Abstract
ObjectiveThe purpose of this study was to investigate chemokine profiles and their functional roles in the early phase of fracture healing in mouse models.MethodsThe 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.ConclusionsMCP-1/CCR2 signaling in the periosteum and endosteum is essential for the recruitment of mesenchymal progenitor cells in the early phase of fracture healing.
Highlights
The prevalence of osteoporosis is increasing with the aging of society
We have previously demonstrated in a bone graft model that stromal cell-derived factor-1 (SDF-1) is induced in the periosteum of fracture sites and promotes endochondral bone repair by recruiting C-X-C chemokine receptor 4 (CXCR4)-expressing mesenchymal stem/progenitor cells [23]
We demonstrate that the expression level of monocyte chemotactic protein-1 (MCP-1) is upregulated exclusively in the early fracture phase and that MCP-1 is expressed at the periosteum and endosteum of the fractured bones
Summary
Osteoporotic fractures are a major public health problem with a low one-year patient’s survival rate [1,2]. Management of the fracture is difficult because of poor bone quality, and there is a high risk of fixation failure and nonunion. To avoid these difficulties, numerous attempts have been made to develop techniques to improve fracture healing, including addition or injection of bone-forming factors or cells such as mesenchymal stem/progenitor cells [3,4]. One major reason is that the mechanisms responsible for fracture healing are complex and not fully understood. Elucidating the mechanisms involved in fracture healing is fundamental to developing novel therapeutic strategies to improve fracture healing
Sign-in/Register to view highlights & summary 
Published Version (
Free)
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call