title: Inhibition of miR-92a enhances fracture healing via promoting angiogenesis in a model of stabilized fracture in young mice.
abstract: MicroRNAs (miRNAs) are endogenous small noncoding RNAs regulating the activities of target mRNAs and cellular processes. Although no miRNA has been reported to play an important role in the regulation of fracture healing, several miRNAs control key elements in tissue repair processes such as inflammation, hypoxia response, angiogenesis, stem cell differentiation, osteogenesis, and chondrogenesis. We compared the plasma concentrations of 134 miRNAs in 4 patients with trochanteric fractures and 4 healthy controls (HCs), and the levels of six miRNAs were dysregulated. Among these miRNAs, miR-92a levels were significantly decreased 24 hours after fracture, compared to HCs. In patients with a trochanteric fracture or a lumbar compression fracture, the plasma concentrations of miR-92a were lower on days 7 and 14, but had recovered on day 21 after the surgery or injury. To determine whether systemic downregulation of miR-92a can modulate fracture healing, we administered antimir-92a, designed using locked nucleic acid technology to inhibit miR-92a, to mice with a femoral fracture. Systemic administration of antimir-92a twice a week increased the callus volume and enhanced fracture healing. Enhancement of fracture healing was also observed after local administration of antimir-92a. Neovascularization was increased in mice treated with antimir-92a. These results suggest that plasma miR-92a plays a crucial role in bone fracture healing in human and that inhibition of miR-92a enhances fracture healing through angiogenesis and has therapeutic potential for bone repair.
authors.affiliation: Department of Orthopaedic Surgery, Kyoto University Graduate School of Medicine, Kyoto, Japan.
authors.forename: Koichi
authors.initials: K
authors.lastname: Murata
authors.forename: Hiromu
authors.initials: H
authors.lastname: Ito
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Yoshitomi
authors.forename: Koji
authors.initials: K
authors.lastname: Yamamoto
authors.forename: Akinobu
authors.initials: A
authors.lastname: Fukuda
authors.forename: Junsuke
authors.initials: J
authors.lastname: Yoshikawa
authors.forename: Moritoshi
authors.initials: M
authors.lastname: Furu
authors.forename: Masahiro
authors.initials: M
authors.lastname: Ishikawa
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Shibuya
authors.forename: Shuichi
authors.initials: S
authors.lastname: Matsuda
mesh_terms: D000818:Animals; D005260:Female; D005264:Femoral Fractures / Q000097:blood* / Q000188:drug therapy / Q000473:pathology; D017102:Fracture Healing; D006801:Humans; D008159:Lumbar Vertebrae / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D035683:MicroRNAs / Q000037:antagonists & inhibitors* / Q000097:blood; D018919:Neovascularization, Physiologic; D016372:RNA, Antisense / Q000494:pharmacology*; D016103:Spinal Fractures / Q000097:blood* / Q000188:drug therapy / Q000473:pathology
chemical_list: C541874:MIRN92 microRNA, human; D035683:MicroRNAs; C541873:Mirn92 microRNA, mouse; D016372:RNA, Antisense
keywords: ANGIOGENESIS; BIOMARKER; FRACTURE HEALING; LOCKED NUCLEIC ACID; MICRORNA