Abstract
The blockage of autophagic flux in chondrocytes has been considered as a major reason for the excessive cellular apoptosis and senescence in osteoarthritis (OA) development; however, the molecular mechanism and therapeutic strategy for interrupted autophagic flux is still not clear. Most recently, the transcription factor EB (TFEB) is identified as a master regulator for autophagic flux via initiating the expression of multiple autophagy-related genes and lysosomal biogenesis. This research was performed to confirm whether TFEB expression and activity are impacted in OA development and to confirm the effect of genetic up-regulation of TFEB on autophagic flux and cellular protection in the in vitro and in vivo models of OA. We demonstrated that the expression and nuclear localization of TFEB is decreased in human and mouse OA cartilage as well as in tert-Butyl hydroperoxide (TBHP)-treated chondrocytes. Applying lentivirus to transfect chondrocytes, we found that TFEB overexpression rescues the TBHP-induced the autophagic flux damage, lysosome dysfunction and protects chondrocyte against TBHP induced apoptosis and senescence; these protections of TFEB are diminished by chloroquine-medicated autophagy inhibition. Our destabilized medial meniscus (DMM) mouse OA model shows that TFEB overexpression ameliorates the surgery-induced cartilage degradation, restrains the apoptosis and senescence of chondrocyte, and enhances the autophagic flux. In summary, our study indicates that the activity of TFEB in chondrocyte is involved in OA development, also TFEB overexpression may be a promising strategy for OA treatment.
Highlights
Osteoarthritis (OA) is a common degenerative disease and is the fourth major cause of disability, but without any effective therapies[1]
We reported that transcription factor EB (TFEB) activity is declined in OA, while TFEB overexpression could suppress the excessive apoptosis and senescence of chondrocyte in vivo and in vitro through the regulation of autophagy lysosome pathway (ALP)
The expression and activation of TFEB is declined in human and mouse knee articular cartilage To ascertain the change of TFEB level in OA development, immunofluorescence was applied to compare the TFEB nuclear translocation status in chondrocytes in normal and OA human articular cartilage
Summary
Osteoarthritis (OA) is a common degenerative disease and is the fourth major cause of disability, but without any effective therapies[1]. Various factors such as age, adiposis, genetics, sexuality are considered to induce and aggravate OA development[2]. As the only cell type in articular cartilage, chondrocyte could produce extracellular matrix molecules (ECM) including collagen and proteoglycans, the essential components for maintaining the function and structure of cartilage[4,5]. With the degradation of articular cartilage, the increasing inflammatory cytokines and oxidant stress induced the ROS production[6,7]; subsequently, ROS accumulation leads to the excessive apoptosis and senescence of chondrocytes[8,9].
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