MicroRNA (miRNA) species (miR) regulate mRNA translation and are implicated as mediators of disease pathology via coordinated regulation of molecular effector pathways. Unraveling miR disease-related activities will facilitate future therapeutic interventions. miR-155 recently has been identified with critical immune regulatory functions. Although detected in articular tissues, the functional role of miR-155 in inflammatory arthritis has not been defined. We report here that miR-155 is up-regulated in synovial membrane and synovial fluid (SF) macrophages from patients with rheumatoid arthritis (RA). The increased expression of miR-155 in SF CD14 + cells was associated with lower expression of the miR-155 target, Src homology 2-containing inositol phosphatase-1 (SHIP-1), an inhibitor of inflammation. Similarly, SHIP-1 expression was decreased in CD68 + cells in the synovial lining layer in RA patients as compared with osteoarthritis patients. Overexpression of miR-155 in PB CD14 + cells led to down-regulation of SHIP-1 and an increase in the production of proinflammatory cytokines. Conversely, inhibition of miR-155 in RA synovial CD14 + cells reduced TNF-α production. Finally, miR-155–deficient mice are resistant to collagen-induced arthritis, with profound suppression of antigen-specific Th17 cell and autoantibody responses and markedly reduced articular inflammation. Our data therefore identify a role of miR-155 in clinical and experimental arthritis and suggest that miR-155 may be an intriguing therapeutic target.

This study provides evidence for an inflammatory cell infiltrate in early mild/moderate human tendinopathy. In particular, the authors demonstrate significant infiltration of mast cells and macrophages, suggesting a role for innate immune pathways in the events that mediate early tendinopathy. Clinical Relevance Further mechanistic studies to evaluate the net contribution and hence therapeutic utility of these cellular lineages and their downstream processes may reveal novel therapeutic approaches to the management of early tendinopathy.

Total hip arthroplasty is one of the most commonly performed and successful elective orthopaedic procedures. However, numerous failure mechanisms limit the long-term success including aseptic osteolysis, aseptic loosening, infection, and implant instability. Aseptic osteolysis and subsequent implant failure occur because of a chronic inflammatory response to implant-derived wear particles. To reduce particulate debris and their consequences, implants have had numerous design modifications including high-molecular-weight polyethylene sockets and noncemented implants that rely on bone ingrowth for fixation. Surgical techniques have improved cementation with the use of medullary plugs, cement guns, lavage of the canal, pressurization, centralization of the stem, and reduction in cement porosity. Despite these advances, aseptic osteolysis continues to limit implant longevity. Numerous proinflammatory cytokines, such as interleukin-1, interleukin-6, tumor necrosis factor-alpha, and prostaglandin E2, have proosteoclastogenic effects in response to implant-derived wear particles. However, none of these cytokines represents a final common pathway for the process of particle-induced osteoclast differentiation and maturation. Recent work has identified the fundamental role of the RANKL-RANK-NF-kappaB pathway not only in osteoclastogenesis but also in the development and function the immune system. Thus, the immune system and skeletal homeostasis may be linked in the process of osteoclastogenesis and osteolysis.

MicroRNA (miRNA) has the potential for cross-regulation and functional integration of discrete biological processes during complex physiological events. Utilizing the common human condition tendinopathy as a model system to explore the cross-regulation of immediate inflammation and matrix synthesis by miRNA we observed that elevated IL-33 expression is a characteristic of early tendinopathy. Using in vitro tenocyte cultures and in vivo models of tendon damage, we demonstrate that such IL-33 expression plays a pivotal role in the transition from type 1 to type 3 collagen (Col3) synthesis and thus early tendon remodelling. Both IL-33 effector function, via its decoy receptor sST2, and Col3 synthesis are regulated by miRNA29a. Downregulation of miRNA29a in human tenocytes is sufficient to induce an increase in Col3 expression. These data provide a molecular mechanism of miRNA-mediated integration of the early pathophysiologic events that facilitate tissue remodelling in human tendon after injury.

Psoriasis is a common chronic autoimmune condition of the skin characterized by hyperplasia of epidermal keratinocytes associated with pro-inflammatory cytokines. IL-33 is a new member of the IL-1 superfamily that signals through the ST2 receptor and was originally defined as an inducer of T helper 2 (Th2) cytokines. Recently, broader immune activatory potential has been defined for IL-33 particularly via mast cell activation and neutrophil migration. Here, we show that ST2 À/À mice exhibit reduced cutaneous inflammatory responses compared with WT mice in a phorbol ester-induced model of skin inflammation. Furthermore, injections of IL-33 into the ears of mice induce an inflammatory skin lesion. This inflammatory response was partially dependent on mast cells as mast cell-deficient mice (Kit W-sh/W-sh ) showed delayed responses to IL-33. IL-33 also recruited neutrophils to the ear, an effect mediated in part by increased production of the chemokine KC (CXCL1). Finally, we show that IL-33 expression is up-regulated in the epidermis of clinical psoriatic lesions, compared with healthy skin. These results therefore demonstrate that IL-33 may play a role in psoriasis-like plaque inflammation. IL-33 targeting may provide a new treatment strategy for psoriasis.

F rozen shoulder is a chronic fibrosing condition of the capsule of the joint. The predominant cells involved are fibroblasts and myofibroblasts which lay down a dense matrix of type-I and type-III collagen within the capsule. This subsequently contracts leading to the typical features of pain and stiffness. Cytokines and growth factors regulate the growth and function of the fibroblasts of connective tissue and remodelling of the matrix is controlled by the matrix metalloproteinases (MMPs) and their inhibitors. Our aim was to determine whether there was an abnormal expression or secretion of cytokines, growth factors and MMPs in tissue samples from 14 patients with frozen shoulder using the reverse transcription/polymerase chain reaction (RT/PCR) technique and to compare the findings with those in tissue from four normal control shoulders and from five patients with Dupuytren's contracture. Tissue from frozen shoulders demonstrated the presence of mRNA for a large number of cytokines and growth factors although the frequency was only slightly higher than in the control tissue. The frequency for a positive signal for the proinflammatory cytokines Il-1 and TNF-and TNF-, was not as great as in the Dupuytren's tissue. The presence of mRNA for fibrogenic growth factors was, however, more similar to that obtained in the control and Dupuytren's tissue. This correlated with the histological findings which in most specimens showed a dense fibrous tissue response with few cells other than mature fibroblasts and with very little evidence of any active inflammatory cell process. Positive expressions of the mRNA for the MMPs were also increased, together with their natural inhibitor TIMP. The notable exception compared with control and Dupuytren's tissue was the absence of MMP-14, which is known to be a membrane-type MMP required for the activation of MMP-2 (gelatinase A). Understanding the control mechanisms which play a part in the pathogenesis of frozen shoulder may lead to the development of new regimes of treatment for this common, protracted and painful chronic fibrosing condition. The term 'frozen shoulder' was first used by Codman 1 who described the common features such as pain of gradual onset, which is felt near the insertion of the deltoid, inability to sleep on the affected side, painful restriction of elevation and external rotation and a normal radiological appearance. The disorder is characterised by dense fibrosis of the capsule of the shoulder, 2-4 in which the cellular element consists of fibroblasts and myofibroblasts, 5,6 leading to a contracture of the rotator interval and the coracohumeral ligament, which restricts movement. 7-9 Cytokines and other cellular growth factors are known to regulate the growth and function of fibroblasts in connective tissue. They are cell messengers derived from lymphoid cells, platelets, epithelial cells, endothelial cells, mesangial cells and fibroblasts and act in minute concentrations (nanomolar and femtomolar) by binding to cell receptors , causing a hormone-like acti...

Hypoxia promotes the expression of proinflammatory cytokines, key apoptotic mediators and drives matrix component synthesis towards a collagen type III profile by human tenocytes. The authors propose hypoxic cell injury as a critical pathophysiological mechanism in early tendinopathy offering novel therapeutic opportunities in the management of tendon disorders.

IL-33 is a new member of the IL-1 family, which plays a crucial role in inflammatory response, enhancing the differentiation of dendritic cells and alternatively activated macrophages (AAM). Based on the evidence of IL-33 expression in bone, we hypothesized that IL-33 may shift the balance from osteoclast to AAM differentiation and protect from inflammatory bone loss. Using transgenic mice overexpressing human TNF, which develop spontaneous joint inflammation and cartilage destruction, we show that administration of IL-33 or an IL-33R (ST2L) agonistic Ab inhibited cartilage destruction, systemic bone loss, and osteoclast differentiation. Reconstitution of irradiated hTNFtg mice with ST2−/− bone marrow led to more bone loss compared with the chimeras with ST2+/+ bone marrow, demonstrating an important endogenous role of the IL-33/ST2L pathway in bone turnover. The protective effect of IL-33 on bone was accompanied by a significant increase of antiosteoclastogenic cytokines (GM-CSF, IL-4, and IFN-γ) in the serum. In vitro IL-33 directly inhibits mouse and human M-CSF/receptor activator for NF-κB ligand-driven osteoclast differentiation. IL-33 acts directly on murine osteoclast precursors, shifting their differentiation toward CD206+ AAMs via GM-CSF in an autocrine fashion. Thus, we show in this study that IL-33 is an important bone-protecting cytokine and may be of therapeutic benefit in treating bone resorption.