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Tryptase as a PAR-2 activator in joint inflammation

Background

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.

Objective

We investigated whether β-tryptase has proinflammatory actions in the mouse knee and specifically whether a tryptase inhibitor can modulate experimentally induced chronic joint inflammation.

Methods

Five micrograms of human β-tryptase was injected into the knee joint cavity of two groups of anaesthetized (Halothane/O2/N2O) mice (30 g): wild-type (PAR-2+/+) C57BL/6J mice and PAR-2 gene disrupted mice (PAR-2-/-). Joint swelling was assessed by comparing caliper measurements of knee joint diameter pre-injection and post-injection. Chronic monoarthritis was induced using the same anaesthetic regime in separate wild-type mice by intra-articular and peri-articular injection of Freunds complete adjuvant (FCA) (in 5% methycellulose). In a parallel group of mice, 50 μg of the tryptase inhibitor 4-amidino phenyl pyruvic acid (APPA) was co-administered with the FCA/methycellulose emulsion. Joint diameter was measured over 10 days.

Results

Intra-articular injection of β-tryptase resulted in rapid joint swelling in wild-type mice that was completely abrogated in PAR-2-/- mice (Fig. 1a), suggesting that tryptase-mediated inflammatory actions require functional PAR-2. Tryptase plays an important role in mediating chronic inflammation as APPA co-administration substantially inhibited FCA-induced joint swelling (Fig. 1b). The present study extends our previous finding [1] that PAR-2 plays a key role in mediating chronic joint inflammation, by demonstrating that tryptase may be a crucial activating protease required for such PAR-2-mediated actions.

Figure 1
figure1

(a) Six hours after intra-articular injection of β-tryptase, knee joint swelling is evident in wild-type (PAR-2+/+) mice but is virtually absent in PAR-2 gene disrupted (PAR-2-/-) mice (P < 0.001, n = 4). (b) Knee joint swelling 10 days after Freunds complete adjuvant (FCA) treatment is significantly inhibited by co-administration of 4-amidino phenyl pyruvic acid (APPA) with FCA (P = 0.014, n = 4).

References

  1. 1.

    Ferrell WR, Lockhart JC, Kelso EB, Dunning L, Plevin R, et al: Essential role for proteinase-activated receptor-2 in arthritis. J Clin Invest. 2003, 111: 35-49. 10.1172/JCI200316913.

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Kelso, E., Dunning, L., Lockhart, J. et al. Tryptase as a PAR-2 activator in joint inflammation. Arthritis Res Ther 7, P99 (2005). https://doi.org/10.1186/ar1620

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Keywords

  • Tryptase
  • Pyruvic Acid
  • Caliper Measurement
  • Anaesthetic Regime
  • Crucial Activate