Interferon-γ inhibits interleukin-1β-induced matrix metalloproteinase production by synovial fibroblasts and protects articular cartilage in early arthritis

Introduction: The first few months after symptom onset represents a pathologically distinct phase in rheumatoid arthritis (RA). We used relevant experimental models to define the pathological role of interferon-γ (IFN-γ) during early inflammatory arthritis. Methods: We studied IFN-γ's capacity to modulate interleukin-1β (IL-1β) induced degenerative responses using RA fibroblast-like synoviocytes (FLS), a bovine articular cartilage explant (BACE)/RA-FLS co-culture model and an experimental inflammatory arthritis model (murine antigen-induced arthritis (AIA)). Results: IFN-γ modulated IL-1β driven matrix metalloproteinases (MMP) synthesis resulting in the down-regulation of MMP-1 and MMP-3 production in vitro. IFN-γ did not affect IL-1β induced tissue inhibitor of metalloproteinase-1 (TIMP-1) production by RA FLS but skewed the MMP/TIMP-1 balance sufficiently to attenuate glycosaminoglycan-depletion in our BACE model. IFN-γ reduced IL-1β expression in the arthritic joint and prevented cartilage degeneration on Day 3 of AIA. Conclusions: Early therapeutic intervention with IFN-γ may be critical to orchestrate tissue-protective responses during inflammatory arthritis

The tropicalization of temperate marine ecosystems: climate-mediated changes in herbivory and community phase shifts

Climate-driven changes in biotic interactions can profoundly alter ecological communities, particularly when they impact foundation species. In marine systems, changes in herbivory and the consequent loss of dominant habitat forming species can result in dramatic community phase shifts, such as from coral to macroalgal dominance when tropical fish herbivory decreases, and from algal forests to ‘barrens’ when temperate urchin grazing increases. Here, we propose a novel phase-shift away from macroalgal dominance caused by tropical herbivores extending their range into temperate regions. We argue that this phase shift is facilitated by poleward-flowing boundary currents that are creating ocean warming hotspots around the globe, enabling the range expansion of tropical species and increasing their grazing rates in temperate areas. Overgrazing of temperate macroalgae by tropical herbivorous fishes has already occurred in Japan and the Mediterranean. Emerging evidence suggests similar phenomena are occurring in other temperate regions, with increasing occurrence of tropical fish on temperate reefs.This is an author's peer-reviewed final manuscript as accepted by the publisher. The published article is copyrighted by the Author(s) and published by The Royal Society. It can be found at: http://rspb.royalsocietypublishing.org/Keywords: tropicalisation, herbivory, macroalgae, phase shift, herbivorous fish, range shift, ecosystem impacts, western boundary currents, Climate change, functional diversit

Multicentric Reticulohistiocytosis–A rare and disabling disease

Key Clinical Message Multicentric reticulohistiocytosis is a rare multisystemic condition associated with papulonodular skin lesions, severe arthritis and malignancy. Histopathology shows histiocytes containing abundant eosinophilic ground glass cytoplasm and multinucleated giant cells. Early recognition, age‐appropriate malignancy work‐up and treatment is important to prevent impairment of daily life activity

Interferon gamma decreases interleukin 1 beta-mediated cartilage loss in rheumatoid arthritis [Abstract]

Introduction: The first few months after symptom onset represents a pathologically distinct phase in rheumatoid arthritis (RA). We used relevant experimental models to define the pathological role of interferon-γ (IFN-γ) during early inflammatory arthritis. Methods: We studied IFN-γ's capacity to modulate interleukin-1β (IL-1β) induced degenerative responses using RA fibroblast-like synoviocytes (FLS), a bovine articular cartilage explant (BACE)/RA-FLS co-culture model and an experimental inflammatory arthritis model (murine antigen-induced arthritis (AIA)). Results: IFN-γ modulated IL-1β driven matrix metalloproteinases (MMP) synthesis resulting in the down-regulation of MMP-1 and MMP-3 production in vitro. IFN-γ did not affect IL-1β induced tissue inhibitor of metalloproteinase-1 (TIMP-1) production by RA FLS but skewed the MMP/TIMP-1 balance sufficiently to attenuate glycosaminoglycan-depletion in our BACE model. IFN-γ reduced IL-1β expression in the arthritic joint and prevented cartilage degeneration on Day 3 of AIA. Conclusions: Early therapeutic intervention with IFN-γ may be critical to orchestrate tissue-protective responses during inflammatory arthritis

Inhibiting IL-6 trans-signalling with soluble gp130Fc potently reduces the incidence and severity of collagen-induced experimental arthritis [Abstract]

Background/Purpose: Cytohistomorphological analysis of the synovial joint provides researchers with an opportunity to unmask specific intra- and extra- cellular mechanisms that regulate the switch from acute to chronic pathology in arthritis. The signal transducer and activator of transcription (STAT) pathway orchestrates this transition and steers the effector functions of interleukin-6 (IL-6) within the inflamed joint. We used a pertinent inflammatory arthritis model, murine collagen-induced arthritis (mCIA), to define the timecourse of STAT3 expression within the inflamed joint and to test the potency of timely targeted therapy with an inhibitor of IL-6 trans-signalling (sgp130Fc). Method: Joint tissues were collected (pre and post arthritis) over the timecourse of mCIA. IL-6, soluble IL-6 receptor (sIL-6R) and STAT3 were measured in joint tissue homogenates by ELISA. To test sgp130Fc’s efficacy, 2.5mg/Kg was injected daily. Control mice received either etanercept (2.5mg/Kg daily) or vehicle; they were administered using an identical dosing regimen. Arthritis severity was gauged macroscopically in each paw; the sum of scores provided a clinical arthritis index (CAI) for each mouse. Therapeutic outcome was determined microscopically in serial histological sections taken from joint tissue specimens at end point. Result: In early mCIA, joint tissue homogenates recorded significant increases in IL-6 (P<0.01), sIL-6R (P<0.05) and STAT3 (P<0.05) levels; they coincided with arthritis onset. sgp130Fc treatment was therefore initiated at arthritis onset. sgp130Fc and etanercept delayed mCIA onset, after 5 doses arthritis incidence was 0% (sgp130Fc) versus 17% (etanercept) and 83% (vehicle). At endpoint (day 7 therapy) all mice had arthritis; CAI (P<0.05) and paw diameters (P<0.05) were significantly reduced in sgp130Fc and etanercept compared with vehicle controls. Histological damage was less severe in the etanercept group versus vehicle controls, but not statistically significantly different. All histological parameters were significantly lower in sgp130Fc vs vehicle controls (synovial hyperplasia (P<0.01), synovial tissue infiltrate (P<0.01)). Cytomorphometric analysis revealed that synovial Ly-6G+-neutrophils (P<0.05), F4/80+-macrophages (P<0.01) and CD3+-T-cells (P<0.01) counts were also significantly lower in sgp130Fc vs. vehicle controls. Tissue protective functionality of sgp130Fc was highlighted further by the absence of lymphoid aggregates, diminutive tartrate resistant acid phosphatase staining for osteoclasts and significantly less bone erosions (P<0.05) compared with vehicle controls. At the dosing regimen under investigation, electrophoretic mobility shift assays revealed that sgp130Fc lowered the level of nuclear factor-kappa B (NFkB) and STAT activation (predominantly STAT3) in joint tissues at endpoint whilst etanercept caused a partial reduction in NFkB. Conclusion: Timely targeted inhibition of IL-6 trans-signalling with sgp130Fc potently reduces clinical disease severity in an experimental model of arthritis. Selective blockade of IL-6 trans-signalling could have therapeutic applicability in the management of rheumatoid arthritis

Contractile, but not endothelial, dysfunction in early inflammatory arthritis: a possible role for matrix metalloproteinase‐9

BACKGROUND AND PURPOSE Excess morbidity/mortality in rheumatoid arthritis (RA) is associated with increased incidence of cardiovascular disease. In this ‘proof-of-concept’ study, vascular function was characterized in the murine collagen-induced arthritis (mCIA) model, the benchmark choice for evaluation of the pathological processes and assessment of new therapies. EXPERIMENTAL APPROACH Mice in the very early stages of arthritis development [and appropriate naïve (non-immunized) age-matched controls] were used in the study. Blood pressure was measured using tail cuff plethysmography. Vascular function in rings of isolated aorta was studied with isometric tension myography. Levels of NO metabolites (NOx), MMP-9 protein and IL-1β in plasma and MMP-9 protein in aortic homogenates were quantified. KEY RESULTS Impaired vascular contractile responses in arthritis were unaffected by ex vivo inhibition of NOS (endothelial/neuronal and inducible) or COX activities. Endothelium-dependent and -independent relaxation, plasma NOx and blood pressure were unaffected by arthritis. Plasma and aortic homogenate MMP-9 protein levels were increased significantly in arthritis. Incubation of aortic tissues from naïve control animals with exogenous MMP-9 impaired subsequent contractile responses, mirroring that observed in arthritis. A role for IL-1β in perpetuating contractile dysfunction and increasing aortic MMP-9 was excluded. CONCLUSIONS AND IMPLICATIONS These data identify for the first time a relationship between early arthritis and contractile dysfunction and a possible role for MMP-9 therein, in the absence of overt endothelial dysfunction or increased NO production. As such, MMP-9 may constitute a significant target for early intervention in RA patients with a view to decreasing risk of cardiovascular disease

Contractile, but not endothelial, dysfunction in early inflammatory arthritis: a possible role for matrix metalloproteinase-9

BACKGROUND AND PURPOSE Excess morbidity/mortality in rheumatoid arthritis (RA) is associated with increased incidence of cardiovascular disease. In this ‘proof-of-concept’ study, vascular function was characterized in the murine collagen-induced arthritis (mCIA) model, the benchmark choice for evaluation of the pathological processes and assessment of new therapies. EXPERIMENTAL APPROACH Mice in the very early stages of arthritis development [and appropriate naïve (non-immunized) age-matched controls] were used in the study. Blood pressure was measured using tail cuff plethysmography. Vascular function in rings of isolated aorta was studied with isometric tension myography. Levels of NO metabolites (NOx), MMP-9 protein and IL-1β in plasma and MMP-9 protein in aortic homogenates were quantified. KEY RESULTS Impaired vascular contractile responses in arthritis were unaffected by ex vivo inhibition of NOS (endothelial/neuronal and inducible) or COX activities. Endothelium-dependent and -independent relaxation, plasma NOx and blood pressure were unaffected by arthritis. Plasma and aortic homogenate MMP-9 protein levels were increased significantly in arthritis. Incubation of aortic tissues from naïve control animals with exogenous MMP-9 impaired subsequent contractile responses, mirroring that observed in arthritis. A role for IL-1β in perpetuating contractile dysfunction and increasing aortic MMP-9 was excluded. CONCLUSIONS AND IMPLICATIONS These data identify for the first time a relationship between early arthritis and contractile dysfunction and a possible role for MMP-9 therein, in the absence of overt endothelial dysfunction or increased NO production. As such, MMP-9 may constitute a significant target for early intervention in RA patients with a view to decreasing risk of cardiovascular disease