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Given the intersection of inflammation with coagulation protease activation, this study was undertaken to examine coagulation protease activities in arthritic mice with a dual\u2010fluorescence ratiometric activatable cell\u2010penetrating peptide (RACPP) that has a linker, norleucine (Nle)\u2010TPRSFL, with a cleavage site for thrombin.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>K\/BxN\u2010transgenic mice with chronic arthritis and mice with day 1 passive serum\u2010transfer arthritis were imaged in\u00a0vivo for Cy5:Cy7 emission ratiometric fluorescence from proteolytic cleavage and activation of RACPP<jats:sub>NleTPRSFL<\/jats:sub>. Joint thickness in mice with serum\u2010transfer arthritis was measured from days 0 to 10. The cleavage\u2010evoked release of Cy5\u2010tagged tissue\u2010adhesive fragments enabled microscopic correlation with immunohistochemistry for inflammatory markers. Thrombin dependence of ratiometric fluorescence was tested by ex\u00a0vivo application of RACPP<jats:sub>NleTPRSFL<\/jats:sub> and argatroban to cryosections obtained from mouse hind paws on day 1 of serum\u2010transfer arthritis.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>In chronic arthritis, RACPP<jats:sub>NleTPRSFL<\/jats:sub> fluorescence ratios of Cy5:Cy7 emission were significantly higher in diseased swollen ankles of K\/BxN\u2010transgenic mice than in normal mouse ankles. A high ratio of RACPP<jats:sub>NleTPRSFL<\/jats:sub> fluorescence in mouse ankles and toes on day 1 of serum\u2010transfer arthritis 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 of serum\u2010transfer arthritis. Ex vivo application of RACPP<jats:sub>NleTPRSFL<\/jats:sub> to cryosections obtained from mice on day 1 of serum\u2010transfer arthritis produced ratiometric fluorescence that was inhibited by argatroban.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>RACPP<jats:sub>NleTPRSFL<\/jats:sub> activation detects established experimental arthritis, and the detection of inflammation by RACPP<jats:sub>NleTPRSFL<\/jats:sub> on day 1 of serum\u2010transfer arthritis correlates with disease progression.<\/jats:p><\/jats:sec>","DOI":"10.1002\/art.40316","type":"journal-article","created":{"date-parts":[[2017,11,22]],"date-time":"2017-11-22T00:02:56Z","timestamp":1511308976000},"page":"69-79","source":"Crossref","is-referenced-by-count":4,"title":["Detection of Subclinical Arthritis in Mice by a Thrombin\u00a0Receptor\u2013Derived Imaging 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