Exosomes Derived from Mesenchymal Stem Cells Inhibit Catabolism in Human Chondrocytes by Activating Autophagy Via Inhibition of the NF-Κb Pathway

Author(s): Jian-Fa Wang, Lei Sun, Shi-kun Shao, Bao-dong Ma, Yao-kun Wang, Ran-ran Jin, Hong-Bo Hao, Han Yue, Zhi Zhu

Objective: We aimed to determine the significance of MSC-derived exosomes (MSC-Exos) in chondrocyte autophagy under normal and inflammatory conditions.

Design: Human umbilical cord-derived MSCs (hMSCs) were cultured in vitro. hMSC-Exos (EX) were isolated by an ultracentrifugation method. Transmission electron microscopy and western analysis were used to identify exosomes. Human chondrocytes were extracted from five adult males with OA undergoing total knee arthroplasty. Primary cultures of chondrocytes from OA patients were stimulated with 50 ng/ml tumor necrosis factor-α (TNF-α) in the presence or absence of hMSC-Exos. Autophagy levels were determined based on expression of autophagic marker LC3, StubRFP-SensGFP-LC3 analysis, and electron microscopy. Catabolic gene and chemokine expression were evaluated using quantitative PCR. The NF-κB inhibitor NS398 was used to analyze the role of the NF-κB pathway in autophagic activation.

Results: hMSC-Exos increased LC3-II levels as well as autophagosome number in chondrocytes. hMSC-Exos inhibited TNF-α–induced expression of MMP-3, -9, and -13; ADAMTS5; CCL-2 and -5; and CXCL1. NF-κB inhibition activated autophagy in TNF-α–treated chondrocytes. These results indicate that hMSC-Exos might suppress the levels of catabolic and inflammatory factors in chondrocytes by promoting autophagy via NF-κB pathway inhibition.

Conclusions: Our data support the interest in hMSC-Exos to develop new therapeutic approaches for joint conditions.