Figure 8.

Current hotspots in autophagy pathway research in OA. Autophagy can be induced by oxidative stress. The kinase mTOR is a critical regulator of autophagy. Activation of mTOR (and consequently AKT and MAPK signaling) can inhibit autophagy. In contrast, negative regulation of mTOR (and thus, AMPK and p53 signaling) will promote autophagy. On inhibition of mTOR, downstream ULK1, Beclin1, phosphatidylinositol 3-kinase complex type 3 (PIK3C3), and LC3-II complexes, act together to promote autophagy and control autophagosome formation. While in mitophagy, the process is formed by the recruitment of the p62/SQSTM1 by the PINK1 to bind to LC3. After the autophagosome matures, it fuses with the lysosome to produce an autolysosome. The enclosed cargo is then degraded, while the nutrients and metabolites are released and re-utilized. In normal cartilage, the expression of ULK, Beclin1, and LC3 is increased, while that of mTOR is inhibited. High levels of autophagy and the polarization of anti-inflammatory M2 macrophages act as cell survival mechanisms. In OA cartilage, the expression of ULK, Beclin1, and LC3 is decreased. Consequently, autophagy is attenuated due to a drop in mTOR inhibiting factor levels, resulting in mitochondrial dysfunction, oxidative stress, inflammatory cytokine production.