Drug therapy targeting pyrophosphate slows the ossification of spinal ligaments in twy mice.
In: Journal of orthopaedic research : official publication of the Orthopaedic Research Society, Jg. 36 (2018-04-01), Heft 4, S. 1256-1261
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Zugriff:
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-specific 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 Enpp1 ttw/ttw (twy) mouse model. Twenty male twy mice were randomized into four groups: (i) vehicle (Control); (ii) alkaline phosphatase inhibitor levamisole (5 mg/kg/day sc continuously); (iii) levamisole + exogenous PPi (160 µmol/kg/day sc continuously); and (iv) nuclear retinoic acid receptor-γ (RARγ) agonist (6 µg/kg sc daily). The RARγ 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-computed 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-treated mice. The development of OSL in twy mice was suppressed by levamisole + PPi and RARγ agonist treatments, but not by levamisole alone. The levamisole + PPi therapy did not cause osteoporosis, whereas RARγ agonist-treated 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. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:1256-1261, 2018.
(© 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc.)
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Drug therapy targeting pyrophosphate slows the ossification of spinal ligaments in twy mice.
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Autor/in / Beteiligte Person: | Hiratsuka, S ; Takahata, M ; Shimizu, T ; Hamano, H ; Ota, M ; Sato, D ; Iwasaki, N |
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Zeitschrift: | Journal of orthopaedic research : official publication of the Orthopaedic Research Society, Jg. 36 (2018-04-01), Heft 4, S. 1256-1261 |
Veröffentlichung: | 2006- : Hoboken, NJ : Wiley ; <i>Original Publication</i>: New York, N.Y. : Raven Press, [c1983-, 2018 |
Medientyp: | academicJournal |
ISSN: | 1554-527X (electronic) |
DOI: | 10.1002/jor.23743 |
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