Format

Send to

Choose Destination
PLoS One. 2014 Aug 18;9(8):e104954. doi: 10.1371/journal.pone.0104954. eCollection 2014.

MCP/CCR2 signaling is essential for recruitment of mesenchymal progenitor cells during the early phase of fracture healing.

Author information

1
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.
2
Department of Orthopaedic Surgery, Kyoto University Graduate School of Medicine, Kyoto, Japan.
3
The Center for Innovation in Immunoregulative Technology and Therapeutics, Kyoto University Graduate School of Medicine, Kyoto, Japan.
4
Center for the Promotion of Interdisciplinary Education and Research, Kyoto University, Kyoto, Japan.

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.

PMID:
25133509
PMCID:
PMC4136826
DOI:
10.1371/journal.pone.0104954
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Public Library of Science Icon for PubMed Central
Loading ...
Support Center