Inhibition of Autotaxin Induces Imbalance of Chondrocyte Metabolism and Suppression of Autophagic Flux in Osteoarthritis

Background: Osteoarthritis (OA) is a degenerative joint disease that couldn’t be cured by drugs. Autotaxin (ATX), which is a secretory glycoprotein related to physiological and pathological processes may possibly participate in the appropriate formation of cartilage. However, the role and specific mechanism of ATX in OA remain unclear. The present study aimed to explore the metabolism of chondrocytes and the mechanism of action of ATX in OA. Results: : In OA chondrocytes, catabolism increased and anabolism decreased. Inhibition of ATX triggered imbalanced metabolism according to the overexpression of a disintegrin and metalloproteinase with thrombospondin type 1 motif-5 (ADAMTS-5) and matrix metalloproteinase 13 (MMP13) and downregulation of collagen type II alpha 1 (COL2A1). Inhibition of ATX also caused the expression of mechanistic target of rapamycin (mTOR) declined while the expression of P62/ SQSTM1 and the microtubule-associated protein light chain 3- (LC3-) II-to-LC3-I ratio were upregulated which illustrated a blockade autophagic flux. The acidity of the lysosomes was dramatically enhanced according to LysoTracker green staining. Infection with Mcherry-EGFP-LC3 adenovirus and measurement of immunofluorescence were performed to detect the formation of autolysosomes. And it was observed that the fusion of autophagosomes and lysosomes was blocked, resulting in the obstruction of autophagic flux. Conclusions: : These data indicate that inhibition of ATX expression in chondrocytes resulted in abnormal metabolism and impaired autophagic flux via blockade of autophagosome and lysosome fusion, revealing a novel mechanism that regulated chondrocytes in OA which may provide a new target for the treatment of OA in the future.