Role of protease‐activated receptor 2 in joint inflammation

Lam, F.

doi:10.1002/art.22935

Cited by 5 publications

(2 citation statements)

References 27 publications

(44 reference statements)

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“…PAR2 also plays important roles in modulating inflammatory [19,34,35], gastrointestinal [36,37], cardiovascular [38,39], respiratory [40][41][42], and metabolic diseases [43][44][45], asthma [41,46] and cancers [47][48][49].…”

Section: Par2 Signaling and Diseasementioning

confidence: 99%

Protease activated receptor 2 (PAR2) modulators: a patent review (2010–2015)

Yau

Lim

Liu

et al. 2016

Expert Opinion on Therapeutic Patents

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In the last six years, substantial efforts were made towards developing PAR2 modulators, but most lack potency or selectivity or have poor pharmacokinetic profiles. Many PAR2 modulators were assessed by measuring Gαq protein-mediated calcium release in cells. This may be insufficient to fully characterize ligand function, since different ligands signal through PAR2 via multiple signaling pathways. It may be feasible to develop biased ligands as drugs that can selectively modulate one or more specific signaling pathways linking PAR2 to a specific diseased state. Accordingly, potent, orally bioavailable, pathway- and receptor-selective PAR2 modulators may be an achievable goal to realizing effective drugs that can treat PAR2-mediated diseases.

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Section: Par2 Signaling and Diseasementioning

confidence: 99%

Protease activated receptor 2 (PAR2) modulators: a patent review (2010–2015)

Yau

Lim

Liu

et al. 2016

Expert Opinion on Therapeutic Patents

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“…PAR2 has been proposed to be important in inflammation (Niu et al ., 2008; Shin et al ., 2009) and proliferation (Nishibori et al ., 2005; Arisawa et al ., 2007; Matej et al ., 2007; Iwaki et al ., 2008). Based mainly on the properties of these exogenous peptide agonists, together with some knockout mouse studies, activation of PAR2 has been purported to be pro‐inflammatory in arthritis (Ferrell et al ., 2003; Kelso et al ., 2007; Lam, 2007; McIntosh et al ., 2007), pancreatitis (Maeda et al ., 2005; Hirota et al ., 2006), gastric (Hansen et al ., 2005; Cottrell et al ., 2007; Kawabata et al ., 2008) and kidney (Moussa et al ., 2007; Vesey et al ., 2007a,b) cells, but anti‐inflammatory in airways inflammation (Cocks et al ., 1999; D'Agostino et al ., 2007). Increased expression of PAR2 associated with proliferation has been consistently found in many types of cancer cells, with reports on PAR2‐induced cancer progression in breast (Matej et al ., 2007), colon (Nishibori et al ., 2005), gastric (Arisawa et al ., 2007) and pancreatic cancers (Iwaki et al ., 2008).…”

Section: Introductionmentioning

confidence: 99%

Modulating human proteinase activated receptor 2 with a novel antagonist (GB88) and agonist (GB110)

Suen

Barry

Lohman

et al. 2012

British J Pharmacology

104

159

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BACKGROUND AND PURPOSEMany cells express proteinase activated receptor 2 (PAR2) on their plasma membrane. PAR2 is activated by proteolytic enzymes, such as trypsin and tryptase that cleave the receptor N-terminus, inititating signalling to intracellular G proteins. Studies on PAR2 have relied heavily upon activating effects of proteases and peptide agonists that lack stability and bioavailability in vivo. EXPERIMENTAL APPROACHA novel small molecule agonist GB110 and an antagonist GB88 were characterized in vitro against trypsin, peptide agonists, PAR2 antibody, PAR1 agonists and flow cytometry,in seven cell lines using intracellular Ca 2+ mobilization and examined in vivo against PAR2-and PAR1-induced rat paw oedema. KEY RESULTSGB110 is a potent non-peptidic agonist activating PAR2-mediated Ca 2+ release in HT29 cells (EC50~200 nM) and six other human cell lines, inducing PAR2 internalization. GB88 is a unique PAR2 antagonist, inhibiting PAR2 activated Ca 2+ release (IC50 2 mM) induced by native (trypsin) or synthetic peptide and non-peptide agonists. GB88 was a competitive and surmountable antagonist of agonist 2f-LIGRLO-NH2, a competitive but insurmountable antagonist of agonist GB110, and a non-competitive insurmountable antagonist of trypsin. GB88 was orally active and anti-inflammatory in vivo, inhibiting acute rat paw oedema elicited by agonist GB110 and proteolytic or peptide agonists of PAR2 but not by corresponding agonists of PAR1 or PAR4. CONCLUSIONS AND IMPLICATIONSThe novel PAR2 agonist and antagonist modulate intracellular Ca 2+ and rat paw oedema, providing novel molecular tools for examining PAR2-mediated diseases.

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Proteinases and their receptors in inflammatory arthritis: an overview

et al. 2018

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Proteinases are enzymes with established roles in physiological and pathological processes such as digestion and the homeostasis, destruction and repair of tissues. Over the past few years, the hormone-like properties of circulating proteinases have become increasingly appreciated. Some proteolytic enzymes trigger cell signalling via proteinase-activated receptors, a family of G protein-coupled receptors that have been implicated in inflammation and pain in inflammatory arthritis. Proteinases can also regulate ion flux owing to the cross-sensitization of transient receptor potential cation channel subfamily V members 1 and 4, which are associated with mechanosensing and pain. In this Review, the idea that proteinases have the potential to orchestrate inflammatory signals by interacting with receptors on cells within the synovial microenvironment of an inflamed joint is revisited in three arthritic diseases: osteoarthritis, spondyloarthritis and rheumatoid arthritis. Unanswered questions are highlighted and the therapeutic potential of modulating this proteinase-receptor axis for the management of disease in patients with these types of arthritis is also discussed.

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Role of protease‐activated receptor 2 in joint inflammation

Cited by 5 publications

References 27 publications

Protease activated receptor 2 (PAR2) modulators: a patent review (2010–2015)

Protease activated receptor 2 (PAR2) modulators: a patent review (2010–2015)

Modulating human proteinase activated receptor 2 with a novel antagonist (GB88) and agonist (GB110)

Proteinases and their receptors in inflammatory arthritis: an overview

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