title: MCP/CCR2 signaling is essential for recruitment of mesenchymal progenitor cells during the early phase of fracture healing.
abstract: OBJECTIVE
  The purpose of this study was to investigate chemokine profiles and their functional roles in the early phase of fracture healing in mouse models.
  
  
  METHODS
  The expression profiles of chemokines were examined during fracture healing in wild-type (WT) mice using a polymerase chain reaction array and histological staining. The functional effect of monocyte chemotactic protein-1 (MCP-1) on primary mouse bone marrow stromal cells (mBMSCs) was evaluated using an in vitro migration assay. MCP-1-/- and C-C chemokine receptor 2 (CCR2)-/- mice were fractured and evaluated by histological staining and micro-computed tomography (micro-CT). RS102895, an antagonist of CCR2, was continuously administered in WT mice before or after rib fracture and evaluated by histological staining and micro-CT. Bone graft exchange models were created in WT and MCP-1-/- mice and were evaluated by histological staining and micro-CT.
  
  
  RESULTS
  MCP-1 and MCP-3 expression in the early phase of fracture healing were up-regulated, and high levels of MCP-1 and MCP-3 protein expression observed in the periosteum and endosteum in the same period. MCP-1, but not MCP-3, increased migration of mBMSCs in a dose-dependent manner. Fracture healing in MCP-1-/- and CCR2-/- mice was delayed compared with WT mice on day 21. Administration of RS102895 in the early, but not in the late phase, caused delayed fracture healing. Transplantation of WT-derived graft into host MCP-1-/- mice significantly increased new bone formation in the bone graft exchange models. Furthermore, marked induction of MCP-1 expression in the periosteum and endosteum was observed around the WT-derived graft in the host MCP-1-/- mouse. Conversely, transplantation of MCP-1-/- mouse-derived grafts into host WT mice markedly decreased new bone formation.
  
  
  CONCLUSIONS
  MCP-1/CCR2 signaling in the periosteum and endosteum is essential for the recruitment of mesenchymal progenitor cells in the early phase of fracture healing.
authors.affiliation: Department of Orthopaedic Surgery, Kyoto University Graduate School of Medicine, Kyoto, Japan; Department of the Control for Rheumatic Disease, Kyoto University Graduate School of Medicine, Kyoto, Japan.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Ishikawa
authors.affiliation: Department of Orthopaedic Surgery, Kyoto University Graduate School of Medicine, Kyoto, Japan.
authors.forename: Hiromu
authors.initials: H
authors.lastname: Ito
authors.affiliation: Department of Orthopaedic Surgery, Kyoto University Graduate School of Medicine, Kyoto, Japan.
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Kitaori
authors.affiliation: Department of Orthopaedic Surgery, Kyoto University Graduate School of Medicine, Kyoto, Japan.
authors.forename: Koichi
authors.initials: K
authors.lastname: Murata
authors.affiliation: Department of Orthopaedic Surgery, Kyoto University Graduate School of Medicine, Kyoto, Japan.
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Shibuya
authors.affiliation: Department of Orthopaedic Surgery, Kyoto University Graduate School of Medicine, Kyoto, Japan; Department of the Control for Rheumatic Disease, Kyoto University Graduate School of Medicine, Kyoto, Japan.
authors.forename: Moritoshi
authors.initials: M
authors.lastname: Furu
authors.affiliation: The Center for Innovation in Immunoregulative Technology and Therapeutics, Kyoto University Graduate School of Medicine, Kyoto, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Yoshitomi
authors.affiliation: Department of Orthopaedic Surgery, Kyoto University Graduate School of Medicine, Kyoto, Japan.
authors.forename: Takayuki
authors.initials: T
authors.lastname: Fujii
authors.affiliation: Center for the Promotion of Interdisciplinary Education and Research, Kyoto University, Kyoto, Japan.
authors.forename: Koji
authors.initials: K
authors.lastname: Yamamoto
authors.affiliation: Department of Orthopaedic Surgery, Kyoto University Graduate School of Medicine, Kyoto, Japan.
authors.forename: Shuichi
authors.initials: S
authors.lastname: Matsuda
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000235:genetics / Q000378:metabolism*; D017102:Fracture Healing; D059630:Mesenchymal Stem Cells / Q000166:cytology*; D051379:Mice; D018345:Mice, Knockout; D060888:Real-Time Polymerase Chain Reaction; D054390:Receptors, CCR2 / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology*
chemical_list: C515335:Ccr2 protein, mouse; D018932:Chemokine CCL2; D054390:Receptors, CCR2