Valproate and bone loss: iTRAQ proteomics show that valproate reduces collagens and osteonectin in SMA cells.
Valproate is commonly used as an anticonvulsant and mood stabilizer, but its long-term side-effects can include bone loss. As a histone deacetylase (HDAC) inhibitor, valproate has also been considered for treatment of spinal muscular atrophy (SMA). Using iTRAQ labeling technology, followed by two-dimensional liquid chromatography and mass spectrometry analysis, a quantitative comparison of the proteome of an SMA cell line, with and without valproate treatment, was performed. The most striking change was a reduction in collagens I and VI, while over 1000 other proteins remained unchanged. The collagen I alpha-chain precursor was also reduced by more than 50% suggesting that valproate affects collagen I synthesis. The collagen-binding glycoprotein, osteonectin (SPARC, BM-40) was one of the few other proteins that were significantly reduced by valproate treatment. Collagen I is the main protein component of bone matrix and osteonectin has a major role in bone development, so the results suggest a possible molecular mechanism for bone loss following long-term exposure to valproate. SMA patients may already suffer bone weakness as a result of SMN1 gene deletion, so further bone loss would be undesirable.
Fuller
Heidi R
HR
Wolfson Centre for Inherited Neuromuscular Disease, RJAH Orthopaedic Hospital, Oswestry, UK.
Man
Nguyen Thi
NT
Lam
Le Thanh
le T
Shamanin
Vladimir A
VA
Androphy
Elliot J
EJ
Morris
Glenn E
GE
D001851:Bone Diseases, Metabolic / Q000139:chemically induced*; D002853:Chromatography, Liquid; D003094:Collagen / Q000378:metabolism*; D004591:Electrophoresis, Polyacrylamide Gel; D005347:Fibroblasts / Q000378:metabolism; D056572:Histone Deacetylase Inhibitors / Q000009:adverse effects*; D006801:Humans; D007150:Immunohistochemistry; D013058:Mass Spectrometry; D009134:Muscular Atrophy, Spinal / Q000188:drug therapy*; D015676:Osteonectin / Q000378:metabolism*; D040901:Proteomics / Q000379:methods*; D012867:Skin / Q000166:cytology; D014635:Valproic Acid / Q000009:adverse effects*
D056572:Histone Deacetylase Inhibitors; D015676:Osteonectin; D014635:Valproic Acid; D003094:Collagen