title: Enhanced in vivo osteogenesis by nanocarrier-fused bone morphogenetic protein-4.
abstract: OBJECTIVE
  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.
  
  
  CONCLUSIONS
  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.
authors: Department of Orthopedic Surgery, Okayama University, Kita-ku, Okayama, Japan.
authors: Yasuyuki
authors: Y
authors: Shiozaki
authors: Takashi
authors: T
authors: Kitajima
authors: Tetsuro
authors: T
authors: Mazaki
authors: Aki
authors: A
authors: Yoshida
authors: Masato
authors: M
authors: Tanaka
authors: Akihiro
authors: A
authors: Umezawa
authors: Mariko
authors: M
authors: Nakamura
authors: Yasuhiro
authors: Y
authors: Yoshida
authors: Yoshihiro
authors: Y
authors: Ito
authors: Toshifumi
authors: T
authors: Ozaki
authors: Akihiro
authors: A
authors: Matsukawa
mesh_terms: D000818:Animals; D055415:Bone Morphogenetic Protein 4 / Q000008:administration & dosage / Q000737:chemistry / Q000235:genetics / Q000494:pharmacology*; D003094:Collagen / Q000378:metabolism; D004337:Drug Carriers / Q000008:administration & dosage / Q000737:chemistry*; D005260:Female; D005353:Fibronectins / Q000737:chemistry / Q000235:genetics / Q000494:pharmacology; D006651:Histocytochemistry; D006801:Humans; D051379:Mice; D053758:Nanoparticles / Q000008:administration & dosage / Q000737:chemistry*; D010012:Osteogenesis / Q000187:drug effects*; D011817:Rabbits; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000494:pharmacology; D012886:Skull / Q000293:injuries; D023822:Tissue Engineering / Q000379:methods*; D054457:Tissue Scaffolds
chemical_list: C525809:BMP4 protein, human; D055415:Bone Morphogenetic Protein 4; D004337:Drug Carriers; D005353:Fibronectins; D011993:Recombinant Fusion Proteins; D003094:Collagen
keywords: BMP4; bone repair; bone tissue engineering; osteogenesis
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