Moderate mechanical stress suppresses the IL‐1β‐induced chondrocyte apoptosis by regulating mitochondrial dynamics

Abstract

Mitochondrial dysfunction contributes to osteoarthritis (OA) onset and progress.Mitochondrial dynamics, coupled with mitophagy, is critical for the maintenance of mitochondrial fitness, involving many cellular processes, such as proliferation and apoptosis. Excessive mechanical stress induces chondrocyte apoptosis; however, the effects of mechanical stress on mitochondrial dynamics remain elusive. In this study, we performed fluorescence staining, flow cytometry, transmission electron microscope, Western blot analysis, and RNA-sequencing to assess the effects of different strength of mechanical stimulation on mitochondrial functions of chondrocyte treated with interleukin-1β (IL-1β). We found that moderate mechanical stress reduced the IL-1β-induced apoptosis by maintaining mitochondrial function and scavenging the reactive oxygen species, while excessive mechanical stress induced strong mitochondrial dysfunction and apoptosis. Moreover, RNAsequencing revealed that mitophagy and mitochondrial dynamics were involved in the regulation of mechanical stress on chondrocyte biology. In addition to the elevated mitophagy, moderate mechanical stress also promoted mitochondrial dynamics by enhancing the expression of MFN1/2 and OPA1 and the translocation of dynamin-related protein 1 from the cytoplasm to the mitochondria. However, an uncoupling of mitochondrial dynamics, characterized by strongly elevated fission, resulted in the unfavorable apoptosis of excessive mechanical stress-stimulated chondrocytes. This study revealed the effects of mechanical stress upon mitochondrial dynamics in chondrocyte.

Whole Transcriptome Mapping Identifies an Immune- and Metabolism-Related Non-coding RNA Landscape Remodeled by Mechanical Stress in IL-1β-Induced Rat OA-like Chondrocytes

“…In our previous comparison study ( Zhang et al, 2021 ), we found the different or same effects between moderate (2,000 μstrain) and extensive (5,000 μstrain) mechanical stress on chondrocyte mitochondrial functions. We observed the effects of mechanical stress on mitochondrial functions and cell fate, or more specifically, apoptosis.…”

“…It is well-documented that IL-1β can induce OA-like phenotypes in cultured chondrocytes, characterized by the reduction of anabolism (decreased ECM components) and the increase of catabolism (increased metalloproteinases) ( Yao et al, 2019 ; Yao et al, 2021 ; Zhang et al, 2021 ). The concentrations of IL-1β ranging from 1 ng/ml to as much as 1,000 ng/ml, compared to <10 pg/ml in body fluids, are considered as supra-physiologic concentrations.…”

“…The subcellular location and morphology of mitochondrion and lysosome was accessed by Mito-Tracker Green (Beyotime, China) and Lyso-Tracker Red (Beyotime, China) staining according to the manufacturer’s instructions ( Lin et al, 2021 ; Zhang et al, 2021 ). Lysosome number of 50 chondrocytes were quantified in a double-blind way by two individual researchers.…”

“…Mitochondrial dysfunction is a well-accepted hallmark of OA ( Buckwalter et al, 2013 ). Mitochondrial fitness is critical for chondrocyte fate and functions, at least, by regulating metabolism ( Zhang et al, 2021 ). Under unfavorable stress, chondrocytes not only increase reactive oxygen species (ROS) production, but also undergo metabolism shift from oxidative phosphorylation to glycolysis via the AMP-activated protein kinase (AMPK) and mechanistic target of rapamycin (mTOR) pathways ( Zheng et al, 2021 ).…”

Potential Methods of Targeting Cellular Aging Hallmarks to Reverse Osteoarthritic Phenotype of Chondrocytes

“…Increased mitochondrial fragmentation, loss of mitochondrial membrane potential, diminished mitophagy activity, and accumulation of abnormally shortened or granulated mitochondria in chondrocytes have been correlated with OA progression [ 79 , 87 , 88 ]. Mitochondrial dysfunction, as well as morphology and polarization alterations, are related to the prevalence, severity, incidence, and progression of OA [ 89 ]. Mechanisms behind this connection include altered energy production, increased production of ROS and reactive nitrogen species (RNS), and enhanced inflammatory reactions [ 90 ].…”