Proteinase activated receptor (PAR) involvement in mediating arthritis pain and inflammation

Abstract

Proteinase activated receptors (PARs) are a newly identified family of G-protein-coupled receptors that are activated by proteinases released into tissues during inflammation. Evidence has accumulated which shows that PARs can exhibit both anti- and pro-inflammatory properties in different organ systems. During arthritis, proteinases are known to be released into the joint where they orchestrate tissue remodelling and degeneration. By activating PARs, these proteinases have the potential to modulate joint inflammation and pain by a highly targeted and selective receptor pathway. The recent identification of PARs on synovial fibroblasts, neutrophils, macrophages and mast cells is further evidence that this intriguing family of receptors could play a role in the pathogenesis and symptoms of arthritis. This review article provides an overview of the current knowledge regarding PARs and their emerging role in arthritis.

Proteinase-activated receptors (PARs) – focus on receptor-receptor-interactions and their physiological and pathophysiological impact

“…Activation of PAR 2 has been implicated in pain in arthritis [100,101,103], pancreatitis [226,227], PAR 2 -triggered hypersensitivity to heat in the skin, and in neuropathic pain induced by paclitaxel [236]. Since in some cases the pain could be diminished by pharmacologic inhibition of TRPV1 with capsazepine, a more effective suppression of pain may be achieved with specific PAR 2 antagonists once these have successfully passed clinical trials.…”

Novel Role for Proteinase-activated Receptor 2 (PAR2) in Membrane Trafficking of Proteinase-activated Receptor 4 (PAR4)

“…Proteinase-activated receptors (PARs) 2 are a class A GPCR family comprised of four family members, PAR 1 through to PAR 4 , which play key roles in aspects of both physiology and pathophysiology including platelet aggregation, wound healing, and various aspects of inflammation (1–3). Detailed characterization of the protein structure of the PAR family has identified proteolytic cleavage sites at the receptor N-terminal (4–7).…”

Challenges and Opportunities in Protease-Activated Receptor Drug Development

“…The initial small-molecule antagonists developed for PAR2 were peptidomimetics based on the tethered ligand sequence generated by trypsin cleavage. ENMD-1068 (N1-3-methylbutryl-N4-6-aminohexanoyl-piperazine) inhibited trypsin-induced PAR2 activation and decreased joint inflammation in vivo ( Table 2) (57); however, it failed to advance to clinical trials owing to a lack of efficacy (53). GB88 (5-isoxazoyl-Cha-Ilespiroindene-1,4-piperidine) (Figure 3) is a more recently developed, potent, reversible antagonist that blocks PAR2 activation by endogenous proteases and by the synthetic peptide agonist both in vitro and in vivo; it has been shown to attenuate inflammation in a rat model of colitis (58,59).…”