Evaluation of protease‐activated receptor 2 in murine models of arthritis

Busso, Natalie; Frasnelli, Matthias; Feifel, Roland; Cenni, Bruno; Steinhoff, Martin; Hamilton, Justin Raymond; So, Alexander

doi:10.1002/art.22312

Cited by 61 publications

(70 citation statements)

References 15 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Of the 4 PARs, the one most strongly implicated in the pathogenesis and progression of inflammatory arthritis is PAR-2 (41,42). Importantly, PAR-2 is also increased in OA human cartilage, can be up-regulated by IL-1␣ and TNF␣, and its activation leads to increased MMP-1 and MMP-13 synthesis (10,11).…”

Section: Discussionmentioning

confidence: 99%

Activation of cartilage matrix metalloproteinases by activated protein C

Jackson

Smith

et al. 2009

Arthritis & Rheumatism

View full text Add to dashboard Cite

Objective. To investigate the role of activated protein C (APC) in cartilage degradation.Methods. Chondrocyte expression of protein C, endothelial protein C receptor (EPCR), and thrombomodulin (TM) were evaluated by reverse transcriptionpolymerase chain reaction (RT-PCR). APC was immunolocalized in developing joints and in osteoarthritic (OA) cartilage from humans. The effect of APC on aggrecan and collagen degradation was examined in explant cultures of ovine cartilage in control cultures and in cultures stimulated with interleukin-1␣ (IL-1␣), tumor necrosis factor ␣ (TNF␣), or retinoic acid (RetA), using colorimetric assays and Western blotting. Chondrocyte expression of matrix metalloproteinases (MMPs), ADAMTS, and tissue inhibitor of metalloproteinases (TIMPs) was measured by RT-PCR. MMP-2 and MMP-9 activity was evaluated by gelatin zymography and MMP-13 by fluorogenic assay.Results. Positive cellular immunostaining for APC was found at sites of MMP activity in developing joints and in OA, but not normal, cartilage. Chondrocytes expressed messenger RNA for protein C, EPCR, and TM, with the latter 2 levels increased by IL-1␣ and TNF␣ stimulation. APC augmented aggrecan release and initiated collagen breakdown in IL-1␣-treated and TNF␣-treated cartilage, but not in normal or in RetAtreated cartilage. APC-stimulated aggrecan and collagen breakdown were due to MMP activity but were not associated with modulation of MMP, ADAMTS, or TIMP expression. APC resulted in MMP-13 activation in cartilage cultures. APC could not directly activate proMMP-13, but it was associated with increased MMP-2 and MMP-9 activity.Conclusion. APC may be a relevant activator of MMPs in cartilage and may play a role in progressive cartilage degradation in arthritis.

show abstract

Section: Discussionmentioning

confidence: 99%

Activation of cartilage matrix metalloproteinases by activated protein C

Jackson

Smith

et al. 2009

Arthritis & Rheumatism

View full text Add to dashboard Cite

show abstract

“…K14 activates PAR-1, −2, and −4, and K5 and K6 activate PAR-2 [196]. Notably, PAR-2-deficient mice are protected from CFA-induced arthritis [32] and are more resistant to EAE [191].…”

Section: Direct Modulation Of Immune Effectormentioning

confidence: 99%

The Multiple Sclerosis Degradome: Enzymatic Cascades in Development and Progression of Central Nervous System Inflammatory Disease

Scarisbrick

2008

Current Topics in Microbiology and Immunology

View full text Add to dashboard Cite

An array of studies implicate different classes of protease and their endogenous inhibitors in multiple sclerosis (MS) pathogenesis based on expression patterns in MS lesions, sera, and/or cerebrospinal fluid (CSF). Growing evidence exists regarding their mechanistic roles in inflammatory and neurodegenerative aspects of this disease. Proteolytic events participate in demyelination, axon injury, apoptosis, and development of the inflammatory response including immune cell activation and extravasation, cytokine and chemokine activation/inactivation, complement activation, and epitope spreading. The potential significance of proteolytic activity to MS therefore relates not only to their potential use as important biomarkers of disease activity, but additionally as prospective therapeutic targets. Experimental data indicate that understanding the net physiological consequence of altered protease levels in MS development and progression necessitates understanding protease activity in the context of substrates, endogenous inhibitors, and proteolytic cascade interactions, which together make up the MS degradome. This review will focus on evidence regarding the potential physiologic role of those protease families already identified as markers of disease activity in MS; that is, the metallo-, serine, and cysteine proteases.

show abstract

“…17). Synovial fibroblasts, chondrocytes, macrophages, neutrophils, mast cells, T cells, and dendritic cells all express PARs, which exhibit both antiinflammatory and proinflammatory properties, although recent data point toward a detrimental role especially in the context of immune-mediated effects in arthritis (157). A study in PAR-2 Ϫ/Ϫ mice confirmed PAR-2 as a key mediator of chronic joint inflammation (158), and this is likely to be a consequence of activation by mast cell-derived tryptase (86,87).…”

Section: Serine Proteinases and Cell Signalingmentioning

confidence: 99%