Much of the work that the research community conducts on age-related disease is similar to the example here: attempting to pick apart the proximate causes of pathology in an altered, aged, diseased cellular metabolism. This is far removed from root causes, and thus presents only limited options for the development of beneficial therapies. The biochemistry of any age-related disease is enormously complex in its details, and manipulating any one part of it still leaves all of the rest to progress and cause issues. Since age-related diseases are the downstream result of a less complex set of root causes, it makes much more sense to investigate the root causes. Unfortunately, this remains a comparatively unpopular strategy in the research community.
Osteoarthritis (OA) is a disease with high morbidity, which mainly afflicts the weight-bearing joints, such as the hips and knees, and causes physical disability. However, the precise pathogenesis of OA has not been detailed completely. Research showed that chondrocyte autophagy, as a self-protective mechanism, has been considered as a potential target for recuperating chondrocytes viability and then suppressing the progression of OA. Cellular dysfunction and death often occur when the capacity of endoplasmic reticulum could not bear the protein folding under prolonged endoplasmic reticulum stress (ERs). Hence, the occurrence of ERs would aggravate OA severity. The effects of autophagy and ERs on osteoarthritis remain to be further explored.
MicroRNAs (miRNAs) have been suggested to participate in regulating gene expression after transcription in OA. These small regulators serve vital function in various biological processes. Accumulating research has suggested that some miRNAs had regulatory effect in the formation and process of OA. For instance, miR-155 inhibits autophagy in chondrocytes by regulating autophagy proteins expression. MiR-375 was also found to be connected with cell autophagy. However, few researchers have explored the role of miR-375 in OA.
In the current research, we analyzed the differentially expressed mRNAs and miRNAs between OA and normal cartilage tissues by analyzing microarray datasets. In human samples, we discovered that miR-375 was overexpressed in OA, while ATG2B was conspicuously down-regulated in pathological OA articular cartilage tissues. In vitro, miR-375 inhibited autophagy and enhanced ERs of chondrocytes by suppressing the expression of ATG2B. Simultaneously, apoptosis of chondrocytes was promoted by miR-375 mimics. Furthermore, OA mice model induced by destabilization of the medial meniscus (DMM) surgery in the right knee was established and verified the function of miR-375 on exacerbating OA. Therefore, miR-375 could be a potential target for OA treatment.