Curcumin induces osteoblast differentiation through mild-endoplasmic reticulum stress-mediated such as BMP2 on osteoblast cells

Life Sci. 2018 Jan 15;193:34-39. doi: 10.1016/j.lfs.2017.12.008. Epub 2017 Dec 6.


Aims: Curcumin (diferuloylmethane or [1E,6E]-1,7-bis[4-hydroxy-3-methoxyphenyl]-1,6heptadiene-3,5-dione) is a phenolic natural product derived from the rhizomes of the turmeric plant, Curcuma longa. It is reported to have various biological actions such as anti-oxidative, anti-inflammatory, and anti-cancer effects. However, the molecular mechanism of osteoblast differentiation by curcumin has not yet been reported.

Main methods: The cytotoxicity of curcumin was identified using the 3-(4,5-dimethylthiazol-2yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Expression of osteogenic markers and endoplasmic reticulum (ER) stress markers in C3H1-T1/2 cells were measured using reverse-transcriptase polymerase chain reaction (RT-PCR) and Western blotting. Alkaline phosphatase (ALP) staining was performed to assess ALP activity in C3H10T1/2 cells. Transcriptional activity was detected using a luciferase reporter assay.

Key findings: Curcumin increased the expression of genes such as distal-less homeobox 5 (Dlx5), runt-related transcription factor 2 (Runx2), ALP, and osteocalcin (OC), which subsequently induced osteoblast differentiation in C3H10T1/2 cells. In addition, ALP activity and mineralization was found to be increased by curcumin treatment. Curcumin also induced mild ER stress similar to bone morphogenetic protein 2 (BMP2) function in osteoblast cells. Next, we confirmed that curcumin increased mild ER stress and osteoblast differentiation similar to BMP2 in C3H10T1/2 mesenchymal stem cells. Transient transfection studies also showed that curcumin increased ATF6-Luc activity, while decreasing the activities of CREBH-Luc and SMILE-Luc. In addition, similar to BMP2, curcumin induced the phosphorylation of Smad 1/5/9.

Significance: Overall, these results demonstrate that curcumin-induced mild ER stress increases osteoblast differentiation via ATF6 expression in C3H10T1/2 cells.

Keywords: BMP2; Curcumin; Mild ER stress; Osteoblast differentiation.

MeSH terms

  • Activating Transcription Factor 6 / drug effects
  • Activating Transcription Factor 6 / metabolism
  • Animals
  • Bone Morphogenetic Protein 2 / metabolism
  • Cell Differentiation / drug effects
  • Cell Line
  • Cells, Cultured
  • Core Binding Factor Alpha 1 Subunit / metabolism
  • Curcumin / chemistry
  • Curcumin / metabolism*
  • Curcumin / pharmacology
  • Endoplasmic Reticulum / metabolism
  • Endoplasmic Reticulum Stress / physiology
  • Humans
  • Mesenchymal Stem Cells / cytology
  • Mice
  • Osteoblasts / drug effects*
  • Osteocalcin / metabolism
  • Osteogenesis / drug effects
  • Phosphorylation
  • Signal Transduction / drug effects


  • ATF6 protein, human
  • Activating Transcription Factor 6
  • BMP2 protein, human
  • Bone Morphogenetic Protein 2
  • Core Binding Factor Alpha 1 Subunit
  • RUNX2 protein, human
  • Osteocalcin
  • Curcumin