861:Bone Regeneration; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism*; D020169:Caspases / Q000378:metabolism; D002454:Cell Differentiation; D004789:Enzyme Activation; D007371:Interferon-gamma / Q000378:metabolism; D018664:Interleukin-12 / Q000378:metabolism; D053762:Interleukin-12 Subunit p40 / Q000172:deficiency / Q000378:metabolism*; D020381:Interleukin-17 / Q000378:metabolism; D053759:Interleukin-23 / Q000378:metabolism; D008297:Male; D059630:Mesenchymal Stem Cells / Q000378:metabolism*; D008810:Mice, Inbred C57BL; D010006:Osteoblasts / Q000166:cytology / Q000378:metabolism; D010012:Osteogenesis
chemical_list: D053762:Interleukin-12 Subunit p40; D020381:Interleukin-17; D053759:Interleukin-23; D018664:Interleukin-12; D007371:Interferon-gamma; D020169:Caspases