Sirtuin 6 (Sirt6) is a mammalian homologue of NAD 1 -dependent histone deacetylase Sir2. Although Sirt62/2 mice exhibit growth retardation, the role of Sirt6 in cartilage metabolism is unclear. The aim of this study was to investigate the Sirt6 signaling pathway in cartilage metabolism. Immunohistological evaluation of the tibial growth plate in Sirt62/2 mice exhibited impaired proliferation and differentiation of chondrocytes, reduced expression of Indian hedgehog (Ihh), and a senescent phenotype. When Sirt6 was knocked down in chondrocytes in vitro, expression of Ihh and its downstream genes were reduced. Impaired differentiation by Sirt6 silencing was completely rescued by administration of a Hh signal agonist. When sirtuins were activated, chondrocyte differentiation was enhanced together with activation of Ihh signal, and these effects were abrogated by Sirt6 silencing. ChIP assay revealed the affinity of ATF4 to the Ihh promoter was markedly decreased by Sirt6 knockdown. These data indicate Sirt6 directly controls proliferation and differentiation of chondrocytes.T he stress-response and chromatin-silencing factor Sir2, a yeast sirtuin, is a NAD 1 -dependent histone deacetylase and is involved in various nuclear actions 1 . Among the seven mammalian sirtuin family members, sirtuin 6 (Sirt6) is localized to the nucleus and is involved in transcriptional silencing, genome stability, and longevity 2,3 . Sirt6 was originally identified as an ADP-ribosyltransferase 4 . Recent studies have demonstrated that the Sirt6 protein is a NAD1-dependent histone 3 deacetylase that targets acetyl-H3K9 and acetyl-H3K56 5,6 . Sirt6 deacetylates histone H3 lysine 9 (H3K9) on telomeres and plays a role in their stability 5 . Human Sirt6 also deacetylates C-terminal binding protein interacting protein (CtIP) and promotes DNA end resection 7 . Recent studies have revealed multiple functions of Sirt6 in the regulation of inflammation and metabolism. Sirt6 inhibits inflammation by suppressing NF-kB target molecules via interaction with the RelA subunit of NF-kB and by deacetylating H3K9 at target promoters 8 . In glycometabolism, Sirt6 functions as a corepressor of the transcription factor Hif1a and inhibits glycolysis through suppression of Hif1a activity 9 . As a result, Sirt6 null mice die before 4 weeks of age due to lethal hypoglycemia 4 .Sirt62/2 mice develop normally for the first two weeks except for reduced body size, which is apparent early after birth 4 . Sirt62/2 mice also exhibit features of premature aging, such as osteopenia and lordokyphosis 4 . Serum insulin-like growth factor 1 (IGF-1) and glucose levels are both markedly reduced in Sirt6 2/2 mice by the age of 24 days 4 . A recent study demonstrated that neural-specific deletion of Sirt6 in mice leads to postnatal growth retardation due to somatotropic attenuation through low growth hormone (GH) and IGF-1 levels 10 . Thus, Sirt6 contributes to skeletal growth in part through the regulation of IGF-1 secretion. However, the local functions of Sirt6 in postnatal gr...
Ginsenoside Rb1is the main component in ginsenosides. It is a protopanaxadiol-type ginsenoside that has a dammarane-type triterpenoid as an aglycone. In this study, ginsenoside Rb1 was transformed into gypenoside XVII, ginsenoside Rd, ginsenoside F2 and compound K by glycosidase from Leuconostoc mesenteroides DC102. The optimum time for the conversion was about 72 h at a constant pH of 6.0 to 8.0 and the optimum temperature was about 30℃. Under optimal conditions, ginsenoside Rb1 was decomposed and converted into compound K by 72 h post-reaction (99%). The enzymatic reaction was analyzed by highperformance liquid chromatography, suggesting the transformation pathway: ginsenoside Rb1→ gypenoside XVII and ginsenoside Rd→ginsenoside F2→compound K.
Osteoarthritis (OA) is a chronic degenerative joint disorder commonly associated with metabolic syndrome. As ageing and obesity has a great impact on the initiation/severity of OA, herein we sought to investigate the involvement of Sirt6 in the crosstalk between ageing and metabolic syndrome/OA. Sirt6 haploinsufficiency in mice promoted the expression of inflammatory cytokines in the IPFP. Enhanced inflammation of the IPFP in the aged Sirt6 ± HFD group was paralleled with accelerated OA change, including osteophyte growth and chondrocyte hypertrophy. Conversely, mesenchyme-specific Sirt6-deficient mice revealed both attenuated chondrocyte hypertrophy and proteoglycan synthesis, although chondrocyte senescence was enhanced as shown in the aged WT mice. Thus Sirt6 has key roles in the relationship among ageing, metabolic syndrome, and OA.
Obesity is a risk factor for osteoarthritis (OA). To investigate the roles of increased mechanical loading in the onset of obesity-induced OA, knee joints were histologically analyzed after applying a tail suspension (TS) model to a high-fat diet (HFD)-induced OA model. Mice were divided into four groups: normal diet (ND) with normal loading (NL) group; HFD with NL group; ND with TS group; and HFD with TS group. Whole knee joints were evaluated by immunohistological analysis. The infrapatellar fat pad (IPFP) was excised and mRNA expression profiles were compared by qPCR analysis. After twelve weeks of the diet, body weight was increased by HFD in both the NL group and TS group. Upon histological analysis, the irregularity of the surface layer of articular cartilage was observed only in the NL+HFD group. Osteophyte area increased as a result of HFD in both the NL and TS groups, although osteophyte area in the TS+HFD group was smaller than that of the NL+HFD group. In the evaluation of the IPFP by qPCR, adipokines and inflammatory cytokines also increased as a result of HFD. While TGF-β increased as a result of HFD, the trend was slightly lower in the TS group, in parallel with osteophyte area. To detect apoptosis of articular chondrocytes, TUNEL staining was employed. TUNEL-positive cells were abundantly observed in the articular cartilage in the HFD mice regardless of mechanical loading. IPFP inflammation, enhanced chondrocyte apoptosis, and osteophyte formation were seen even in the TS group as a result of a HFD. In all, these data demonstrate that HFD contributed to osteophyte formation through mechanical loading dependent and independent mechanisms.
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