CXCL12/CXCR4 signaling and other recruitment and homing pathways in fracture repair

Abstract

Cell recruitment, migration and homing to the fracture site are essential for the inflammatory process, neovascularization, chondrogenesis, osteogenesis and ultimately bone remodeling. Mesenchymal stem cells (MSCs) are required to navigate from local sources such as the periosteum and local bone marrow, and may also be recruited from the circulation and distant bone marrow. While the local recruitment process may involve matrix binding and degradation, systemic recruitment may utilize extravasation, a process used by leukocytes to exit the vasculature. CXCL12 (stromal cell-derived factor-1 (SDF-1)), a member of the CXC family of chemokines, is thought to have an important role in cell migration at the fracture site. However, there are many molecules upregulated in the hematoma and callus that have chemotactic potential not only for inflammatory cells but also for endothelial cells and MSCs. Surprisingly, there is little direct data to support their role in cell homing during bone healing. Current therapeutics for bone regeneration utilize local or systemic stem cell transplantation. More recently, a novel strategy that involves mobilization of large numbers of endogenous stem and progenitor cells from bone marrow into the circulation has been shown to have positive effects on bone healing. A more complete understanding of the molecular mechanisms underlying cell recruitment and homing subsequent to fracture will facilitate the fine-tuning of such strategies for bone.

Bone Marrow Cell Trafficking Analyzed by 89Zr-oxine Positron Emission Tomography in a Murine Transplantation Model

“…Endothelial cells, osteoblasts and reticular cells produce CXCL12 in these organs (25). We observed that the CXCR4 blockade with plerixafor (12) prevented the homing of cells to the BM and the effect lasted longer when G-CSF was co-administered (Fig.…”

BMP2 Regulation of CXCL12 Cellular, Temporal, and Spatial Expression Is Essential During Fracture Repair

“…There is some evidence for the action of CXCL12 on the skeletal system in inducing chondrocyte hypertrophy and BMP-dependent osteoblastic differentiation of progenitors, (23,33,34) as well as cell recruitment in bone injuries. (38,39) An appropriate control of CXCL12 expression appears critical, in fact, long-term continuous treatment before fracture or load-induced bone formation can inhibit bone production. (40,41) We identified the temporally regulated expression pattern of CXCL12 and showed that it is initially induced by the fracture event and then decreases with the progression of the repair process.…”

Role of Mesenchymal Stem Cells in Bone Regenerative Medicine: What Is the Evidence?

“…In addition, hypoxia by the expression of the hypoxia-inducible factor 1-α (HIF-1α) subunit transcription factor may induce the upregulation of SDF1 and ultimately regulate the homing of progenitor cells. The SDF1/CXCR4 (CXC chemokine receptor R4) axis is thought to be a master mediator of MSC recruitment and migration [Yellowley, 2013]. Because of the hypoxic condition at the injured (fracture) site, it is possible that the expression of chemokines such as SDF1 is regulated by hypoxia and HIF-1α.…”