Synergistic effects of the dual release of stromal cell-derived factor-1 and bone morphogenetic protein-2 from hydrogels on bone regeneration

Abstract

The objective of this study is to evaluate the activity of gelatin hydrogels incorporating combined stromal cell-derived factor-1 (SDF-1) and bone morphogenetic protein-2 (BMP-2) on the in vivo bone regeneration at an ulna critical-sized defect and subcutaneous site of rats, and compared with that of those incorporating either SDF-1 or BMP-2. The similar release profile of SDF-1 and BMP-2 from the hydrogels was observed with or without the combination of BMP-2 and SDF-1, respectively. An enhanced bone regeneration by the hydrogels incorporating combined SDF-1 and BMP-2 was observed. In addition, the implantation of hydrogels incorporating combined SDF-1 and BMP-2 enhanced the expression level of CXC chemokine cell-surface receptor-4 (Cxcr4), Runt-related factor-2 (Runx2), and Osteocalcin genes. The experiments with green fluorescent protein (GFP)-positive Chimeric mice revealed that the recruitment of bone marrow-derived cells was promoted and a vascular-like structure together with strong accumulation of CD31- and CD34-positive cells was observed at the site of hydrogels incorporating combined SDF-1 and BMP-2 implanted. In addition, a large fraction of CD29- and CD44-positive non-hematopoietic cells was detected. It is concluded that the combined release of SDF-1 and BMP-2 enhanced the recruitment of osteogenic cells and angiogenesis, resulting in the synergistic effect on bone regeneration.

Low-Dose Bone Morphogenetic Protein-2/Stromal Cell-Derived Factor-1β Cotherapy Induces Bone Regeneration in Critical-Size Rat Calvarial Defects

“…AMD3100, a bicyclam antagonist of CXCR4, was initially developed for selective inhibition of CXCR4-facilitated human immunodeficiency virus (HIV) entry into cells, 47 and later it was reported to mobilize hematopoietic stem cells by directly antagonizing the CXCR4-mediated sensing of the SDF-1 chemotactic gradient in bone marrow. 48 Our data demonstrate, for the first time, that SDF-1b plays a pivotal role in suboptimal BMP-2-induced bone formation and maturation through regulating CXCR4 signaling in vivo, extending previous reports [26][27][28][29] and confirming our earlier findings in vitro.…”

“…38 Previous studies have suggested that the CXCR4/SDF-1 signaling axis regulates BMP-2 osteoinduction in vitro 24,25 and in vivo. [21][22][23][26][27][28][29] However, clear distinctions between involved SDF-1 isoforms were not reported. Thus, the specific contribution of SDF-1b, the second most abundant splice variant, to BMP-2-induced bone formation remained unknown.…”

“…24 These in vitro findings were later extended using primary mouse and human bone-marrow-derived mesenchymal stem cells (BMSCs), 25 setting the stage for investigating the BMP-2/SDF-1 interaction employing orthotopic and ectopic bone formation models. [26][27][28][29] Previous studies have suggested that the CXCR4/SDF-1 axis functions in postnatal bone formation by regulating osteoblast development in cooperation with BMP signaling, and that CXCR4 acts as an endogenous signaling component necessary for bone formation. 29 We 30 and others 31 have shown that bone marrow endothelial and stromal cells, and osteoblasts express both major SDF-1 splice variants, and that unexpectedly the beta isoform may be present at a high level in bone tissues.…”

Non-viral gene therapy for bone tissue engineering

“…GMP containing constructs were implanted subcutaneously in mice for 6 weeks to investigate whether bone formation can be induced in cell-free constructs by chemokine attraction of host MSCs or if bone formation can be enhanced in seeded constructs due to a synergistic BMP-2/SDF-1α combination 67 . Transfection of seeded MSCs with BMP-2 plasmid DNA is possible in alginate constructs.…”

“…The recruitment of MSCs towards BMP-2 protein or genetically engineered BMP-2 producing MSCs, via SDF-1α or -β induces osteogenic differentiation 224 . When both growth factors are released from a combined construct, a synergistic effect on bone formation has even been reported 67 . The mechanism behind this increased bone formation has been described as a combination of enhanced mobilization and homing of bone marrow-derived osteoprogenitor cells to the implant leading to increased numbers of cells available for bone regeneration at ectopic bone implants 66 .…”