A thrombin receptor - derived imaging agent detects subclinical arthritis in mice.

A thrombin receptor - derived imaging agent detects subclinical arthritis in mice.

Arthritis Rheumatol. 2017 Nov 22;:

Authors: Friedman B, Whitney MA, Savariar EN, Caneda C, Steinbach P, Xiong Q, Hingorani DV, Crisp J, Adams SR, Kenner M, Lippert CN, Nguyen QT, Guma M, Tsien RY, Corr M

Abstract
OBJECTIVE: Functional imaging of synovitis could improve both early detection of rheumatoid arthritis (RA) and long-term outcomes. Motivated by the intersection of inflammation with coagulation protease activation, we examine coagulation protease activities in arthritic mice with a dual fluorescent Ratiometric thrombin-Activatable Cell Penetrating Peptide (RACPPNleTPRSFL ).
METHOD: Mice with chronic transgenic K/BxN arthritis, or with arthritis on Day 1 of passive serum transfer induced arthritis (STIA), were imaged in vivo for Cy5 em: Cy7 em ratiometric fluorescence from proteolytic cleavage and activation of RACPPNleTPRSFL . Joint thickness was measured from Days 0 to 10 in STIA mice. Microscopic localization of fluorescence, enabled by cleavage-evoked release of Cy5 tissue-adhesive fragments, was correlated with immune-reactivity to markers of inflammation. Thrombin dependence of ratiometric fluorescence was tested by ex vivo application of RACPPNleTPRSFL and argatroban to cryosections from Day 1 STIA hindpaws.
RESULTS: In chronic arthritis, RACPPNleTPRSFL fluorescence ratios of Cy5:Cy7 em were significantly higher in diseased swollen ankles of K/BxN transgenic mice than in normal ankles. On Day 1 of STIA, high ratio RACPPNleTPRSFL fluorescence in ankles and toes correlated with subsequent joint swelling. Foci of high ratiometric fluorescence localized to inflammation, as demarcated by immune-reactivity for citrullinated histones, macrophages, mast cells and neutrophils, in soft tissue on Day 1 STIA. Ex vivo application of RACPPNleTPRSFL to Day 1 STIA cryosections produced ratiometric fluorescence that was inhibited by argatroban.
CONCLUSION: RACPPNleTPRSFL activation detects established experimental arthritis and the detection of inflammation by RACPPNleTPRSFL on Day 1 of STIA correlates with disease progression. This article is protected by copyright. All rights reserved.

PMID: 29164814 [PubMed - as supplied by publisher]

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