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

Xu, Jiajia; Wang, Yiyun; Li, Jing; Zhang, Xudong; Geng, Yiyun; Huang, Yan; Dai, Kerong; Xiao-ling, Zhang

doi:10.1038/cdd.2016.72

Cited by 55 publications

(43 citation statements)

References 37 publications

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“…Mice lacking IL-12 and IL-23 show increased bone formation [26]. We demonstrated significantly higher concentrations of IL-12 within the immunologically restricted patients than those seen in the controls.…”

Section: Discussionmentioning

confidence: 61%

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A Pronounced Inflammatory Activity Characterizes the Early Fracture Healing Phase in Immunologically Restricted Patients

Hoff

Gaber

Strehl

et al. 2017

IJMS

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Abstract:Immunologically restricted patients such as those with autoimmune diseases or malignancies often suffer from delayed or insufficient fracture healing. In human fracture hematomas and the surrounding bone marrow obtained from immunologically restricted patients, we analyzed the initial inflammatory phase on cellular and humoral level via flow cytometry and multiplex suspension array. Compared with controls, we demonstrated higher numbers of immune cells like monocytes/macrophages, natural killer T (NKT) cells, and activated T helper cells within the fracture hematomas and/or the surrounding bone marrow. Also, several pro-inflammatory cytokines such as Interleukin (IL)-6 and Tumor necrosis factor α (TNFα), chemokines (e.g., Eotaxin and RANTES), pro-angiogenic factors (e.g., IL-8 and Macrophage migration inhibitory factor: MIF), and regulatory cytokines (e.g., IL-10) were found at higher levels within the fracture hematomas and/or the surrounding bone marrow of immunologically restricted patients when compared to controls. We conclude here that the inflammatory activity on cellular and humoral levels at fracture sites of immunologically restricted patients considerably exceeds that of control patients. The initial inflammatory phase profoundly differs between these patient groups and is probably one of the reasons for prolonged or insufficient fracture healing often occurring within immunologically restricted patients.

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Section: Discussionmentioning

confidence: 61%

“…IL-12 stimulates T helper cells to produce IFNγ which we have also shown to be significantly increased within the IR-patients. In turn, high IFNγ can inhibit the differentiation of mesenchymal stem cells and thus contribute to impaired fracture healing [26]. Mesenchymal stem cells are essential for fracture healing [27].…”

Section: Discussionmentioning

confidence: 99%

A Pronounced Inflammatory Activity Characterizes the Early Fracture Healing Phase in Immunologically Restricted Patients

Hoff

Gaber

Strehl

et al. 2017

IJMS

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“…Serial sections were then cut and imaged through fluorescence microscopy (Leica). The mineral apposition rate (MAR) was calculated as reported previously . MS/BS was calculated as (dLS + sLS/2)/BS and BFR/BS = MAR*MS/BS.…”

Section: Methodsmentioning

confidence: 99%

MiR-146a Deletion Protects From Bone Loss in OVX Mice by Suppressing RANKL/OPG and M-CSF in Bone Microenvironment

Zhao

Huang

Zhang

et al. 2019

Journal of Bone and Mineral Research

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MicroRNAs play important roles in osteoporosis and show great potential for diagnosis and therapy of osteoporosis. Previous studies have demonstrated that miR‐146a affects osteoblast (OB) and osteoclast (OC) formation. However, these findings have yet to be identified in vivo, and it is unclear whether miR‐146a is related to postmenopausal osteoporosis. Here, we demonstrated that miR‐146a knockout protects bone loss in mouse model of estrogen‐deficient osteoporosis, and miR‐146a inhibits OB and OC activities in vitro and in vivo. MiR‐146a−/− mice displayed the same bone mass as the wild type (WT) but exhibited a stronger bone turnover than the WT did under normal conditions. Nevertheless, miR‐146a−/− mice showed an increase in bone mass after undergoing ovariectomy (OVX) compared with those subjected to sham operation. OC activities were impaired in the miR‐146a−/− mice exposed to estrogen deficiency, which was diametrically opposite to the enhanced bone resorption ability of WT. Macrophage colony‐stimulating factor (M‐CSF) and receptor activator of NF‐κB ligand (RANKL)/osteoprotegerin (OPG) from a bone microenvironment affect this extraordinary phenomenon. Therefore, our results implicate that miR‐146a plays a key role in estrogen deficiency–induced osteoporosis, and the inhibition of this molecule provides skeleton protection. © 2019 American Society for Bone and Mineral Research.

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“…Subcutaneous stem cell implantation was performed as previously described [26, 27]. Briefly, BMSCs were infected with different lentiviruses.…”

Section: Methodsmentioning

confidence: 99%

BMPER Enhances Bone Formation by Promoting the Osteogenesis-Angiogenesis Coupling Process in Mesenchymal Stem Cells

Xiao

Wang

Gao

et al. 2018

Cell Physiol Biochem

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Background/Aims: During bone repair and remodeling, osteogenesis is coupled with angiogenesis. Bone morphogenetic protein (BMP) antagonists are important modulators of BMP signaling and bone homeostasis. Several investigations have demonstrated that one ‘BMP antagonist’, BMP-binding endothelial cell precursor-derived regulator (BMPER), participates in the regulation of BMP signaling. In this study, we examined the role of BMPER in the osteogenesis-angiogenesis coupling process. Methods: Human bone mesenchymal stem cells (hBMSCs) and human umbilical vein endothelial cells (HUVECs) were used in this experiment. After overexpressing or silencing BMPER with lentiviruses or siRNA, hBMSCs were stimulated by BMP-2, and osteogenic differentiation activity was detected by alkaline phosphatase and alizarin red staining. VEGF and endostatin release were assessed by ELISA. HUVEC migration was detected by the cell scratch test and transwell migration assay, and in vitro angiogenesis was determined by the tube formation assay. Bone formation was assessed using in vivo femoral monocortical defect and ectopic bone formation models. Results: BMP-2 upregulated BMPER expression. Overexpression of BMPER remarkably enhanced BMP-2-induced osteogenic differentiation, while suppression of BMPER effectively inhibited this process both in vitro and in vivo. In addition, overexpression of BMPER promoted BMP-2-induced VEGF expression in vitro and vascularization in the ectopic bone formation model. Conclusion: BMPER functions as a positive regulator of the osteogenesis-angiogenesis coupling process in hBMSCs, suggesting a novel therapeutic role of BMPER in the regenerative capacity of bone repair.

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

Cited by 55 publications

References 37 publications

A Pronounced Inflammatory Activity Characterizes the Early Fracture Healing Phase in Immunologically Restricted Patients

A Pronounced Inflammatory Activity Characterizes the Early Fracture Healing Phase in Immunologically Restricted Patients

MiR-146a Deletion Protects From Bone Loss in OVX Mice by Suppressing RANKL/OPG and M-CSF in Bone Microenvironment

BMPER Enhances Bone Formation by Promoting the Osteogenesis-Angiogenesis Coupling Process in Mesenchymal Stem Cells

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