Pivotal roles of interleukin-17 in bone remodelling via osteocytes

Abstract

Bone remodelling is a strictly regulated dynamic process of bone formation and resorption. The cytokine interleukin (IL)-17 critically orchestrates the activation and differentiation of both osteoblasts and osteoclasts. Osteocytes, which are the most abundant cells in bone, have long been thought to orchestrate bone remodelling in response to the flow of extracellular fluid by detecting and coordinating the function of osteoblasts and osteoclasts. However, the contribution of IL-17 to osteocyte-related bone resorption and/or formation remains unclear. To investigate the role of IL-17 in osteoclastogenesis, we tested the osteocyte-like MLO-Y4 cell line and bone marrow macrophages (BMMs). It was found that IL-17 activated osteoclastic differentiation in the co-culture system of MLO-Y4 and BMMs, and this differentiation was attenuated by shear stress. Additionally, the extracellular signal-regulated kinase (ERK)1/2 and the signal transducer and activator of transcription (STAT)3 pathways in osteocytes were suppressed by IL-17 but activated by shear stress. The intercellular EphA2-ephrinA2 and EphB4-ephrinB2 signalling pathways played important roles in the IL-17-dependent osteoclastic differentiation. To study the role of IL-17 in osteogenesis, we tested mesenchymal stem cells (MSCs), MC3T3-E1 pre-osteoblasts, MLO-A5 post-osteoblasts and MLO-Y4 osteocytes. It was found that IL-17 induced the osteogenesis of the MSCs and was further promoted when co-cultured with osteocytes. The inflammatory factors IL-6 and IL-1β played important roles in the IL-17-dependent differentiation by activating the phosphorylation of signalling pathways AKT, STAT3 and ERK1/2 in the MSC niche. Our results indicate that IL-17 plays various roles in the different stages of osteogenesis and osteoclastogenesis, and osteocytes pivotally regulated the IL-17-dependent differentiation. These findings provide important insights into the mechanisms underlying osteoclastic and osteoblastic differentiation. IL-17 modulation-based approaches could be developed as novel therapeutic strategies for enhancing bone remodelling efficiency and stability.