Decorin inhibits nucleus pulposus apoptosis by matrix‐induced autophagy via the mTOR pathway

Abstract

Decorin (Dcn) is a member of the class I small leucine‐rich proteoglycans, whose expression in the nucleus pulposus (NP) of intervertebral discs (IVDs) has been shown to increase with aging in humans and sheep. Dcn induces autophagy in endothelial cells; however, its precise role in NP and IVD degeneration during aging is not well understood. We addressed this question in the present study by treating rat nucleus pulposus cells (NPCs) with different concentrations of Dcn. The Western blot analysis and terminal deoxynucleotidyl transferase dUTP nick end labeling assay results showed that Dcn treatment induced autophagy and decreased apoptosis caused by interleukin (IL)‐1β application. This effect was dependent on the protein kinase B/mechanistic target of rapamycin (mTOR)/p70 S6 kinase signaling. Dcn treatment also decreased the expression of matrix metalloproteinase‐3 and ‐13 and decreased the IL‐1β‐induced attenuation of collagen type II and aggrecan levels. The role of Dcn in stimulating autophagy was further supported by the fact that the observed effects were abrogated by knocking down autophagy‐related protein 7 with Atg7 small interfering RNA. Thus, Dcn protects NPCs in IVDs from IL‐1β‐induced apoptosis and degeneration by promoting autophagy through mTOR signaling.

Decorin Protects Retinal Pigment Epithelium Cells from Oxidative Stress and Apoptosis via AMPK-mTOR-Regulated Autophagy

“…We found that the induction of autophagy by DCN was completely reversed after coincubation with 3-MA or MHY1485. These results indicate that DCN activates AMPK to inhibit mTOR and promotes autophagy in AMPK-dependent manner in ARPE-19 cells, in line with previous studies that observed DCN evoked autophagy by regulating AMPK-mTOR signaling in endothelial, nucleus pulposus, and glioma cells [ 22 , 39 , 46 ].…”

“…Downregulated autophagy in RPE cells is associated with the increased susceptibility to oxidative stress in AMD [ 38 ]. Previous studies found that DCN could activate autophagy in different kinds of cells including glioma, human hepatoma HepG2, endothelial, and nucleus pulposus cells [ 22 , 23 , 39 , 40 ]. To investigate the underlying protective mechanism of DCN against oxidative stress, autophagic markers were evaluated.…”

The Proteolysis of ECM in Intervertebral Disc Degeneration

“…As age and degeneration progress, aggrecan is cleaved into non-aggregating fractions, leading to reduced hydration of the IVD [15]. Decorin is a member of small leucine-rich proteoglycans (SLRPs), which are widely expressed in connective tissue [21]. Decorin binds to a variety of ECM proteins such as collagen type I, II, III, and VI, which contribute to ECM assembly [22,23].…”

“…In addition, decorin binds to various signaling factors to regulate cell proliferation and differentiation and ECM turnover [24,25]. Decorin has been shown to be highly expressed in degenerating discs and may be involved in tissue repair [21]. Versican is a large extracellular proteoglycan that plays important roles in cell division, adhesion, migration, differentiation, and ECM turnover [26,27].…”

Pulsed Electromagnetic Field Alleviates Intervertebral Disc Degeneration by Activating Sirt1-Autophagy Signaling Network

“…Moreover, these effects were reversed by 3-MA administration. Recently, studies have shown that various matrix molecules, including glycosaminoglycans, collagen, constituting the intervertebral disc and cartilage ECM, regulate autophagy through mTOR signaling ( Chen F. et al, 2020 ; Zhang et al, 2021 ). Moreover, autophagy can in turn regulate ECM composition, directly or indirectly altering cellular function, i.e., the secretion of ECM molecules ( Novais et al, 2021b ).…”