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

Inflammation is an important regulator of bone regeneration. Following fracture injury, there is an initial inflammatory response that has a crucial role in bone healing. However, severe or prolonged inflammatory response leads to delayed healing or bone repair failure. Therefore, defining the crosstalk between proinflammatory cytokines and bone marrow mesenchymal stem cell (BMMSCs) is an important goal of the newly emerging osteoimmunology field, and such insights may also be helpful for designing improved protocols for BMMSC-mediated bone repair and regeneration.

In this study, researchers from the Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences and Shanghai Jiao Tong University School of Medicine 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 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.

A paper describing this work, entitled “IL-12p40 impairs mesenchymal stem cell-mediated bone regeneration via CD4+ T cells” was published in Cell Death & Differentiation in December, 2016.

This research was conducted by graduate student Jiajia Xu under the supervision of Dr. Kerong Dai and Dr. Xiaoling Zhang at the Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences and Shanghai Jiao Tong University School of Medicine.

This research was supported by National Natural Science Foundation of China, Science and Technology Commission of Shanghai, Shanghai Municipal Commission of Health and Family Planning, and Key Discipline Construction Fund of Shanghai Education Commission.


Proposed role of IL-12 and IL-23 in fracture healing. With severe inflammation in the body, immune cells accumulate to the damaged tissue. These cells release large amounts of IL-12 and IL-23, which further promote the immune cells to produce other inflammatory factors (e.g., IFN-γ and IL-17). Locally produced IFN-γ and IL-17 can affect the function of BMMSCs and lead to BMMSC apoptosis. (Image provided by Dr. Kerong Dai’s group)


Key words: inflammation; bone marrow mesenchymal stem cells; IL-12p40; apoptosis; bone repair

Correspondence: Dr. Kerong Dai and Dr. Xiaoling Zhang, The Key Laboratory of Stem Cell Biology, Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences and Shanghai Jiao Tong University School of Medicine.
E-mail: krdai@163.com and xlzhang@sibs.ac.cn

 
 
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