Protease-activated receptor-2 : a novel pathogenic pathway in a murine model of osteoarthritis

Osteoarthritis (OA) is a global clinical challenge for which no effective disease modifying agents currently exist. Herein we identify protease-activated receptor-2 (PAR-2) as a novel pathogenic mechanism and potential therapeutic target in OA. Experimental OA was induced in wild-type and PAR-2 deficient mice by sectioning the medial menisco-tibial ligament (MMTL), leading to development of a mild arthropathy. Cartilage degradation and increased subchondral bone formation were assessed as indicators of OA pathology. Four weeks following MMTL section, cartilage erosion and increased subchondral bone formation was evident in wild type mice but substantially reduced in PAR-2 deficient mice. Crucially, therapeutic inhibition of PAR-2 in wild type mice,using either a PAR-2 antagonist or a monoclonal antibody targeting the protease cleavage site of PAR-2, was also equally effective at reducing OA progression in vivo. PAR-2 wasupregulated in chondrocytes of wild-type but not sham-operated mice. Wild type mice showed further joint degradation eight weeks following induction of OA, but PAR-2 deficient mice were still protected. The substantial protection from pathology afforded by PAR-2 deficiency following induction of OA provides proof of concept that PAR-2 has a key role in OA and suggests this receptor as a potential therapeutic target. Osteoarthritis (OA) is a chronic disabling condition currently affecting millions globally 1 with radiological evidence of OA in approximately 80% of the population aged over 65. 2OA is characterised by cartilage degradation and increased subchondral bone formation (osteosclerosis). Despite extensive pathophysiologic investigations, clinical management has not altered significantly and comprises administration of analgesics and non-steroidal anti-inflammatory agents and recourse upon joint failure to arthroplasty. No unifying pathogenetic model exists - suggested hypotheses encompass primary cartilage metabolic dysregulation, enthesial disease together with biomechanical dysregulation. Thus far, no critical checkpoint pathway has been identified that is essential for disease progression and which might by corollary represent a valid, disease-modifying OA therapeutic target. Protease-activated receptor-2 (PAR-2) is a G-protein coupled receptor whose 'tethered' ligand is activated by serine proteases. 3 PAR-2 is present in chondrocytes in cartilage from OA patients 4, and following its activation, matrix metalloproteases (MMPs) are generated. 5 However, these previous observations are associative and do not establish the role of PAR-2 in the pathogenesis of OA. We here sought direct evidence of a causal relationship between PAR-2 expression and cartilage and bone pathology in a murine model of OA

Singularly Perturbed Monotone Systems and an Application to Double Phosphorylation Cycles

The theory of monotone dynamical systems has been found very useful in the modeling of some gene, protein, and signaling networks. In monotone systems, every net feedback loop is positive. On the other hand, negative feedback loops are important features of many systems, since they are required for adaptation and precision. This paper shows that, provided that these negative loops act at a comparatively fast time scale, the main dynamical property of (strongly) monotone systems, convergence to steady states, is still valid. An application is worked out to a double-phosphorylation ``futile cycle'' motif which plays a central role in eukaryotic cell signaling.Comment: 21 pages, 3 figures, corrected typos, references remove

Protease-activated receptor-2 (PAR-2): a potential new target in arthritis

Protease-activated receptors (PARs) are a novel family of seven-transmembrane G-protein-coupled receptors. The unique feature of this family is that activation is initiated by cleavage of the N-terminus by serine or other proteases, thereby unmasking a tethered ligand that then interacts with the receptor, leading to activation. PARs have been described in the context of inflammation, and recent evidence indicates a particular role for the second member of this family, PAR-2, in arthritis. Synovial expression of this receptor is greatly upregulated in murine models of arthritis, and both acute and chronic experimental monoarthritis are substantially attenuated in Par2 knockout mice, suggesting a key role for PAR-2 in inflammatory joint disease. These findings translate to inflammatory disease in humans, since PAR-2 expression is upregulated in synovial tissues from patients with rheumatoid arthritis (RA), and appears to be an upstream regulator of proinflammatory cytokine generation, including tumor necrosis factor alpha (TNF-alpha). These findings identify PAR-2 as a new therapeutic target in the management of RA, and the challenge is now to develop potent and selective agents to prevent activation of this receptor

Getting the most out of student selected components: 12 tips for participating students

<p><b>Background:</b> Student Selected Components (SSCs) are an established feature of UK undergraduate medical curricula that offer students choice. They represent a large investment in time and resources. Although programmes vary between Schools, the major learning objectives remain broadly similar. Providing students engage fully with the activity, the final learning outcomes should also be comparable. However, engaging effectively and purposefully with such programmes may not be a clear and straightforward process for students.</p> <p><b>Aim:</b> To present the challenges and solutions to inform students how to derive the greatest benefit from the learning activities in their SSC programmes.</p> <p><b>Methods:</b> Synthesis of the accumulated experience over more than 10 years of developing, running and evaluating SSCs by the Directors of SSCs in five Scottish Medical Schools, combined with analysis of course evaluation and student feedback.</p> <p><b>Results:</b> Consensus defined 12 tips aimed at improving the approach taken by students to their SSCs, and to provide a structure to maximise their final learning outcomes.</p> <p><b>Conclusion:</b> SSC programmes provide diverse opportunities for students to develop and expand their learning. With increasing emphasis being placed upon student assessment to judge a wide range of professional skills and standards into foundation and specialist training, much greater importance is now being given to SSCs as an opportunity for personal, professional and academic developments. However, it is important that this is performed in a purposeful manner to maximise this opportunity. These 12 tips provide guidance to students on how they can maximise the opportunity presented to them by SSCs.</p&gt

Tryptase as a PAR-2 activator in joint inflammation

Protease-activated receptor-2 (PAR-2) is one of a family of G-protein coupled transmembrane receptors activated by proteolytic release of a 'tethered' ligand. We previously reported this receptor has a pivotal role in chronic joint inflammation using a PAR-2 'knockout' mouse [1], but the serine protease responsible for its activation remains uncertain