Unknown,Transcriptomics,Genomics,Proteomics

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Leptin-Mediated Gene Expression Profiling Exhibits New Candidate Genes Associated with Osteoarthritis in Rat

ABSTRACT: Osteoarthritis (OA) is the most prevalent chronic joint disease and the precise genetic mechanisms are yet to be fully elucidated. The aim of this study is to evaluate, for the first time, the differences in gene expression profiles of healthy and leptin-induced cartilage in rat. To investigate the underlying pathogenic factors in OA, alterations in gene expression between leptin-induced articular cartilage rat models and healthy control rat models were investigated using the Whole Rat Genome Oligo Microarray. In the present study, 1857 differentially expressed genes (DEGs; 1197 up-regulated and 660 down-regulated) were identified. Expression of some OA-related known genes is known to be associated with leptin induction, including matrix metalloproteinase (MMP), inflammatory factors, growth factors and genes involved in cell death, apoptosis and osteoclast differentiation. However, some new candidate genes that had never been reported to be related with OA, such as BCL2L11, were consistently observed to be up-regulated, suggesting they might be involved in OA progression. Our findings indicate that leptin plays an important role in the progression of OA by mediating expression change in multiple genes, although the molecular mechanisms need to be further clarified. Further study of these leptin-induced genes may provide new insights into understanding the molecular mechanisms underlying OA. To identify genes with changed expression in response to leptin, genome wide expression profiles were generated for leptin-affected cartilage (L group) and healthy controls (H group) in rats. 24 rats were divided into two groups: control animals (H group, n = 12) and leptin-induced animals (L group, n = 12). H group included two replicates, sample1 and sample2. L group also included two replicates, sample3 and sample4.

ORGANISM(S): Rattus norvegicus

SUBMITTER: Ziming Zhang

PROVIDER: E-GEOD-85785 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description:Caloric Restriction in Leptin Deficiency Worsens Myocardial Steatosis: Failure to Upregulate PPAR gamma and Thermogenic Glyecrolipid/Fatty Acid Cycling Growing evidence supports an anti-lipotoxic role for leptin in preventing inappropriate peripheral tissue lipid deposition. Obese, leptin deficient ob/ob mice develop left ventricular (LV) hypertrophy and myocardial steatosis with increased apoptosis and decreased longevity. Here we investigated the cardiac effects of caloric restriction in leptin deficiency. Echocardiography was performed on C57Bl/6 wild-type mice (WT) and 7-month-old ob/ob mice fed ad lib, leptin-repleted (LR-ob/ob), or calorie-restricted (CR-ob/ob) for four weeks. Ventricular tissue was examined by electron microscopy (EM), mitochondrial coupling assay, and microarray expression profiling. LR and CR-ob/ob mice showed decreased body weight, heart weight, and LV wall thickness compared to ad lib ob/ob mice. LV fractional shortening was decreased in ad lib ob/ob mice, but restored to WT levels in LR and CR groups. However, EM revealed severe cardiac steatosis in the CR-ob/ob group compared to only moderate steatosis in ad lib ob/ob . Despite marked cardiac steatosis, CR (like LR) restored mitochondrial coupling to WT levels. CR up-regulated genes associated with oxidative stress and cell death, changes suggestive of cardiac lipotoxicity. LR, but not CR was shown to induce core genes involved in glycerolipid/free fatty acid cycling, a highly thermogenic pathway that can reduce intracellular lipid stores. LR, but not CR up-regulated and restored PGC1 and PPARto wild type levels; CR paradoxically further suppressed cardiac PPAR. Thus, leptin is essential in protecting the heart from lipotoxicity, and the inability to up-regulate the thermogenic glycerolipid/free fatty acid cycling pathway may impair the response of leptin deficient animals to the lipotoxic stress of calorie restriction. 6 month aged ob/ob mice were either leptin repleted with osmotic mini-pumps, calorie restricted to match the caloric intake of the leptin repleted mice, or fed ad lib for one month. 6-8 month C57Bl/6J mice were aged to serve as controls.

Project description:Osteoarthritis (OA) is an age-related degenerative musculoskeletal disease characterised by loss of articular cartilage, synovitis, abnormal bone proliferation and subchondral bone sclerosis. The underlying pathogenesis of OA is yet to be fully elucidated with no OA specific biomarkers in clinical use. Nuclear magnetic resonance (NMR) spectroscopy and mass spectrometry (MS) allow identification of the global metabolome and proteome respectively. During this study, ex-vivo equine cartilage explants (n=5) were incubated in TNF-α/IL-1β supplemented culture media for 8 days, with media removed and replaced at 2, 5 and 8 days. Acetonitrile metabolite extractions of 8 day cartilage explants and media samples at all time points underwent 1H NMR metabolic analysis with media samples also undergoing MS proteomic analysis. Within the cartilage, metabolites glucose and lysine were elevated following TNF-α/IL-1β treatment whilst adenosine, alanine, betaine, creatine, myo-inositol and uridine levels decreased. Within the culture media, four, four and six metabolites were identified as being differentially abundant between control and treatment groups for 1-2 day, 3-5 day and 6-8 day time points respectively. Culture media proteomics identified 154, 138 and 72 proteins differentially abundant, with > 2 fold change, between control and treatment groups for 1-2 day, 3-5 day and 6-8 day time points respectively. Nine potential novel OA neopeptides were elevated in treated media. This is the first study to use a multi ‘omics’ approach to simultaneously investigate the metabolomic profile of ex-vivo cartilage and metabolomic/proteomic profiles of culture media using the TNF-α/IL-1β ex-vivo OA cartilage model. This study has identified a panel of metabolites, proteins and extracellular matrix derived neopeptides which are differentially abundant during an early phase of the OA model which may provide further information on underlying disease pathogenesis, allow potential translation for clinical markers and possible novel therapeutic targets.

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Leptin-Mediated Gene Expression Profiling Exhibits New Candidate Genes Associated with Osteoarthritis in Rat

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