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To investigate host and gut-microbiota related Tryptophan metabolism in hand osteoarthritis (HOA). The baseline serum concentration of 20 Tryptophan metabolites was measured in 416 HOA patients in a cross-sectional analysis of the DIGICOD cohort. Tryptophan metabolites levels, metabolite-ratios and metabolism pathway activation were compared between erosive (N = 141) and non-erosive HOA (N = 275) by multiple logistic regressions adjusted on age, BMI and sex. The association between Tryptophan metabolite levels and HOA symptoms was investigated by a Spearman's rank correlation analysis. Four serum Tryptophan metabolites, eight metabolite ratios and one metabolism pathway were associated with erosive HOA. Erosive HOA was negatively associated with Tryptophan (odds ratio (OR) = 0.41, 95% confidence interval [0.24–0.70]), indole-3-aldehyde (OR = 0.67 [0.51–0.90]) and 3-OH-anthranilic acid (OR = 1.32 [1.13–1.54]) and positively with 5-OH-Tryptophan levels (OR = 1.41 [1.13–1.77]). The pro-inflammatory kynurenine–indoleamine 2,3-dioxygenase pathway was upregulated in erosive HOA (OR = 1.60 [1.11–2.29]). Eleven metabolites were correlated with HOA symptoms and were mostly pain-related. Serotonin and N-acetyl serotonin levels were negatively correlated with number of tender joints. Indole-3-aldehyde level was negatively correlated and 3-OH-anthranilic acid, 3-OH-kynurenine and 5-OH-Tryptophan levels were positively correlated with number of patients-reported painful joints. Quinolinic acid and 3-OH-kynurenine levels correlated positively with AUSCAN pain. Tryptophan metabolites disturbance is associated with erosive HOA and pain and emphasize the role of low-grade inflammation and gut dysbiosis in HOA. [ABSTRACT FROM AUTHOR]

Carboxymethyllysine (CML) and homocitrulline (HCit) are the products of two non-enzymatic post-translational modifications of protein, a process related to age. We investigated whether serum CML and HCit concentrations were associated with hand osteoarthritis (HOA), especially erosive HOA. Serum CML and HCit were measured by using liquid chromatography coupled with tandem mass spectrometry at inclusion in 386 patients included in the DIGItal Cohort Design (DIGICOD) cohort. We investigated whether serum CML and/or HCit concentrations were associated with erosive HOA or with HOA clinical and radiological features. Moreover, we compared the tissular concentrations of CML and HCit in OA and non-OA cartilage from proximal interphalangeal and metacarpo-phalangeal (MCP) joints from human cadaveric donors. Median (IQR) serum CML concentration was lower in patients with erosive HOA than those with non-erosive HOA (178.7 [157.1–208.8] vs 194.7 [168.9–217.1] μmol/mol Lys, P = 0.002), but median HCit concentration did not differ between the groups (193.9 [162.9–232.0] vs 193.9 [155.9–224.6] μmol/mol Lys). Cartilage HCit and CML concentrations were not correlated with clinical features. Serum CML concentration was higher in OA than non-OA MCPs (7.0 vs 4.0 mmol/mol Lys, P = 0.01). Serum CML concentration was lower in erosive HOA than non-erosive HOA, and cartilage CML concentration was higher in OA than non-OA cartilage. These results encourage further studies to test whether serum CML could be a new prognostic biomarker in HOA. [ABSTRACT FROM AUTHOR]

Osteoarthritis (OA) poses a major health and economic burden worldwide due to an increasing number of patients and the unavailability of disease-modifying drugs. In this review, the latest understanding of the involvement of the cholinergic system in joint homeostasis and OA will be outlined. First of all, the current evidence on the presence of the cholinergic system in the normal and OA joint will be described. Cholinergic innervation as well as the non-neuronal cholinergic system are detected. In a variety of inflammatory diseases, the classic cholinergic anti-inflammatory pathway lately received a lot of attention as via this pathway cholinergic agonists can reduce inflammation. The role of this cholinergic anti-inflammatory pathway in the context of OA will be discussed. Activation of this pathway improved the progression of the disease. Secondly, chondrocyte hypertrophy plays a pivotal role in osteophyte formation and OA development; the impact of the cholinergic system on hypertrophic chondroblasts and endochondral ossification will be evaluated. Cholinergic stimulation increased chondrocyte proliferation, delayed chondrocyte differentiation and caused early mineralisation. Moreover, acetylcholinesterase and butyrylcholinesterase affect the endochondral ossification via an acetylcholine-independent pathway. Thirdly, subchondral bone is critical for cartilage homeostasis and metabolism; the cholinergic system in subchondral bone homeostasis and disorders will be explored. An increase in osteoblast proliferation and osteoclast apoptosis is observed. Lastly, current therapeutic strategies for OA are limited to symptom relief; here the impact of smoking on disease progression and the potential of acetylcholinesterase inhibitors as candidate disease-modifying drug for OA will be discussed. [ABSTRACT FROM AUTHOR]

Objective: TGFβ is a key player in cartilage homeostasis and OA pathology. However, few data are available on the role of TGFβ signalling in the different OA phenotypes. Here, we analysed the TGFβ pathway by transcriptomic analysis in six mouse models of OA.Method: We have brought together seven expert laboratories in OA pathophysiology and, used inter-laboratories standard operating procedures and quality controls to increase experimental reproducibility and decrease bias. As none of the available OA models covers the complexity and heterogeneity of the human disease, we used six different murine models of knee OA: from post-traumatic/mechanical models (meniscectomy (MNX), MNX and hypergravity (HG-MNX), MNX and high fat diet (HF-MNX), MNX and seipin knock-out (SP-MNX)) to aging-related OA and inflammatory OA (collagenase-induced OA (CIOA)). Four controls (MNX-sham, young, SP-sham, CIOA-sham) were added. OsteoArthritis Research Society International (OARSI)-based scoring of femoral condyles and ribonucleic acid (RNA) extraction from tibial plateau samples were done by single operators as well as the transcriptomic analysis of the TGFβ family pathway by Custom TaqMan® Array Microfluidic Cards.Results: The transcriptomic analysis revealed specific gene signatures in each of the six models; however, no gene was deregulated in all six OA models. Of interest, we found that the combinatorial Gdf5-Cd36-Ltbp4 signature might discriminate distinct subgroups of OA: Cd36 upregulation is a hallmark of MNX-related OA while Gdf5 and Ltbp4 upregulation is related to MNX-induced OA and CIOA.Conclusion: These findings stress the OA animal model heterogeneity and the need of caution when extrapolating results from one model to another. [ABSTRACT FROM AUTHOR]

Objective: An overview of the economic consequences - overall costs as well as cost breakdown (direct and indirect) - of hip and knee osteoarthritis (OA) worldwide.Methods: A systematic literature search of EMBASE, MEDLINE, Scopus and Cochrane databases for articles was performed independently by two rheumatologists who used the same predefined eligible criteria. Papers without abstracts and in languages other than English or French were excluded. Extracted costs were converted to an annual cost and to 2013 euros (€) by using the Consumer Price Index of the relevant countries and the 2013 Purchasing Power Parities between these countries and the European Union average.Results: A total of 45 abstracts were selected, and 32 articles were considered for the review. The studied populations were heterogeneous: administrative, hospital and national health survey data. Annual total costs per patient ranged from 0.7 to 12 k€, direct costs per patient from 0.5 to 10.9 k€ and indirect costs per patient from 0.2 to 12.3 k€. The weighted average annual costs per patient living with knee and hip OA were 11.1, 9.5 and 4.4 k€ for total, direct and indirect costs, respectively.Conclusions: This review highlights the heterogeneity of studies and lack of methodologic consensus to obtain reliable cost-of-illness estimates for lower-limb OA. However, costs induced by the disease seem substantial and deserve to be more extensively explored. [ABSTRACT FROM AUTHOR]

Osteoarthritis (OA) is a heterogeneous disorder with several risk factors. Among them, obesity has a major impact on both loading and non-loading joints. Mechanical overload and activity of systemic inflammatory mediators derived from adipose tissue (adipokines, free fatty acids (FFA), reactive oxygen species (ROS)) provide clues to the increased incidence and prevalence of OA in obesity. Recently, research found greater OA prevalence and incidence in obese patients with cardiometabolic disturbances than "healthy" obese patients, which led to the description of a new OA phenotype - metabolic syndrome (MetS)-associated OA. Indeed, individual metabolic factors (diabetes, dyslipidemia, and hypertension) may increase the risk of obesity-induced OA. This review discusses hypotheses based on pathways specific to a metabolic factor in MetS-associated OA, such as the role of advanced glycation end products (AGEs) and glucose toxicity. A better understanding of these phenotypes based on risk factors will be critical for designing trials of this specific subset of OA. [ABSTRACT FROM AUTHOR]

Summary Objective To examine the relationship between osteoarthritis (OA) and type 2 diabetes mellitus (DM). Methods OA cartilage from DM and non-DM patients undergoing knee replacement were stimulated by IL-1β for 24 h and release of interleukin-6 (IL-6) and prostaglandin E 2 (PGE 2 ) was measured. Primary cultured murine chondrocytes were stimulated for 24 and 72 h with or without IL-1β (5 ng/mL) under normal-glucose (5.5 mM) or high-glucose (25 mM) conditions. The expression and release of pro-inflammatory mediators (IL-6, cyclooxygenase 2 [COX2]/PGE 2 ) were analyzed by quantitative RT-PCR and ELISA/EIA. Glucose uptake was assessed with ( 14 C)-2-deoxyglucose. Reactive oxygen species (ROS) and nitric oxide (NO) production were measured. To analyze the mechanism of IL-1β-induced inflammation, cells were pretreated or treated with inhibitors of glucose transport (cytochalasin B), the polyol pathway (epalrestat), mitochondrial oxidative stress (MitoTEMPO) or nitric oxide synthase ( l -NAME). Results With IL-1β stimulation, IL-6 and PGE 2 release was greater in human DM than non-DM OA cartilage (2.7- and 3-fold, respectively) ( P < 0.05). In vitro , with IL-1β stimulation, IL-6 and COX2 mRNA expression, IL-6 and PGE 2 release, and ROS and NO production were greater under high-than normal-glucose conditions in cultured chondrocytes. IL-1β–increased IL-6 release was reduced with cytochalasin B, epalrestat, l -NAME or MitoTEMPO treatment (−45%, −62%, −38% and −40%, respectively). Conclusion OA cartilages from DM patients showed increased responsiveness to IL-1β–induced inflammation. Accordingly, high glucose enhanced IL-1β–induced inflammation in cultured chondrocytes via oxidative stress and the polyol pathway. High glucose and diabetes may thus participate in the increased inflammation in OA. [ABSTRACT FROM AUTHOR]