Overexpression of Sirtuin 6 suppresses cellular senescence and NF-κB mediated inflammatory responses in osteoarthritis development

Abstract

The aim of our study was to evaluate if Sirt6, a NAD + dependent histone deacetylase, plays a protective role in cartilage degeneration by suppressing cellular senescence and inflammatory responses. The expression level of sirt6 in normal and OA human knee articular cartilage was compared by immunofluorescence and western blotting. The effect of sirt6 overexpression on replicative senescence of chondrocytes and NF-κB target genes expression was evaluated. Histological assessment of OA mice knee joint was carried out to assess the in vivo effects of sirt6 overexpression on mice chondrocytes. We found sirt6 level was significantly decreased in the articular chondrocytes of OA patients compare to normal human. SA-β-gal staining revealed that overexpression of sirt6 suppressed replicative senescence of chondrocytes. Meanwhile, the expression of NF-κB dependent genes were significantly attenuated by sirt6 overxpression. Safranin-O staining and OARSI score of knee joint cartilage in OA mice revealed that Lenti-Sirt6 intraarticular injection could protect mice chondrocytes from degeneration. These data strongly suggest that overexpression of Sirt6 can prevent OA development by reducing both the inflammatory response and chondrocytes senescence. Therefore, the development of specific activators of Sirt6 may have therapeutic potential for the treatment of OA.

The Current State of NAD+‐Dependent Histone Deacetylases (Sirtuins) as Novel Therapeutic Targets

“…Sirt6 overexpression was shown to attenuate the expression of NF‐κB‐dependent genes. Moreover, Sirt6 levels were found to be significantly decreased in the articular chondrocytes of patients with osteoarthritis . A similar anti‐inflammatory role of Sirt6 has been observed in rheumatoid arthritis .…”

SIRT6 delays cellular senescence by promoting p27Kip1 ubiquitin-proteasome degradation

“…Depletion of SIRT6 leads to p16 upregulation in chondrocytes [42] and bone marrow mesenchymal stem cell (BM-MSC) [44]. Overexpression of SIRT6 decreases p16 protein levels in chondrocytes [45]. In contrast, p16 levels are undetectable when silencing SIRT6 in HUVEC cells [37].…”

Ageing and the pathogenesis of osteoarthritis

“…SIRT6 depletion also increased expression of MMP1 and MMP13 , which are implicated in the pathogenesis of OA. Compared with cells from normal human tissue, human OA chondrocytes show reduced expression of SIRT6 at both the mRNA and protein level, and lentivirus-induced overexpression of SIRT6 in the knee joint protects young mice from surgically induced OA 99 . These studies highlight a potential role for SIRT6 in cartilage homeostasis that warrants further investigation.…”