{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,4]],"date-time":"2026-03-04T16:47:55Z","timestamp":1772642875629,"version":"3.50.1"},"reference-count":21,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2017,10,9]],"date-time":"2017-10-09T00:00:00Z","timestamp":1507507200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Journal Orthopaedic Research"],"published-print":{"date-parts":[[2018,4]]},"abstract":"<jats:title>ABSTRACT<\/jats:title><jats:sec><jats:label\/><jats:p>The lack of an effective drug therapy against ossification of spinal ligament (OSL) warrants investigation into the therapeutic target of this disease. An endogenous inhibitor of biomineralization, pyrophosphate (PPi) is a potential therapy for ectopic ossification; however, exogenous PPi is rapidly hydrolyzed by tissue non\u2010specific alkaline phosphatase (TNAP) present in body fluids. In this study, we examined whether a drug therapy targeting PPi is efficacious for the treatment of OSL using the <jats:italic>Enpp1<jats:sup>ttw\/ttw<\/jats:sup><\/jats:italic> (twy) mouse model. Twenty male twy mice were randomized into four groups: (i) vehicle (Control); (ii) alkaline phosphatase inhibitor levamisole (5\u2009mg\/kg\/day sc continuously); (iii) levamisole\u2009+\u2009exogenous PPi (160\u2009\u00b5mol\/kg\/day sc continuously); and (iv) nuclear retinoic acid receptor\u2010\u03b3 (RAR\u03b3) agonist (6\u2009\u00b5g\/kg sc daily). The RAR\u03b3 agonist, which is a proven inhibitor of ectopic endochondral ossification, was used as a positive control. Treatments commenced when the mice were 5 weeks of age and continued for 4 weeks. Longitudinal micro\u2010computed tomography and postmortem histological analysis were performed. Administration of levamisole alone and in combination with PPi increased serum PPi concentration by 17% and 52%, respectively, compared to that in vehicle\u2010treated mice. The development of OSL in twy mice was suppressed by levamisole\u2009+\u2009PPi and RAR\u03b3 agonist treatments, but not by levamisole alone. The levamisole\u2009+\u2009PPi therapy did not cause osteoporosis, whereas RAR\u03b3 agonist\u2010treated mice developed osteoporosis. Treatment of twy mice with levamisole in combination with exogenous PPi increased serum PPi level, which slowed the progression of OSL without producing adverse effect on bone. \u00a9 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. 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