Valproate and Bone Loss: iTRAQ Proteomics Show that Valproate Reduces Collagens and Osteonectin in SMA Cells

• Published in: Journal of proteome research 2010-08, Vol.9 (8), p.4228-4233
• Main Authors: Fuller, Heidi R, Man, Nguyen Thi, Lam, Le Thanh, Shamanin, Vladimir A, Androphy, Elliot J, Morris, Glenn E
• Format: Article
• Language: English
• Subjects: Bone Diseases, Metabolic - chemically induced; Chromatography, Liquid; Collagen - metabolism; Electrophoresis, Polyacrylamide Gel; Fibroblasts - metabolism; Histone Deacetylase Inhibitors - adverse effects; Humans; Immunohistochemistry; Mass Spectrometry; Muscular Atrophy, Spinal - drug therapy; Osteonectin - metabolism; Proteomics - methods; Skin - cytology; Valproic Acid - adverse effects
• ISSN: 1535-3893; 1535-3907
• DOI: 10.1021/pr1005263

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.