Prevention of bone growth defects, increased bone resorption and marrow adiposity with folinic acid in rats receiving long-term methotrexate

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dc.contributor.authorFan, C.
dc.contributor.authorFoster, B.
dc.contributor.authorHui, S.
dc.contributor.authorXian, C.
dc.contributor.editorHeymann, D.
dc.date.issued2012
dc.description.abstractThe underlying pathophysiology for bone growth defects in paediatric cancer patients receiving high dose methotrexate chemotherapy remains unclear and currently there are no standardized preventative treatments for patients and survivors. Using a model in young rats, we investigated damaging effects of long-term treatment with methotrexate on growth plate and metaphyseal bone, and the potential protective effects of antidote folinic acid. This study demonstrated that chronic folinic acid supplementation can prevent methotrexate-induced chondrocyte apoptosis and preserve chondrocyte columnar arrangement and number in the growth plate. In the metaphysis, folinic acid supplementation can preserve primary spongiosa heights and secondary spongiosa trabecular volume by preventing osteoblasts from undergoing apoptosis and suppressing methotrexate-induced marrow adiposity and osteoclast formation. Systemically, plasma of folinic acid supplemented rats, in comparison to plasma from rats treated with MTX alone, contained a significantly lower level of IL-1b and suppressed osteoclast formation in vitro in normal bone marrow cells. The importance of IL-1b in supporting plasma-induced osteoclast formation was confirmed as the presence of an anti-IL-1b neutralizing antibody attenuated the ability of the plasma (from MTX-treated rats) in inducing osteoclast formation. Findings from this study suggest that folinic acid supplementation during chronic methotrexate treatment can alleviate growth plate and metaphyseal damages and therefore may be potentially useful in paediatric patients who are at risk of skeletal growth suppression due to chronic methotrexate chemotherapy.
dc.description.statementofresponsibilityChia-Ming Fan, Bruce K. Foster, Susanta K. Hui and Cory J. Xian
dc.identifier.citationPLoS One, 2012; 7(10):1-12
dc.identifier.doi10.1371/journal.pone.0046915
dc.identifier.issn1932-6203
dc.identifier.issn1932-6203
dc.identifier.orcidXian, C. [0000-0002-8467-2845]
dc.identifier.urihttp://hdl.handle.net/2440/74989
dc.language.isoen
dc.publisherPublic Library of Science
dc.rights© 2012 Fan et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
dc.source.urihttps://doi.org/10.1371/journal.pone.0046915
dc.subjectFemur
dc.subjectChondrocytes
dc.subjectOsteoclasts
dc.subjectOsteoblasts
dc.subjectBone Marrow
dc.subjectAnimals
dc.subjectHumans
dc.subjectRats
dc.subjectRats, Sprague-Dawley
dc.subjectBone Resorption
dc.subjectMethotrexate
dc.subjectLeucovorin
dc.subjectVitamin B Complex
dc.subjectAntimetabolites, Antineoplastic
dc.subjectCytokines
dc.subjectReverse Transcriptase Polymerase Chain Reaction
dc.subjectApoptosis
dc.subjectGene Expression
dc.subjectOsteogenesis
dc.subjectChild
dc.subjectMale
dc.subjectAdiposity
dc.subjectRANK Ligand
dc.subjectPrecursor Cell Lymphoblastic Leukemia-Lymphoma
dc.subjectX-Ray Microtomography
dc.titlePrevention of bone growth defects, increased bone resorption and marrow adiposity with folinic acid in rats receiving long-term methotrexate
dc.typeJournal article
pubs.publication-statusPublished

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