ABSTRACT
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-ß 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.
Subject(s)
Diet, High-Fat/adverse effects , Osteoarthritis, Knee/etiology , Adipose Tissue/pathology , Animals , Apoptosis , Biomechanical Phenomena , Body Weight , Cartilage, Articular/pathology , Chondrocytes/pathology , In Situ Nick-End Labeling , Lower Extremity/diagnostic imaging , Lower Extremity/pathology , Mice , Mice, Inbred C57BL , Organ Size , Osteoarthritis, Knee/diagnostic imaging , Osteoarthritis, Knee/pathology , Osteoarthritis, Knee/physiopathology , Osteophyte/pathology , RNA, Messenger/genetics , RNA, Messenger/metabolism , Real-Time Polymerase Chain Reaction , Weight-Bearing , X-Ray MicrotomographyABSTRACT
A metabolic syndrome (MetS) is accompanied by hyperuricemia, during which xanthine oxidoreductase (XOR) catalyzes the production of uric acid. In the cohort study, a correlation between uric acid concentration in the synovial fluid and osteoarthritis (OA) incidence is observed. The purpose of our study was to elucidate XOR function in terms of correlation between MetS and OA. Seven week-old male C57BL6J mice were fed normal diet (ND) or high fat diet (HFD) with or without febuxostat (FEB), a XOR inhibitor. HFD stimulated xanthine oxidase activity in the IPFP and the visceral fat. OA changes at the site of the knee joints had progressed due to HFD, but these changes were reduced upon FEB administration. IL-1ß expression in the HFD group was increased in accordance with the enhancement of NLRP3 or iNOS expression in the IPFP, whereas it was inhibited by FEB administration. In the organ culture system, when the IPFP was stimulated with insulin, IL-1ß expression was increased in accordance with the increase of NLRP3 expression; however, they were reduced by FEB administration. Based on the above results, we showed that inflammasome activation accompanied by an increase in XOR activity contributed to IPFP inflammation followed by OA progression.
Subject(s)
Metabolic Syndrome/complications , Metabolic Syndrome/metabolism , Osteoarthritis/etiology , Osteoarthritis/metabolism , Xanthine Dehydrogenase/metabolism , Adipose Tissue/drug effects , Adipose Tissue/metabolism , Animals , Apoptosis , Carrier Proteins/genetics , Chondrocytes/pathology , Diet, High-Fat/adverse effects , Enzyme Activation , Enzyme Inhibitors/pharmacology , Febuxostat/pharmacology , Hyperuricemia/complications , Hyperuricemia/metabolism , Inflammasomes/metabolism , Male , Metabolic Syndrome/pathology , Mice , Mice, Inbred C57BL , NLR Family, Pyrin Domain-Containing 3 Protein , Nitric Oxide Synthase Type II/genetics , Osteoarthritis/pathology , Osteophyte/pathology , RNA, Messenger/genetics , RNA, Messenger/metabolism , Synovial Membrane/pathology , Uric Acid/metabolism , Xanthine Dehydrogenase/antagonists & inhibitorsABSTRACT
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.