Inflammation is a process whose main function is to fight against invading pathogens or foreign agents. Nonetheless, it is widely accepted that inflammation takes part in multiple processes in a physiological or pathophysiological context. Among these processes the inflammation has been closely related to bone metabolism. It is well-known that in systemic inflammatory diseases such as rheumatoid arthritis the inflammatory environment contributes to the reduction of the bone mineral density. This has been further evidenced in different animals models of osteoporosis where the deletion of key inflammatory molecules dramatically reduced the bone loss. On the contrary, it is also well-known that certain degree of inflammation is required to allow bone fractures healing. In fact, excessive use of anti-inflammatory drugs inhibits bone fracture consolidation. The innate immune responses (IIRs) contribute to the development and maintenance of the inflammation. These responses have been observed in cells of the musculoskeletal system. Chondrocytes and osteoblasts are equipped with the molecular repertoire necessary to setting up these IIR, including the expression of several toll-like receptors. Specifically, toll-like receptor 4 (TLR4) activation in mesenchymal stem cells, osteoblasts, and osteocytes has been involved in catabolic and anabolic process. Accordingly, in this review we have summarized the current knowledge about the physiology of TLR4, including its signaling, and its endogenous agonists. In addition we have focused on its role on osteoblast metabolism and function.

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.

Background and Purpose: 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.Experimental Approach: 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.Key Results: 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 Abbreviations: 2-ddCt, 2-delta-delta cycle threshold; dCt, delta CT; DDA, data-dependent acquisition; NAMPT, nicotinamide phosphoribosyl transferase; SWATH, sequential window acquisition of all theoretical mass spectra.

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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.

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Distal radius fractures are a common disorder in industrialized nations associated with osteoporosis, with a reported incidence of two fractures per thousand patients per year. We performed a retrospective study comparing two sets of 40 patients, with fracture of the distal radius treated with Penning external fixator, compared to 40 patients treated with fixed-angle volar-locking plate (Plate Depuy ® DVR), with the objective of finding differences between both treatment methods in anatomical values, functional outcomes and complication rates. All fractures were classified according to the AO classification. Postero-anterior and lateral radiographs of the wrist were taken after fracture, after surgery and at 6 months after surgery. We also assessed functional outcome. Minimum follow up was of 10 months. We compared complications between both groups. In the group of patients treated with fixed-angle volar-locked plate, radiological results are found to be closer to the anatomical references. Final outcomes revealed similar functional scores between both groups. The complications rate was statistically higher in the group of patients who underwent external fixation. In the fixed-angle volar-locked plate group, most of complications were related to patient discomfort due to the volar-locking plate.