Interleukin 4 promotes anti-inflammatory macrophages that clear cartilage debris and inhibits osteoclast development to protect against osteoarthritis.

Objective: Osteoarthritis (OA), the leading cause of joint failure, is characterized by breakdown of articular cartilage and remodeling of subchondral bone in synovial joints. Despite the high prevalence and debilitating effects of OA, no disease-modifying drugs exist. Increasing evidence, including genetic variants of the interleukin 4 (IL-4) and IL-4 receptor genes, implicates a role for IL-4 in OA, however, the mechanism underlying IL-4 function in OA remains unknown.

Dysregulated integrin αVβ3 and CD47 signaling promotes joint inflammation, cartilage breakdown, and progression of osteoarthritis.

Osteoarthritis (OA) is the leading cause of joint failure, yet the underlying mechanisms remain elusive, and no approved therapies that slow progression exist. Dysregulated integrin function was previously implicated in OA pathogenesis. However, the roles of integrin αVβ3 and the integrin-associated receptor CD47 in OA remain largely unknown.

IgE-mediated mast cell activation promotes inflammation and cartilage destruction in osteoarthritis.

Unlabelled: Osteoarthritis is characterized by articular cartilage breakdown, and emerging evidence suggests that dysregulated innate immunity is likely involved. Here, we performed proteomic, transcriptomic, and electron microscopic analyses to demonstrate that mast cells are aberrantly activated in human and murine osteoarthritic joint tissues. Using genetic models of mast cell deficiency, we demonstrate that lack of mast cells attenuates osteoarthritis in mice.

Urokinase plasminogen activator and receptor promote collagen-induced arthritis through expression in hematopoietic cells.

The plasminogen activation (PA) system has been implicated in driving inflammatory arthritis, but the precise contribution of PA system components to arthritis pathogenesis remains poorly defined. Here, the role of urokinase plasminogen activator (uPA) and its cognate receptor (uPAR) in the development and severity of inflammatory joint disease was determined using uPA- and uPAR-deficient mice inbred to the strain DBA/1J, a genetic background highly susceptible to collagen-induced arthritis (CIA). Mice deficient in uPA displayed a near-complete amelioration of macroscopic and histological inflammatory joint disease following CIA challenge.

The tyrosine kinase inhibitor imatinib mesylate suppresses uric acid crystal-induced acute gouty arthritis in mice.

Gouty arthritis is caused by the deposition of monosodium urate (MSU) crystals in joints. Despite many treatment options for gout, there is a substantial need for alternative treatments for patients unresponsive to current therapies. Tyrosine kinase inhibitors have demonstrated therapeutic benefit in experimental models of antibody-dependent arthritis and in rheumatoid arthritis in humans, but to date, the potential effects of such inhibitors on gouty arthritis has not been evaluated.

Nicotine drives neutrophil extracellular traps formation and accelerates collagen-induced arthritis.

Objectives: The aim was to investigate the effects of nicotine on neutrophil extracellular traps (NETs) formation in current and non-smokers and on a murine model of RA.

Methods: We compared spontaneous and phorbol 12-myristate 13-acetate-induced NETosis between current and non-smokers by DNA release binding. Nicotine-induced NETosis from non-smokers was assessed by DNA release binding, NET-specific (myeloperoxidase (MPO)-DNA complex) ELISA and real-time fluorescence microscopy.

CCL2/CCR2, but not CCL5/CCR5, mediates monocyte recruitment, inflammation and cartilage destruction in osteoarthritis.

Objectives: While various monocyte chemokine systems are increased in expression in osteoarthritis (OA), the hierarchy of chemokines and chemokine receptors in mediating monocyte/macrophage recruitment to the OA joint remains poorly defined. Here, we investigated the relative contributions of the CCL2/CCR2 versus CCL5/CCR5 chemokine axes in OA pathogenesis.

Methods: -, -, - and -deficient and control mice were subjected to destabilisation of medial meniscus surgery to induce OA.

Low-grade inflammation as a key mediator of the pathogenesis of osteoarthritis.

Osteoarthritis (OA) has long been viewed as a degenerative disease of cartilage, but accumulating evidence indicates that inflammation has a critical role in its pathogenesis. Furthermore, we now appreciate that OA pathogenesis involves not only breakdown of cartilage, but also remodelling of the underlying bone, formation of ectopic bone, hypertrophy of the joint capsule, and inflammation of the synovial lining. That is, OA is a disorder of the joint as a whole, with inflammation driving many pathologic changes.

Mice expressing a mutant form of fibrinogen that cannot support fibrin formation exhibit compromised antimicrobial host defense.

Fibrin(ogen) is central to hemostasis and thrombosis and also contributes to multiple physiologic and pathologic processes beyond coagulation. However, the precise contribution of soluble fibrinogen vs insoluble fibrin matrices to vascular integrity, tissue repair, inflammation, and disease has been undefined and unapproachable. To establish the means to distinguish fibrinogen- and fibrin-dependent processes in vivo, Fib(AEK) mice were generated that carry normal levels of circulating fibrinogen but lack the capacity for fibrin polymer formation due to a germ-line mutation in the Aα chain thrombin cleavage site.

Transglutaminase factor XIII promotes arthritis through mechanisms linked to inflammation and bone erosion.

Rheumatoid arthritis is a chronic inflammatory disease characterized by synovial hyperplasia, inflammatory cell infiltration, irreversible cartilage and bone destruction, and exuberant coagulation system activity within joint tissue. Here, we demonstrate that the coagulation transglutaminase, factor XIII (fXIII), drives arthritis pathogenesis by promoting local inflammatory and tissue degradative and remodeling events. All pathological features of collagen-induced arthritis (CIA) were significantly reduced in fXIII-deficient mice.

Plasminogen is a joint-specific positive or negative determinant of arthritis pathogenesis in mice.

Objective: A fundamental metric in the diagnosis of arthropathies is the pattern of joint involvement, including differences in proximal versus distal joints and patterns of symmetric or asymmetric disease. The basis for joint selectivity among arthritides and/or within a defined disease such as rheumatoid arthritis remains enigmatic. Coagulation and fibrinolytic activity are observed in both experimental animals with inflammatory joint disease and patients with inflammatory arthritis.

Genetic elimination of the binding motif on fibrinogen for the S. aureus virulence factor ClfA improves host survival in septicemia.

Fibrinogen can support host antimicrobial containment/clearance mechanisms, yet selected pathogens appear to benefit from host procoagulants to drive bacterial virulence. Here, we explored the hypothesis that host fibrin(ogen), on balance, supports Staphylococcus aureus infection in the context of septicemia. Survival studies following intravenous infection in control and fibrinogen-deficient mice established the overall utility of host fibrin(ogen) to S.

Targeting the coagulation factor fibrinogen for arthritis therapy.

Fibrinogen is a provisional matrix protein of the coagulation system that following proteolytic cleavage by the protease thrombin polymerizes to form fibrin, the structural basis of the blood clot. Fibrin polymer formation at sites of vessel injury is critical to normal hemostasis. However, fibrin deposition within damaged tissues is also a common pathological feature of inflammatory diseases, including rheumatoid arthritis.