Enhanced in vivo osteogenesis by nanocarrier-fused bone morphogenetic protein-4

Yasuyuki Shiozaki, Takashi Kitajima, Tetsuro Mazaki, Aki Yoshida, Masato Tanaka, Akihiro Umezawa, Mariko Nakamura, Yasuhiro Yoshida, Yoshihiro Ito, Toshifumi Ozaki, Akihiro Matsukawa

Research output: Contribution to journalArticle

22 Citations (Scopus)

Abstract

Purpose: Bone defects and nonunions are major clinical skeletal problems. Growth factors are commonly used to promote bone regeneration; however, the clinical impact is limited because the factors do not last long at a given site. The introduction of tissue engineering aimed to deter the diffusion of these factors is a promising therapeutic strategy. The purpose of the present study was to evaluate the in vivo osteogenic capability of an engineered bone morphogenetic protein-4 (BMP4) fusion protein. Methods: BMP4 was fused with a nanosized carrier, collagen-binding domain (CBD), derived from fibronectin. The stability of the CBD-BMP4 fusion protein was examined in vitro and in vivo. Osteogenic effects of CBD-BMP4 were evaluated by computer tomography after intramedullary injection without a collagen-sponge scaffold. Recombinant BMP-4, CBD, or vehicle were used as controls. Expressions of bone-related genes and growth factors were compared among the groups. Osteogenesis induced by CBD-BMP4, BMP4, and CBD was also assessed in a bone-defect model. Results: In vitro, CBD-BMP4 was retained in a collagen gel for at least 7 days while BMP4 alone was released within 3 hours. In vivo, CBD-BMP4 remained at the given site for at least 2 weeks, both with or without a collagen-sponge scaffold, while BMP4 disappeared from the site within 3 days after injection. CBD-BMP4 induced better bone formation than BMP4 did alone, CBD alone, and vehicle after the intramedullary injection into the mouse femur. Bone-related genes and growth factors were expressed at higher levels in CBD-BMP4-treated mice than in all other groups, including BMP4-treated mice. Finally, CBD-BMP4 potentiated more bone formation than did controls, including BMP4 alone, when applied to cranial bone defects without a collagen scaffold. Conclusion: Altogether, nanocarrier-CBD enhanced the retention of BMP4 in the bone, thereby promoting augmented osteogenic responses in the absence of a scaffold. These results suggest that CBD-BMP4 may be clinically useful in facilitating bone formation.

Original languageEnglish
Pages (from-to)1349-1360
Number of pages12
JournalInternational journal of nanomedicine
Volume8
DOIs
Publication statusPublished - Apr 8 2013

Keywords

  • BMP4
  • Bone repair
  • Bone tissue engineering
  • Osteogenesis

ASJC Scopus subject areas

  • Biophysics
  • Bioengineering
  • Biomaterials
  • Pharmaceutical Science
  • Drug Discovery
  • Organic Chemistry

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  • Cite this

    Shiozaki, Y., Kitajima, T., Mazaki, T., Yoshida, A., Tanaka, M., Umezawa, A., Nakamura, M., Yoshida, Y., Ito, Y., Ozaki, T., & Matsukawa, A. (2013). Enhanced in vivo osteogenesis by nanocarrier-fused bone morphogenetic protein-4. International journal of nanomedicine, 8, 1349-1360. https://doi.org/10.2147/IJN.S44124