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Beer consumption has been identified as a risk factor for osteoarthritis (OA), a rheumatic disease characterised by cartilage degradation, joint inflammation, and eventual joint failure. One of the main isoflavonoids in beer is formononetin (FNT), an estrogenic compound also found in multiple plants and herbs. In this study, we aimed to investigate the effect of FNT on chondrocyte viability, inflammation, and metabolism. Cells were treated with FNT with or without IL-1β for 48 h and during 7 days of differentiation. Cell viability was determined via MTT assay. Nitrite accumulation was determined by Griess reaction. The expression of genes involved in inflammation and metabolism was determined by RT-PCR. The results revealed that a low concentration of FNT had no deleterious effect on cell viability and decreased the expression of inflammation-related genes. However, our results suggest that FNT overexposure negatively impacts on chondrocytes by promoting catabolic responses. Finally, these effects were not mediated by estrogen receptors (ERs) or aryl hydrocarbon receptor (AhR). In conclusion, factors that favour FNT accumulation, such as long exposure times or metabolic disorders, can promote chondrocyte catabolism. These data may partially explain why beer consumption increases the risk of OA.

Osteoarthritis, a major cause of disability in developed countries does not have effective treatment. Activation of TLR4 and innate immune response factors contribute to osteoarthritis progressive cartilage degradation. There are no clinically available TLR4 inhibitors. Interestingly, the antidepressant amitriptyline could block this receptor. Thus, we evaluated amitriptyline anti-TLR4 effects on human osteoarthritis chondrocytes in order to repurpose it as an inhibitor of innate immune response in joint inflammatory pathologies.Using in silico docking analysis, RT-PCR, siRNA, elisa, proteomics and clinical data mining of drug consumption, we explored the clinical relevance of amitriptyline blockade of TLR4-mediated innate immune responses in human osteoarthritis chondrocytes.Amitriptyline bound TLR4 but not IL-1 receptor. Interestingly, amitriptyline binding to TLR4 inhibited TLR4- and IL-1 receptor-mediated innate immune responses in human osteoarthritis chondrocytes, synoviocytes and osteoblasts cells. Amitriptyline reduced basal innate immune responses and promoted anabolic effects in human osteoarthritis chondrocytes. Supporting its anti-innate immune response effects, amitriptyline down-regulated basal and induced expression of NLRP3, an inflammasome member from IL-1 receptor signalling linked to osteoarthritis and gout pathologies. Accordingly, mining of dissociated and aggregated drug consumption data from 107,172 elderly patients (65 years) revealed that amitriptyline consumption was significantly associated with lower colchicine consumption associated with inflammatory gout flare treatment.Amitriptyline blocks TLR4-, IL-1 receptor and NLRP3-dependent innate immune responses. This together with clinical data amitriptyline could be repurposed for systemic or local innate immune response management in diverse joint inflammatory pathologies.

Musculoskeletal pathologies (MSPs) such as osteoarthritis (OA) and osteoporosis (OP), are a set of disorders that cause severe pain, motion difficulties, and even permanent disability. In developed countries, the current incidence of MSPs reaches about one in four adults and keeps escalating as a consequence of aging and sedentarism. Interestingly, OA and OP have been closely related to similar risk factors, including aging, metabolic alterations, and inflammation. Visfatin, an adipokine with an inflammatory and catabolic profile, has been associated with several OA and OP metabolic risk factors, such as obesity, insulin resistance, and type II diabetes. Furthermore, visfatin has been associated with the innate immune receptor toll-like receptor 4 (TLR4), which plays a key role in cartilage and bone inflammatory and catabolic responses. Moreover, visfatin has been related to several OA and OP pathologic features. The aim of this work is to bring together basic and clinical data regarding the common role of visfatin in these pathologies and their major shared risk factors. Finally, we discuss the pitfalls of visfatin as a potential biomarker and therapeutic target in both pathologies.

Osteoarthritis (OA), the most common chronic rheumatic disease, is mainly characterized by a progressive degradation of the hyaline articular cartilage, which is essential for correct joint function, lubrication, and resistance. Articular cartilage disturbances lead to joint failure, pain, and disability. Hyaline cartilage is also present in the growth plate and plays a key role in longitudinal bone growth. Alterations of this cartilage by diverse pathologies have been related to longitudinal bone growth inhibition (LBGI), which leads to growth retardation. Diet can play a crucial role in processes involved in the OA and LBGI’s onset and evolution. Specifically, there is ample evidence pointing to the negative impacts of caffeine consumption on hyaline cartilage. However, its effects on these tissues have not been reviewed. Accordingly, in this review, we summarize all current knowledge in the PubMed database about caffeine catabolic effects on articular and growth plate cartilage. Specifically, we focus on the correlation between OA and LBGI with caffeine prenatal or direct exposure. Overall, there is ample evidence indicating that caffeine intake negatively affects the physiology of both articular and growth plate cartilage, increasing consumers predisposition to suffer OA and LBGI. As a result, caffeine consumption should be avoided for these pathologies.