The resolution of inflammation and cancer

Inflammation has long been thought to contribute to the development of cancer; however there is also clear evidence that the immune system can recognize and eliminate cancer cells. Current research suggests that cancer-associated inflammation has a dual role in tumor progression; inflammatory mediators promote the malignant activity of cancer cells by acting as growth factors and also stimulate angiogenesis, however, cancer-associated inflammation is also linked with immune-suppression that allows cancer cells to evade detection by the immune system. In this review we will discuss the dual role of inflammation in cancer and how endogenous anti-inflammatory mechanisms may equally be important in carcinogenesis.     

On the predictive utility of animal models of osteoarthritis

Animal models of osteoarthritis are extensively used for investigating disease pathways and for preclinical testing of novel therapies. Their predictive utility, however, has often been questioned, mainly because preclinical efficacy of novel therapeutics is poorly translated in clinical trials. In the current narrative review, we consider the preclinical models that were used to support undertaking clinical trials for disease-modifying osteoarthritis drugs, and compare outcomes between clinical and preclinical studies. We discuss this in light of the 1999 Food and Drug Administration draft guidelines for industry for use in the development of drugs, devices, and biological products intended for the treatment of osteoarthritis, which raised five considerations on the usefulness of osteoarthritis models. We systematically discuss what has been learnt regarding these five points since 1999, with emphasis on replicating distinct risk factors and subtypes of human osteoarthritis, and on comprehensive evaluation of the disease in animals, including pathology of all joint tissues, biomarker analysis, and assessment of pain and joint function. Finally, we discuss lessons learnt and propose some recommendations for how the evidence from preclinical research might be strengthened with a view to improving success in clinical translation.     

Current and emerging therapeutic strategies for preventing inflammation and aggrecanase-mediated cartilage destruction in arthritis

Arthritis is a multifactorial disease for which current therapeutic intervention with high efficacy remains challenging. Arthritis predominately affects articular joints, and cartilage deterioration and inflammation are key characteristics. Current therapeutics targeting inflammatory responses often cause severe side effects in patients because of the systemic inhibition of cytokines or other global immunosuppressive activities. Furthermore, a lack of primary response or failure to sustain a response to treatment through acquired drug resistance is an ongoing concern. Nevertheless, treatments such as disease-modifying anti-rheumatic drugs, biological agents, and corticosteroids have revealed promising outcomes by decreasing pain and inflammation in patients and in some cases reducing radiographic progression of the disease. Emerging and anecdotal therapeutics with anti-inflammatory activity, alongside specific inhibitors of the A Disintegrin-like And Metalloproteinase domain with Thrombospondin-1 repeats (ADAMTS) cartilage-degrading aggrecanases, provide promising additions to current arthritis treatment strategies. Thus, it is paramount that treatment strategies be optimized to increase efficacy, reduce debilitating side effects, and improve the quality of life of patients with arthritis. Here, we review the current strategies that attempt to slow or halt the progression of osteoarthritis and rheumatoid arthritis, providing an up-to-date summary of pharmaceutical treatment strategies and side effects. Importantly, we highlight their potential to indirectly regulate ADAMTS aggrecanase activity through their targeting of inflammatory mediators, thus providing insight into a mechanism by which they might inhibit cartilage destruction to slow or halt radiographic progression of the disease. We also contrast these with anecdotal or experimental administration of statins that could equally regulate ADAMTS aggrecanase activity and are available to arthritis sufferers worldwide. Finally, we review the current literature regarding the development of synthetic inhibitors directed toward the aggrecanases ADAMTS4 and ADAMTS5, a strategy that might directly inhibit cartilage destruction and restore joint function in both rheumatoid arthritis and osteoarthritis.     

Requirement of IL-17 receptor signaling in radiation-resistant cells in the joint for full progression of destructive synovitis

IL-17 is a proinflammatory cytokine suspected to be involved in inflammatory and autoimmune diseases such as rheumatoid arthritis. In the present study, we report that IL-17R signaling is required in radiation-resistant cells in the joint for full progression of chronic synovitis and bone erosion. Repeated injections of Gram-positive bacterial cell wall fragments (streptococcal cell wall) directly into the knee joint of naive IL-17R-deficient (IL-17R-/-) mice had no effect on the acute phase of arthritis but prevented progression to chronic destructive synovitis as was noted in wild-type (wt) mice. Microarray analysis revealed significant down-regulation of leukocyte-specific chemokines, selectins, cytokines, and collagenase-3 in the synovium of IL-17R-/- mice. Bone marrow (BM) chimeric mice revealed the need for IL-17R expression on radiation-resistant joint cells for destructive inflammation. Chimeric mice of host wt and donor IL-17R-/- BM cells developed destructive synovitis in this chronic reactivated streptococcal cell wall arthritis model similar to wt-->wt chimeras. In contrast, chimeric mice of host IL-17R-/- and donor wt BM cells were protected from chronic destructive arthritis similar as IL-17R-/- -->IL-17R-/- chimeras. These data strongly indicate that IL-17R signaling in radiation-resistant cells in the joint is required for turning an acute macrophage-mediated inflammation into a chronic destructive synovitis.     

Elevated expression of ICAM-1 in synovium is associated with early inflammatory response for cartilage degeneration in type 2 diabetes mellitus

Type 2 diabetes mellitus (T2DM) is increasingly being recognized as an independent risk factor for the onset and progression of osteoarthritis (OA). Extensive studies have focused on the contribution of obesity (excessive mechanical stress), comorbidity frequently found in T2DM, to cartilage destruction during OA development. However, a little is known about how diabetes-related inflammation may affect the local cartilage in a diabetic objective. In the present study, we were able to establish a T2DM rat model using a combination of a low dose of streptozotocin with high-fat and high-sugar diet. Although the cartilage integrity was comparable between the control and T2DM groups, the expression of matrix metalloproteinases-13 (MMP-13) was significantly upregulated in T2DM, indicating the initiation of an early cascade of cartilage degeneration. In parallel, an obvious alteration of subchondral bone remodeling (inhibition of bone formation) was observed, as evidenced by the reduction of osterix-expressing positive cells. Moreover, we demonstrated that the expression of intercellular adhesion molecule-1 (ICAM-1) in the serum and synovium of T2DM rats was elevated, accompanied by an increase of synovitis score. We also noticed that the number of F4/80-positive macrophage cells was significantly increased in the T2DM group. Mechanistically, the expression of ICAM-1 in fibroblast-like synoviocytes can be triggered by glucose and interleukin-1β, which are the two important factors within the joint of T2DM. Given that MMP-13 expression was significantly upregulated in the T2DM cartilage, and that ICAM-1-mediated filtration of macrophage was associated with synovitis, we propose that ICAM-1 is essential for triggering a vicious cycle of inflammation within the joint, which together subsequently drivers the cartilage degradation.     

Cellular ageing mechanisms in osteoarthritis

Age is the strongest independent risk factor for the development of osteoarthritis (OA) and for many years this was assumed to be due to repetitive microtrauma of the joint surface over time, the so-called ‘wear and tear’ arthritis. As our understanding of OA pathogenesis has become more refined, it has changed our appreciation of the role of ageing on disease. Cartilage breakdown in disease is not a passive process but one involving induction and activation of specific matrix-degrading enzymes; chondrocytes are exquisitely sensitive to changes in the mechanical, inflammatory and metabolic environment of the joint; cartilage is continuously adapting to these changes by altering its matrix. Ageing influences all of these processes. In this review, we will discuss how ageing affects tissue structure, joint use and the cellular metabolism. We describe what is known about pathways implicated in ageing in other model systems and discuss the potential value of targeting these pathways in OA.     

Cartilage development and degeneration: a Wnt Wnt situation

The Wnt signaling pathway plays a crucial role in the development and homeostasis of a variety of adult tissues and, as such, is emerging as an important therapeutic target for numerous diseases. Factors involved in the Wnt pathway are expressed throughout limb development and chondrogenesis and have been shown to be critical in joint homeostasis and endochondral ossification. Therefore, in this review, we discuss Wnt regulation of chondrogenic differentiation, hypertrophy and cartilage function. Moreover, we detail the role of the Wnt signaling pathway in cartilage degeneration and its potential to act as a target for therapy in osteoarthritis. Copyright © 2012 John Wiley & Sons, Ltd.     

Heart Failure in Chronic Myocarditis: A Role for microRNAs?

Myocarditis is an inflammatory disease of the heart, which can persist over a long time. During this time, known as the chronic phase of myocarditis, ongoing inflammation damages the cardiomyocytes. The loss of cardiac cells culminates in the development of dilated cardiomyopathy, often followed by non-ischemic heart failure due to diminished cardiac function. During the course of the disease, expression levels of non-coding small RNAs, called microRNAs (miRNAs), change. Although mainly studied in the acute setting, some of these changes in expression level appear to persist in the chronic phase. In addition to being a much-needed diagnostic tool, these miRNA could provide new treatment options. miRNA-based intervention strategies already showed promising results in the treatment of ischemic cardiovascular diseases in preclinical animal models. By implementing more knowledge on the role of miRNAs in the progression towards heart failure, this can potentially be used in the development of miRNA-based therapeutic interventions in the treatment of myocarditis and thereby preventing the progression towards heart failure. The first part of this review will focus on the natural course of myocarditis and the progression towards heart failure. Secondly, we will discuss the current knowledge on alterations of miRNA expression patterns, and suggest some possible future interventions.     

Heat shock protein 60 reactive T cells in juvenile idiopathic arthritis: what is new?

Juvenile idiopathic arthritis (JIA) is a disease characterized by chronic joint inflammation, caused by a deregulated immune response. In patients with JIA, heat shock proteins (HSPs) are highly expressed in the synovial lining tissues of inflamed joints. HSPs are endogenous proteins that are expressed upon cellular stress and are able to modulate immune responses. In this review, we concentrate on the role of HSPs, especially HSP60, in modulating immune responses in both experimental and human arthritis, with a focus on JIA. We will mainly discuss the tolerogenic immune responses induced by HSPs, which could have a beneficial effect in JIA. Overall, we will discuss the immune modulatory capacity of HSPs, and the underlying mechanisms of HSP60-mediated immune regulation in JIA, and how this can be translated into therapy.     

Tissue remodelling in liver diseases

Tissue remodelling is a dynamic process that occurs during fetal or adult life and involves a modification of the original organization and function of a tissue. Tissue remodelling is observed in physiological and pathological conditions such as during wound healing or in the mammary gland during the course of pregnancy. In this review we will discuss the remodelling occurring in the liver as a consequence of chronic inflammation, as observed in chronic hepatitis, or as a consequence of hepatocellular carcinoma (HCC) progression in more detail. We will consider how altered deposition and turn-over of extracellular matrix (ECM) proteins could lead to development of liver fibrosis, and how the exacerbation of fibrosis could underlie the development of cirrhosis. The involvement of inflammatory and anti-inflammatory cytokines commonly used as therapeutic agents, such as Interferon-a, is then evaluated with a particular focus on modulation of ECM proteolysis. Finally, we analyze the role of alterations of the surrounding microenvironment including ECM, growth factors, cytokines and membrane receptors for ECM ligands in the development of HCC and in its invasive behaviour.     

Fibroblast biology. Effector signals released by the synovial fibroblast in arthritis

There is mounting evidence indicating that the synovial fibroblast is a direct effector of tissue injury and matrix remodeling in inflammatory synovitis. Through the elaboration of effector signals including cytokines and chemokines, mesenchymal cells stimulate or suppress inflammation via autocrine and paracrine mechanisms. Synovial fibroblasts are the principal cells mediating joint destruction through secretion of metalloproteinases, and recent evidence suggests that they may also promote bone resorption by stimulating osteoclastogenesis. Moreover, they may play an integral role in the initial phases of synovitis by releasing chemokines that recruit leukocytes to the joint, and cytokines that trigger angiogenesis. Studies focusing on synoviocyte-leukocyte interactions mediated via the cytokine network and the role of cell-cell contact in driving synoviocyte activation will help define the complex interplay that leads to the initiation and perpetuation of synovial inflammation.     

Fibroblast biology: Effector signals released by the synovial fibroblast in arthritis

There is mounting evidence indicating that the synovial fibroblast is a direct effector of tissue injury and matrix remodeling in inflammatory synovitis. Through the elaboration of effector signals including cytokines and chemokines, mesenchymal cells stimulate or suppress inflammation via autocrine and paracrine mechanisms. Synovial fibroblasts are the principal cells mediating joint destruction through secretion of metalloproteinases, and recent evidence suggests that they may also promote bone resorption by stimulating osteoclastogenesis. Moreover, they may play an integral role in the initial phases of synovitis by releasing chemokines that recruit leukocytes to the joint, and cytokines that trigger angiogenesis. Studies focusing on synoviocyte-leukocyte interactions mediated via the cytokine network and the role of cell-cell contact in driving synoviocyte activation will help define the complex interplay that leads to the initiation and perpetuation of synovial inflammation.     

Mouse models of atherosclerosis: explaining critical roles of lipid metabolism and inflammation

Atherosclerosis is the most common cause of death globally. It is a complex disease involving morphological and cellular changes in vascular walls. Studying molecular mechanism of the disease is hindered by disease complexity and lack of robust noninvasive diagnostics in human. Mouse models are the most popular animal models that allow researchers to study the mechanism of disease progression. In this review we discuss the advantage and development of mouse as a model for atherosclerotic research. Along with commonly used models, this review discusses strains that are used to study the role of two critical processes associated with the disease—lipid metabolism and inflammation.     

New developments in osteoarthritis: Posttraumatic osteoarthritis: pathogenesis and pharmacological treatment options

Joint trauma can lead to a spectrum of acute lesions, including osteochondral fractures, ligament or meniscus tears and damage to the articular cartilage. This is often associated with intraarticular bleeding and causes posttraumatic joint inflammation. Although the acute symptoms resolve and some of the lesions can be surgically repaired, joint injury triggers a chronic remodeling process in cartilage and other joint tissues that ultimately manifests as osteoarthritis in a majority of cases. The objective of the present review is to summarize information on pathogenetic mechanisms involved in the acute and chronic consequences of joint trauma and discuss potential pharmacological interventions. The focus of the review is on the early events that follow joint trauma since therapies for posttraumatic joint inflammation are not available and this represents a unique window of opportunity to limit chronic consequences.     

Modulation of inflammatory signaling pathways by phytochemicals in ovarian cancer

Inflammation has been suggested to be involved in cancer development and progression. Many clinical and experimental studies have shown that inflammation could contribute to ovarian carcinogenesis through activation of the NF-κB and AP-1 pathways by chronic inflammatory mediators. Phytochemicals, which are natural compounds derived from fruits and vegetables, have shown anti-inflammatory and anti-cancer effects. Due to their relatively low toxicity and easy accessibility, phytochemicals have been investigated for their chemopreventive potential against various cancers. In this review, we discuss the role of phytochemicals in preventing ovarian cancer through anti-inflammatory mechanisms.     

Pseudolaric acid B ameliorates synovial inflammation and vessel formation by stabilizing PPARγ to inhibit NF-κB signalling pathway

Synovial macrophage polarization and inflammation are essential for osteoarthritis (OA) development, yet the molecular mechanisms and regulation responsible for the pathogenesis are still poorly understood. Here, we report that pseudolaric acid B (PAB) attenuated articular cartilage degeneration and synovitis during OA. PAB, a diterpene acid, specifically inhibited NF-κB signalling and reduced the production of pro-inflammatory cytokines, which further decreased M1 polarization and vessel formation. We further provide in vivo and in vitro evidences that PAB suppressed NF-κB signalling by stabilizing PPARγ. Using PPARγ antagonist could abolish anti-inflammatory effect of PAB and rescue the activation of NF-κB signalling during OA. Our findings identify a previously unrecognized role of PAB in the regulation of OA and provide mechanisms by which PAB regulates NF-κB signalling through PPARγ, which further suggest targeting synovial inflammation or inhibiting vessel formation at early stage could be an effective preventive strategy for OA.     

Mitochondria in monocytes and macrophages-implications for translational and basic research

The mitochondrion plays a crucial role in the immune system particularly in regulating the responses of monocytes and macrophages to tissue injury, pathogens, and inflammation. In systemic diseases such as atherosclerosis and chronic kidney disease (CKD), it has been established that disruption of monocyte and macrophage function can lead to chronic inflammation. Polarization of macrophages into the pro-inflammatory (M1) and anti-inflammatory (M2) phenotypes results in distinct metabolic reprograming which corresponds to the progression and resolution of inflammation. In this review, we will discuss the role of the mitochondrion in monocyte and macrophage function and how these cells specifically influence the pathophysiology of atherosclerosis and CKD. We propose that assessing monocyte bioenergetics in different disease states could (1) enhance our understanding of the energetic perturbations occurring in systemic inflammatory conditions and (2) aid in identifying therapeutic interventions to mitigate these disorders in patients.     

Toll样受体4对动脉粥样硬化发生、发展的研究进展

动脉粥样硬化（atherosclerosis,AS）是多种细胞、炎性介质参与形成的慢性炎症性疾病。Toll样受体家族（Toll like receptors,TLRs）中的TLR4是机体重要的诱导分泌多种炎性因子的模式识别受体。现有证据表明,TLR4不仅产生多种炎性因子诱发血管炎症反应,而且促进AS斑块形成和发展,造成斑块不稳定,甚至破裂,对AS的发生、发展具有重要作用。因此,了解TLR4对AS的影响有助于发现新的治疗靶点和对策。主要对TLR4在AS发病机制和易损斑块发展中的作用进行综述。     

Role of iNOS in osteoarthritis: Pathological and therapeutic aspects

Accumulating evidence suggests that inflammation has a key role in the pathogenesis of osteoarthritis (OA). Nitric oxide (NO) has been established as one of the major inflammatory mediators in OA and drives many pathological changes during the development and progression of OA. Excessive production of NO in chondrocytes promotes cartilage destruction and cellular injury. The synthesis of NO in chondrocytes is catalyzed by inducible NO synthase (iNOS), which is thereby an attractive therapeutic target for the treatment of OA. A number of direct and indirect iNOS inhibitors, bioactive compounds, and plant-derived small molecules have been shown to exhibit chondroprotective effects by suppressing the expression of iNOS. Many of these iNOS inhibitors hold promise for the development of new, disease-modifying therapies for OA; however, attempts to demonstrate their success in clinical trials are not yet successful. Many plant extracts and plant-derived small molecules have also shown promise in animal models of OA, though further studies are needed in human clinical trials to confirm their therapeutic potential. In this review, we discuss the role of iNOS in OA pathology and the effects of various iNOS inhibitors in OA.