title: Tranexamic acid, an inhibitor of plasminogen activation, reduces urinary collagen cross-link excretion in both experimental and rheumatoid arthritis.
abstract: The plasminogen activation system is one of the enzyme systems held responsible for bone and cartilage degradation in rheumatoid arthritis (RA). In this study, we evaluated the effect of tranexamic acid (TEA), an inhibitor of plasminogen activation, on urinary collagen cross-link excretion and radiological joint damage in rat adjuvant arthritis (AA) and on urinary collagen cross-link excretion in patients with RA. In the animal study, adjuvant arthritis was induced in male Lewis rats. From day 7 onward, high-dose TEA (500 mg/kg body weight, once daily) or placebo was administered orally. Study groups consisted of TEA-treated normal rats (C + TEA), placebo-treated normal rats (C + plac), AA rats treated with TEA (AA + TEA) or with placebo (AA + plac). To monitor joint destruction, urinary collagen cross-link excretion (pyridinoline, HP; deoxypyridinoline, LP) was measured by high-performance liquid chromatography at days 14 and 21. Radiological evaluation of joints was performed at day 21. In the patient study, TEA was administered to nine patients with RA as adjuvant medication (approximately 20 mg/kg body weight, three times daily) for 12 weeks. Urinary HP and LP excretion levels were measured before and during TEA treatment, and 4 weeks after the cessation of TEA treatment. In AA + TEA rats, a significant reduction of HP and a tendency towards a reduction of LP excretion were found compared with AA + plac rats (P < 0.05), at day 14, whereas the HP/LP ratio did not change. No difference was observed in HP, LP excretion, HP/LP ratio and radiological damage score between the TEA- and placebo-treated AA rats at day 21. In RA patients, a significant reduction of HP and LP excretion was found during the TEA treatment period (P < 0.05). After the cessation of TEA treatment, HP and LP excretion increased towards baseline levels. No effect on disease activity was observed. The plasmin antagonist TEA reduced the excretion of collagen pyridinoline cross-links in both experimental and rheumatoid arthritis. As such, this study not only supports the involvement of the plasminogen activation system in the destructive phase of arthritis, but also suggests a beneficial effect of therapeutic strategies directed against inhibition of matrix proteolysis.
authors.affiliation: Gaubius Laboratory, TNO Prevention and Health, Leiden, The Netherlands.
authors.forename: H K
authors.initials: HK
authors.lastname: Ronday
authors.forename: J M
authors.initials: JM
authors.lastname: Te Koppele
authors.forename: R A
authors.initials: RA
authors.lastname: Greenwald
authors.forename: S A
authors.initials: SA
authors.lastname: Moak
authors.forename: J A
authors.initials: JA
authors.lastname: De Roos
authors.forename: B A
authors.initials: BA
authors.lastname: Dijkmans
authors.forename: F C
authors.initials: FC
authors.lastname: Breedveld
authors.forename: J H
authors.initials: JH
authors.lastname: Verheijen
mesh_terms: D000596:Amino Acids / Q000652:urine; D000818:Animals; D000933:Antifibrinolytic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001168:Arthritis / Q000139:chemically induced / Q000000981:diagnostic imaging / Q000188:drug therapy / Q000652:urine*; D001172:Arthritis, Rheumatoid / Q000188:drug therapy / Q000652:urine*; D015415:Biomarkers / Q000652:urine; D003094:Collagen / Q000652:urine*; D006801:Humans; D008297:Male; D011859:Radiography; D051381:Rats; D011917:Rats, Inbred Lew; D013997:Time Factors; D014148:Tranexamic Acid / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D000596:Amino Acids; D000933:Antifibrinolytic Agents; D015415:Biomarkers; C015484:pyridinoline; D014148:Tranexamic Acid; C036020:deoxypyridinoline; D003094:Collagen