However, it is possible that titrating the dose of BMP-2 for delivery beside a recruitment factor vs. exogenous cells is required in order to achieve comparable bone growth. Though complete healing in the cranial defect was not observed, significantly higher bone formation was measured at the defect site in the FTY720 treated animals compared to those treated with BMP-2. The surprising effectiveness of FTY720 may be attributed to the underlying effects on bone progenitor recruitment. Previous studies have shown that FTY720 promotes SDF-1/CXCR4 dependent migration of hematopoietic stem cells into the bone marrow in a S1P1 dependent manner and the osteoblastic differentiation of C2C12 cells. Though S1P2 activation in pre-osteoblasts serve as a chemo-repellant receptor, FTY720 has no activity at S1P2, thus its role in the bone healing environment would not hinder pre-osteoblast migration to the site of injury. In addition, we’ve shown that activation of S1P3 signaling results in a concentration dependent phosphorylation of Nutlin-3 Smad-1 and smad-2 proteins, members of the smad family of intracellular signaling molecules. Smad-1 is known to transduce signals from BMP-2 receptors, indicating the cross activation of this signaling pathway by S1P3 activation. Additionally, activation of S1P3 has also been shown to activate CXCR4 signaling, which can also contribute to the observed increased recruitment of MSCs to the injury site. Future studies will be required to determine the respective contributions of enhanced chemokinesis and directed SDF-1 mediated chemotaxis among cells treated by the combination of the two factors. The inflammatory response at the injury site is also a critical determinant of the rate of regeneration. While inflammation initiates the various steps of healing, uncontrolled upregulation of pro-inflammatory cytokines could negatively impact the process of regeneration. Local suppression of inflammation has also been shown to increase the effect of BMP-2 in critical size defect healing. FTY720 has been shown to suppress inflammation when delivered both locally and systemically. S1P receptor activation is also known to play an important role in myeloid cell recruitment during acute inflammation and promote the recruitment of monocytes and macrophages in atherosclerosis. We’ve recently shown that local delivery of FTY720 can tune the local inflammatory environment in a manner that may be beneficial to processes involved in bone regeneration, such as arteriogenesis, by selectively recruiting antiinflammatory monocytes.