Released fibroblast growth factor18 from a collagen membrane induces osteoblastic activity involved with downregulation of miR-133a and miR-135a

J Biomater Appl. 2018 May;32(10):1382-1391. doi: 10.1177/0885328218763318. Epub 2018 Mar 15.


We have developed a unique delivery system of growth factors using collagen membranes (CMs) to induce bone regeneration. We hypothesized that fibroblast growth factor18 (FGF-18), a pleiotropic protein that stimulates proliferation in several tissues, can be a good candidate to use our delivery system for bone regeneration. Cell viability, cell proliferation, alkaline phosphatase activity, mineralization, and marker gene expression of osteoblastic differentiation were evaluated after mouse preosteoblasts were cultured with a CM containing FGF-18, a CM containing platelet-derived growth factor, or a CM alone. Furthermore, expression of microRNA, especially miR-133a and miR-135a involving inhibition of osteogenic factors, was measured in preosteoblasts with CM/FGF-18 or CM alone. A sustained release of FGF-18 from the CM was observed over 21 days. CM/FGF-18 significantly promoted cell proliferation, alkaline phosphatase activity, and mineralization compared to CM alone. Gene expression of type I collagen, runt-related transcription factor 2, osteocalcin, Smad5, and osteopontin was significantly upregulated in CM/FGF-18 compared to CM alone, and similar to CM/platelet-derived growth factor. Additionally, CM/FGF-18 downregulated expression of miR-133a and miR-135a. These results suggested that released FGF-18 from a CM promotes osteoblastic activity involved with downregulation of miR-133a and miR-135a.

Keywords: Fibroblast growth factor-18; bone regeneration; collagen membrane; microRNA; osteoblasts; signaling pathway.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Biocompatible Materials / chemistry*
  • Cell Line
  • Collagen / chemistry*
  • Down-Regulation / drug effects*
  • Drug Delivery Systems
  • Drug Liberation
  • Fibroblast Growth Factors / administration & dosage*
  • Fibroblast Growth Factors / pharmacology
  • Membranes, Artificial
  • Mice
  • MicroRNAs / genetics*
  • Osteoblasts / cytology
  • Osteoblasts / drug effects*
  • Osteoblasts / metabolism
  • Osteogenesis / drug effects


  • Biocompatible Materials
  • Membranes, Artificial
  • MicroRNAs
  • Mirn133 microRNA, mouse
  • Mirn135 microRNA, mouse
  • fibroblast growth factor 18
  • Fibroblast Growth Factors
  • Collagen