Valproate reduces collagen and osteonectin in cultured bone cells

•The long-term side effects of valproate can include bone loss, although the exact mechanism for this is currently unknown.•Here we show that valproate treatment reduces collagen I and osteonectin in an osteoblast-like cell line.•Collagen I is the main protein in bone matrix and osteonectin has a major role in bone development and mineralisation.•Reduced levels of these proteins may contribute to bone loss following long-term in vivo exposure to valproate.

SummaryValproate is a histone deacetylase (HDAC) inhibitor that was introduced more than 40 years ago and is commonly used to treat epilepsy and mood disorders. Its long-term side effects can include bone loss, although the exact mechanism for this is currently unknown. In a previous study, we used iTRAQ labelling and mass spectrometry to profile the effect of valproate on skin fibroblast cells. We found, for the first time, that valproate reduced the amount of two key bone proteins; collagen I and osteonectin (SPARC, BM-40) while over 1000 other proteins remained unchanged (Fuller et al., 2010). We now show that valproate treatment also reduces the protein levels of collagen I and osteonectin in the hFOB1.19 osteoblast-like cell line. Pro-collagen I was reduced by 48% and osteonectin by 25% after 24 h exposure to a clinically-relevant concentration of valproate. Collagen I is the main protein component of bone matrix and osteonectin has a major role in bone development and mineralisation, so reduced levels may contribute to bone loss following long-term in vivo exposure to valproate.