IADR Abstract Archives
Proangiogenic therapy as a treatment modality in the management of BRONJ
Objectives: Bisphosphonates (BPs) are known to have a direct effect on the local vasculature, but their effect on the differentiation of progenitor cells into endothelial cells, which may ultimately contribute to the pathogenesis of bisphosphonate-related osteonecrosis of the jaw (BRONJ), is unknown. This study evaluated both the in vitro effect(s) of differing potency bisphosphonates on the differentiation of human placenta-derived mesenchymal stem cells (pMSCs) into an endothelial lineage and the in vivo effect of locally delivered VEGF on a healing extraction socket in a BRONJ rat model.
Methods: The effect of different concentrations of clodronate (CLO), alendronate (ALN) and zoledronate (ZA) on pMSC proliferation and viability was assessed to determine the appropriate non-cytotoxic concentrations for subsequent differentiation studies. pMSC differentiation in endothelial media (+ VEGF) was assessed by LDL uptake assay, Von Willebrand factor immunofluorescence staining and endothelial marker gene expression analysis. Functional morphogenic assessment of the endothelial cells was assessed by tube formation assay. In vivo, the local delivery of VEGF using a hyaluronic acid hydrogel placed in a molar extraction socket of ZA treated rats was evaluated histologically after four weeks of healing.
Results: ALN and ZA had a significant inhibitory effect on pMSC endothelial gene expression, cell migration and the resultant endothelial phenotype. Furthermore, both ALN and ZA were shown to significantly inhibit subsequent endothelial tube formation by VEGF treated pMSCs. In vivo, wound healing as evidenced by increased vascular density in ZA treated rats was significantly enhanced by the VEGF hydrogel.
Conclusions: This study provides new evidence supporting a multi-modal effect of BPs on angiogenesis, which may be involved in the pathogenesis of BRONJ. Further, local delivery of angiogenic agents is a potential therapeutic approach the prevention and management of BRONJ lesions.
Methods: The effect of different concentrations of clodronate (CLO), alendronate (ALN) and zoledronate (ZA) on pMSC proliferation and viability was assessed to determine the appropriate non-cytotoxic concentrations for subsequent differentiation studies. pMSC differentiation in endothelial media (+ VEGF) was assessed by LDL uptake assay, Von Willebrand factor immunofluorescence staining and endothelial marker gene expression analysis. Functional morphogenic assessment of the endothelial cells was assessed by tube formation assay. In vivo, the local delivery of VEGF using a hyaluronic acid hydrogel placed in a molar extraction socket of ZA treated rats was evaluated histologically after four weeks of healing.
Results: ALN and ZA had a significant inhibitory effect on pMSC endothelial gene expression, cell migration and the resultant endothelial phenotype. Furthermore, both ALN and ZA were shown to significantly inhibit subsequent endothelial tube formation by VEGF treated pMSCs. In vivo, wound healing as evidenced by increased vascular density in ZA treated rats was significantly enhanced by the VEGF hydrogel.
Conclusions: This study provides new evidence supporting a multi-modal effect of BPs on angiogenesis, which may be involved in the pathogenesis of BRONJ. Further, local delivery of angiogenic agents is a potential therapeutic approach the prevention and management of BRONJ lesions.