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Cell death and differentiation
12, 2016;23 (12): 1941-1951.

IL-12p40 impairs mesenchymal stem cell-mediated bone regeneration via CD4 T cells.

Jiajia Xu, Yiyun Wang, Jing Li, Xudong Zhang, Yiyun Geng, Yan Huang, Kerong Dai, Xiaoling Zhang
Author Information
  1. Jiajia Xu: 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. ORCID
  2. Yiyun Wang: 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.
  3. Jing Li: 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.
  4. Xudong Zhang: 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.
  5. Yiyun Geng: 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.
  6. Yan Huang: 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.
  7. Kerong Dai: 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.
  8. Xiaoling Zhang: 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.
PMID: 27472064 DOI: 10.1038/cdd.2016.72

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.

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MeSH Term

Animals
Apoptosis
Bone Marrow Cells
Bone Regeneration
CD4-Positive T-Lymphocytes
Caspases
Cell Differentiation
Enzyme Activation
Interferon-gamma
Interleukin-12
Interleukin-12 Subunit p40
Interleukin-17
Interleukin-23
Male
Mesenchymal Stem Cells
Mice, Inbred C57BL
Osteoblasts
Osteogenesis

Chemicals

Interleukin-12 Subunit p40
Interleukin-17
Interleukin-23
Interleukin-12
Interferon-gamma
Caspases
Journal Article
Article has an altmetric score of 7

Word Cloud

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