Small molecule natural compound agonist of SIRT3 as a therapeutic target for the treatment of intervertebral disc degeneration

Abstract

Oxidative stress-induced mitochondrial dysfunction is implicated in the pathogenesis of intervertebral disc degeneration (IVDD). Sirtuin 3 (SIRT3), a sirtuin family protein located in mitochondria, is essential for mitochondrial homeostasis; however, the role of SIRT3 in the process of IVDD has remained elusive. Here, we explored the expression of SIRT3 in IVDD in vivo and in vitro; we also explored the role of SIRT3 in senescence, apoptosis, and mitochondrial homeostasis under oxidative stress. We subsequently activated SIRT3 using honokiol to evaluate its therapeutic potential for IVDD. We assessed SIRT3 expression in degenerative nucleus pulposus (NP) tissues and oxidative stress-induced nucleus pulposus cells (NPCs). SIRT3 was knocked down by lentivirus and activated by honokiol to determine its role in oxidative stress-induced NPCs. The mechanism by which honokiol affected SIRT3 regulation was investigated in vitro, and the therapeutic potential of honokiol was assessed in vitro and in vivo. We found that the expression of SIRT3 decreased with IVDD, and SIRT3 knockdown reduced the tolerance of NPCs to oxidative stress. Honokiol (10 μM) improved the viability of NPCs under oxidative stress and promoted their properties of anti-oxidation, mitochondrial dynamics and mitophagy in a SIRT3-dependent manner. Furthermore, honokiol activated SIRT3 through the AMPK-PGC-1α signaling pathway. Moreover, honokiol treatment ameliorated IVDD in rats. Our study indicated that SIRT3 is involved in IVDD and showed the potential of the SIRT3 agonist honokiol for the treatment of IVDD.

Reciprocal Regulation of TRPS1 and miR-221 in Intervertebral Disc Cells

“…To determine the causative role of expression levels of TRPS1, miR-221 and FOXO3 in driving disc degeneration or homeostasis, and to provide more prospects for therapeutic targets, in vivo strategies will be needed. Further studies are needed also to investigate possible relationships of these molecules with perturbations of Wnt/β-catenin, Notch, interferon-alpha, hypoxia, nuclear factor kappa B (NF-kB), Sirtuin 3 and mitogen-activated protein kinase (MAPK) pathways that have been identified as important regulators of progress of disc degeneration [7,44,45,46,47,48,49].…”

Allicin Attenuated Advanced Oxidation Protein Product-Induced Oxidative Stress and Mitochondrial Apoptosis in Human Nucleus Pulposus Cells

“…Immunofluorescence staining was done to NP cells according to previous descriptions [ 36 ]. Primary antibodies aiming at cleaved caspase-3 (1: 400; #9579, Cell Signaling Technology) were first used to incubate with NP cells at 4°C for all night.…”

Targeting mitochondrial dysfunction with small molecules in intervertebral disc aging and degeneration

“…It has been found that honokiol upregulates Drp-1 and Mfn-2 and increases mitophagy in the sirtuin 3-dependent manner [114] TBHP-treated NP cells, AF-punctured rat model Anti-apoptotic, preserved ECM homeostasis via mitophagy induction both in vitro and in vivo [115] IL-1β-treated NP cells Attenuated NLRP3 inflammasome activation, decreased mtROS level [116] ALA (206. Accelerated aging ERCC1 −/Δ mouse model Ameliorated IVD degeneration, enhanced disc ECM content [59] which was determined by upregulation of BNIP3 and the ratio of LC3-II to LC3-I [139].…”