title: Anti-epileptic drugs and bone loss: Phenytoin reduces pro-collagen I and alters the electrophoretic mobility of osteonectin in cultured bone cells.
abstract: Phenytoin is an antiepileptic drug used in the management of partial and tonic-clonic seizures. In previous studies we have shown that valproate, another antiepileptic drug, reduced the amount of two key bone proteins, pro-collagen I and osteonectin (SPARC, BM-40), in both skin fibroblasts and cultured osteoblast-like cells. Here we show that phenytoin also reduces pro-collagen I production in osteoblast-like cells, but does not appear to cause a decrease in osteonectin message or protein production. Instead, a 24h exposure to a clinically relevant concentration of phenytoin resulted in a dose-dependent change in electrophoretic mobility of osteonectin, which was suggestive of a change in post-translational modification status. The perturbation of these important bone proteins could be one of the mechanisms to explain the bone loss that has been reported following long-term treatment with phenytoin.
authors.affiliation: Wolfson Centre for Inherited Neuromuscular Disease, RJAH Orthopaedic Hospital, Oswestry SY10 7AG, United Kingdom.
authors.forename: Emma L
authors.initials: EL
authors.lastname: Wilson
authors.affiliation: Rheumatology Department, RJAH Orthopaedic NHS Foundation Trust SY10 7AG, United Kingdom.
authors.forename: Mark
authors.initials: M
authors.lastname: Garton
authors.affiliation: Wolfson Centre for Inherited Neuromuscular Disease, RJAH Orthopaedic Hospital, Oswestry SY10 7AG, United Kingdom; Institute for Science and Technology in Medicine, Keele University, United Kingdom. Electronic address: h.r.fuller@keele.ac.uk.
authors.forename: Heidi R
authors.initials: HR
authors.lastname: Fuller
mesh_terms: D000818:Animals; D000927:Anticonvulsants / Q000633:toxicity*; D015153:Blotting, Western; D001842:Bone and Bones / Q000187:drug effects / Q000378:metabolism; D002220:Carbamazepine / Q000633:toxicity; D002460:Cell Line; D024042:Collagen Type I / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004591:Electrophoresis, Polyacrylamide Gel; D005455:Fluorescent Antibody Technique; D005632:Fructose / Q000031:analogs & derivatives; D020869:Gene Expression Profiling; D000077213:Lamotrigine; D000077287:Levetiracetam; D018613:Microscopy, Confocal; D010006:Osteoblasts / Q000187:drug effects* / Q000378:metabolism; D015676:Osteonectin / Q000378:metabolism*; D010672:Phenytoin / Q000633:toxicity*; D010889:Piracetam / Q000031:analogs & derivatives / Q000633:toxicity; D011347:Procollagen / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction; D000077236:Topiramate; D014227:Triazines / Q000633:toxicity; D014635:Valproic Acid / Q000633:toxicity
chemical_list: D000927:Anticonvulsants; D024042:Collagen Type I; D015676:Osteonectin; D011347:Procollagen; D014227:Triazines; D000077236:Topiramate; D005632:Fructose; D002220:Carbamazepine; D000077287:Levetiracetam; D014635:Valproic Acid; D010672:Phenytoin; D000077213:Lamotrigine; D010889:Piracetam
keywords: AEDs; Anti-epileptic drugs; Bone; Collagen; Osteonectin; Phenytoin; SPARC; Valproate