Extracellular IL-37 promotes osteogenic differentiation of human bone marrow mesenchymal stem cells via activation of the PI3K/AKT signaling pathway

Chenyi Ye,Weiduo Hou,Xi Chen,Baojian Hong,Kai Hang,Lan Tang,Qianhai Ding,Wei Zhang,Jianzhong Chen,Jinwei Lu,Rongxin He,Mo Chen,Guangyao Jiang,Erman Chen

doi:10.1038/s41419-019-1904-7

Abstract

Interleukin (IL)-37, a pivotal anti-inflammatory cytokine and a fundamental inhibitor of innate immunity, has recently been shown to be abnormally expressed in several autoimmune-related orthopedic diseases, including rheumatoid arthritis, ankylosing spondylitis, and osteoporosis. However, the role of IL-37 during osteogenic differentiation of mesenchymal stem cells (MSCs) remains largely unknown. In this study, extracellular IL-37 significantly increased osteoblast-specific gene expression, the number of mineral deposits, and alkaline phosphatase activity of MSCs. Moreover, a signaling pathway was activated in the presence of IL-37. The enhanced osteogenic differentiation of MSCs due to supplementation of IL-37 was partially rescued by the presence of a PI3K/AKT signaling inhibitor. Using a rat calvarial bone defect model, IL-37 significantly improved bone healing. Collectively, these findings indicate that extracellular IL-37 enhanced osteogenesis of MSCs, at least in part by activation of the PI3K/AKT signaling pathway.

Highlights

Large bone defects or non-unions are one of the most common complications following severe fracture, bone tumor ablation, and debridement of a wide range of bone infections and congenital defects; these complications continue to be a challenge for orthopedic surgeons
IL-37 had no cytotoxicity on bone marrow MSCs (BMSCs) proliferation To determine whether IL-37 influence the viability of human BMSCs, Cell Counting Kit-8 (CCK-8) analysis was performed
The results showed no decrease in the relative proliferation rate of BMSCs

Summary

Introduction

Large bone defects or non-unions are one of the most common complications following severe fracture, bone tumor ablation, and debridement of a wide range of bone infections and congenital defects; these complications continue to be a challenge for orthopedic surgeons. The administration of BMSCs has been applied for the treatment of several diseases, including bone defects, rheumatoid arthritis (RA), and osteoarthritis, with promising results in animal models and in clinical trials as well[7,8,9]. Ye et al Cell Death and Disease (2019)10:753 of BMSCs during bone healing remains poorly understood, recent studies have suggested that bone healing is not induced by seeded BMSCs alone but is a result of interactions with host cells and a variety of cytokines that they release[10,11]. A variety of inflammatory cytokines were recently found to affect the osteogenic differentiation of stem cells[15,16,17,18].

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Conclusion