Sirtuin 6 suppresses hypoxia‐induced inflammatory response in human osteoblasts via inhibition of reactive oxygen species production and glycolysis—A therapeutic implication in inflammatory bone resorption

Abstract

Elevated glycolytic activity and redox imbalance induced by tissue hypoxia are common phenomena of chronic inflammation, including inflammatory bone diseases such as arthritis. However, relation between glycolysis and redox signaling in the inflammatory milieu is unclear. The histone deacetylase sirtuin 6 (SIRT6) is a crucial modulator of inflammation and glucose metabolism, and it is also involved in cellular protection against oxidative injury. The aims of the study were to examine the connection between glycolysis and reactive oxygen species (ROS) production in human osteoblastic cells (HOB) and whether SIRT6 modulates inflammatory response via regulation of glycolytic activity and ROS generation. In HOB cultured under hypoxia, expression of lactate dehydrogenase A (LDHA), lactate production and ROS generation were examined. The reciprocal effects between lactate and ROS production and their impact on inflammatory cytokine induction were assessed. The action of SIRT6 on the above reactions was determined. In a rat model of collagen-induced arthritis (CIA), the relation between inflammatory activity and osteoblastic expression of LDHA, level of oxidative lesions, Cyr61 synthesis and macrophage recruitment were examined in joints with or without lentiviral-SIRT6 gene therapy. Results showed that hypoxia stress enhanced lactate and LDHA production in HOB. ROS generation was also increased, and there was a positive feedback between glycolysis and ROS formation. Overexpression of SIRT6 attenuated hypoxia-enhanced glycolysis and ROS generation. Hypoxia-induced expressions of Cyr61, TNF-α, IL-1β, and IL-6 were suppressed by SIRT6 and the inhibitory effects overlapped with antiglycolytic and antioxidation mechanisms. In the model of CIA, forced expression of SIRT6 ameliorated disease progression, osteoblastic synthesis of Cyr61, and macrophage recruitment. More importantly, expression of LDHA and oxidative lesions were decreased in osteoblasts of SIRT6-treated joints. Our findings suggest that SIRT6 suppresses inflammatory response in osteoblasts via modulation of glucose metabolism and redox homeostasis. SIRT6-based strategy may possess therapeutic potential for inflammatory bone resorption. © 2016 BioFactors, 43(2):170-180, 2017.

SIRT6 promotes angiogenesis and hemorrhage of carotid plaque via regulating HIF-1α and reactive oxygen species

“…In addition, other researches on the effect of SIRT6 on ROS were contrasting in different cells. Overexpression of SIRT6 attenuated hypoxia-enhanced glycolysis and ROS generation in human osteoblastic cells 28 . Whereas in glioma cells, SIRT6 was reported to increase ROS, thus reduced cell survival under H 2 O 2 treatment 29 .…”

Pathways that Regulate ROS Scavenging Enzymes, and Their Role in Defense Against Tissue Destruction in Periodontitis

“…Activation of Sirtuin, by resveratrol (Tamaki et al, 2014) or overexpression of SIRT6 in osteoblasts by lentiviral gene transfer (Kok et al, 2015; Hou et al, 2016), inhibited bone destruction. Therefore, not only NRF2- but also Sirtuin-mediated cytoprotective mechanisms control periodontal tissue homeostasis.…”

Myeloid sirtuin 6 deficiency accelerates experimental rheumatoid arthritis by enhancing macrophage activation and infiltration into synovium

“…As a histone deacetylase, Sirt6 deacetylates histone H3 lysine 9 (H3K9) and H3K56 and represses the transcriptional activity of nuclear factor κB (NF-κB) [9]. Accordingly, overexpression of Sirt6 downregulates local and systemic levels of proinflammatory cytokines and attenuates bone destruction in mice with collagen-induced arthritis [10,11]. As a non-histone protein deacetylase, Sirt6 deacetylates GCN5 [12], pyruvate kinase M2 [13], forkhead box protein O1 (FoxO1) [14], and GATA binding protein 3 [15].…”