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Imiquimod Acts Synergistically with BMP9 through the Notch Pathway as an Osteoinductive Agent In Vitro.

  • Alverdy, Alexandria K1
  • Pakvasa, Mikhail
  • Zhao, Chen
  • Mostafa, Sami
  • Liu, Wei
  • Luo, Wenping
  • Wolf, Jennifer M
  • Ameer, Guillermo A
  • He, Tong-Chuan
  • Reid, Russell R
  • 1 North Chicago, Chicago, and Evanston, Ill.; and Chongqing, People's Republic of China From the Chicago Medical School, Rosalind Franklin University of Medicine and Science; the Department of Surgery, Laboratory of Craniofacial Biology and Development, Section of Plastic Surgery, and the Molecular Oncology Laboratory, Department of Orthopaedic Surgery and Rehabilitation Medicine, University of Chicago Medical Center; the Department of Orthopaedic Surgery and the Chongqing Key Laboratory for Oral Diseases and Biomedical Sciences, the Affiliated Hospitals of Chongqing Medical University; the Department of Biomedical Engineering, the Department of Surgery, Feinberg School of Medicine, and the Center for Advanced Regenerative Engineering, Northwestern University. , (China)
Published Article
Plastic and reconstructive surgery
Publication Date
Nov 01, 2019
DOI: 10.1097/PRS.0000000000006159
PMID: 31385892


Autologous bone grafts used for surgical reconstruction are limited by infection or insufficient supply of host material. Experimental agents that promote differentiation of stem cells into mature bone are currently being studied for future use in the repair of bone defects. The authors hypothesized that imiquimod, a synthetic immune response modifier, increases Notch pathway gene expression and acts synergistically with bone morphogenetic protein (BMP) 9 to induce differentiation of mesenchymal stem cells toward an osteogenic phenotype. Alkaline phosphatase activity was used to assess the osteogenic potential of cultured mouse immortalized multipotent adipose-derived cells (iMADs) treated with 0, 4, 6, and 8 μg/ml of imiquimod with and without BMP9. Adenoviral vectors expressing human BMP9 and a dominant-negative mutant of mouse Notch1 were used to assess BMP9 and Notch blockade on osteogenic activity, respectively. Expression of Notch signaling mediators and osteogenic markers were assayed by quantitative polymerase chain reaction. Alizarin red staining was used to assess the synergism between BMP9 and imiquimod. Imiquimod exposure enhanced osteogenic differentiation of iMADs by 2.8-fold (p < 0.001) and potentiated BMP9-induced osteogenic differentiation of iMADs by 1.6-fold (p < 0.001), shown by increased alkaline phosphatase activity and augmented matrix mineralization. Quantitative-real time polymerase chain reaction analysis demonstrated that imiquimod induced the expression of downstream genes (p < 0.01) of the Notch signaling pathway Hey1, Hey2, and Hes1, by increases of 9.7-, 22-, and 2.7-fold, respectively. These findings identify a novel role for imiquimod to shift mesenchymal stem cells toward an osteogenic phenotype. Imiquimod may be useful clinically when scaffolds are applied to treat bone defects.

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