ACY‑1215, a HDAC6 inhibitor, decreases the dexamethasone‑induced suppression of osteogenesis in MC3T3‑E1 cells

Mol Med Rep. 2020 Sep;22(3):2451-2459. doi: 10.3892/mmr.2020.11319. Epub 2020 Jul 9.

Abstract

Glucocorticoid‑induced osteoporosis is the commonest form of drug‑induced osteoporosis. Histone deacetylase 6 (HDAC6) is involved in the differentiation from mesenchymal stem cells to osteoblasts. However, the role of ricolinostat (ACY‑1215, HDAC6 inhibitor) in the dexamethasone (Dex)‑induced proliferation and differentiation of preosteoblasts remains to be elucidated. The protein expression and mRNA expression levels of HDAC6, osteopontin (OPN), runt‑related transcription factor 2 (Runx2), osterix (Osx), collagen I (COL1A1) and glucocorticoid receptor (GR) in MC3T3‑E1 cells were analyzed by western blot analysis and reverse transcription‑quantitative PCR analysis. The cell viability was detected by CCK‑8 assay. The alkaline phosphatase (ALP) activity and capacity of mineralization was determined by ALP assay kit and alizarin red staining. HDAC6 expression was increased in patient serum and Dex‑induced MC3T3‑E1 cells at a certain concentration range; 1 µM Dex was selected for further experimentation. Cell viability was decreased after Dex induction and restored following ACY‑1215 treatment. The ALP activity and capability for mineralization was decreased when MC3T3‑E1 cells were induced by 1 µM Dex and was gradually improved by the treatment of ACY‑1215 at 1, 5 and 10 mM. The expression of OPN, Runx2, Osx and COL1A1 was similar, with the changes of capability for mineralization. Furthermore, GR expression was increased in Dex‑induced MC3T3‑E1 cells. ACY‑1215 promoted the GR expression in MC3T3‑E1 cells from 1‑5 mM while GR receptor expression was increased with 10 mM ACY‑1215 treatment. In conclusion, ACY‑1215 reversed the Dex‑induced suppression of proliferation and differentiation of MC3T3‑E1 cells.

Keywords: acY-1215; histone deacetylase 6 inhibitor; dexamethasone; osteogenesis.

MeSH terms

  • Adult
  • Animals
  • Case-Control Studies
  • Cell Differentiation / drug effects
  • Cell Line
  • Cell Proliferation / drug effects
  • Cell Survival / drug effects
  • Dexamethasone / adverse effects*
  • Disease Models, Animal
  • Female
  • Gene Expression Regulation / drug effects
  • Histone Deacetylase 6 / genetics
  • Histone Deacetylase 6 / metabolism*
  • Humans
  • Hydroxamic Acids / pharmacology*
  • Male
  • Mice
  • Middle Aged
  • Osteogenesis / drug effects
  • Osteoporosis / chemically induced
  • Osteoporosis / drug therapy*
  • Osteoporosis / genetics
  • Osteoporosis / metabolism
  • Pyrimidines / pharmacology*
  • Receptors, Glucocorticoid / genetics
  • Receptors, Glucocorticoid / metabolism*

Substances

  • Hydroxamic Acids
  • Pyrimidines
  • Receptors, Glucocorticoid
  • Dexamethasone
  • HDAC6 protein, human
  • Histone Deacetylase 6
  • ricolinostat