Osteoclast-derived exosomes inhibit osteogenic differentiation through Wnt/β-catenin signaling pathway in simulated microgravity model

Abstract

In the microgravity environment of space, astronauts undergo osteoporosis due to an imbalance in bone remodeling. Recent studies have shown that exosomes derived from osteoclasts could mediate cell-to-cell communication in bone remodeling. However, the role of osteoclast-derived exosomes in bone remodeling in microgravity remains a mystery. Our objective is to investigate the cellular processes modulated by exosomes from RAW264.7 cell-derived osteoclasts and the underlying mechanism of action for the exosomes-mediated osteogenesis of osteoblast-like MC3T3-E1 cells in simulated microgravity. We took advantage of the random positioning machine (RPM) to simulate microgravity for the model and investigated the role of exosomes from RAW264.7 cell-derived osteoclasts in osteoclast-osteoblast communication. The results showed that this type of mature osteoclast-derived exosomes (OC-Exos) in the RPM evidently inhibited the cellular proliferation of osteoblasts via inducing cellular apoptosis and altering their cell cycle distribution. Alkaline phosphatase and mineralization activity of MC3T3-E1 cells were significantly lower after treatment with OC-Exos from RPM and mRNA expression of osteoblast-specific genes were down-regulated. Further study confirmed that OC-Exos in RPM obstructed the differentiation of MC3T3-E1 cells by interfering with Wnt/β-catenin signaling pathway. Together, these observations demonstrated that OC-Exos played an essential role in the regulation of bone remodeling in the microgravity environment. These results shed light on a novel pathway of cross-talk between osteoclasts and osteoblasts, which will be helpful to explain the possible mechanisms underlying osteoporosis in microgravity.