Medication-related osteonecrosis of the jaw (MRONJ) is a serious adverse effect of antiresorptive and antiangiogenic therapies. MRONJ is identified by chronic wounds in the oral mucosa associated with exposed necrotic bone. We hypothesized that zoledronic acid (ZOL) impairs keratinocyte and fibroblast function and reduces soft tissue vascularization; therefore, treating MRONJ with proangiogenic cells may benefit MRONJ patients. The effect of ZOL and dexamethasone (DEX) on gingival fibroblasts and keratinocytes was investigated. In-vitro, ZOL inhibited fibroblast and keratinocyte proliferation, delaying scratch healing. In-vivo, exposed bone was detected at tooth extraction sites, mainly in ZOL(+)/DEX(+) rats; and was associated with significantly decreased soft tissue vascularization, serum-VEGF, and tissue-VEGF. Local injection of early and late endothelial progenitor cells (EPCs) healed 13 of 14 MRONJ lesions compared with 2/7 lesions in the mesenchymal stem cells, and 2/6, in culture-medium group. The EPCs reduced necrotic bone area, increased serum and tissue VEGF levels. EPCs engraftment was minimal, suggesting their paracrine role in MRONJ healing. The EPC-conditioned medium improved scratch healing of keratinocytes and fibroblasts via VEGF pathway and elevated mRNA of VEGFA and collagen1A1. In conclusion, a novel MRONJ treatment with EPCs, increased vascularization and improved epithelial and fibroblast functions as well as cured the lesion.
Vascularization is a prerequisite for bone formation. Endothelial progenitor cells (EPCs) stimulate bone formation by creating a vascular network. Moreover, EPCs secrete various bioactive molecules that may regulate bone formation. The aim of this research was to shed light on the pathways of EPCs in bone formation. In a subcutaneous nude mouse ectopic bone model, the transplantation of human EPCs onto β-TCP scaffold increased angiogenesis (p < 0.001) and mineralization (p < 0.01), compared to human neonatal dermal fibroblasts (HNDF group) and a-cellular scaffold transplantation (β-TCP group). Human EPCs were lining blood vessels lumen; however, the majority of the vessels originated from endogenous mouse endothelial cells at a higher level in the EPC group (p < 01). Ectopic mineralization was mostly found in the EPCs group, and can be attributed to the recruitment of endogenous mesenchymal cells ten days after transplantation (p < 0.0001). Stromal derived factor-1 gene was expressed at high levels in EPCs and controlled the migration of mesenchymal and endothelial cells towards EPC conditioned medium in vitro. Blocking SDF-1 receptors on both cells abolished cell migration. In conclusion, EPCs contribute to osteogenesis mainly by the secretion of SDF-1, that stimulates homing of endothelial and mesenchymal cells. This data may be used to accelerate bone formation in the future.
Clinical trials have demonstrated the safety and efficacy of autologous endothelial progenitor cell (EPC) therapy in various diseases. Since EPCs’ functions are influenced by genetic, systemic and environmental factors, the therapeutic potential of each individual EPCs is unknown and may affect treatment outcome. Therefore, our aim was to compare EPCs function among healthy donors in order to predict blood vessel formation (angiogenesis) before autologous EPC transplantation. Human EPCs were isolated from the blood of ten volunteers. EPCs proliferation rate, chemoattractant ability, and CXCR4 mRNA levels were different among donors (p < 0.0001, p < 0.01, p < 0.001, respectively). A positive correlation was found between SDF-1, CXCR4, and EPCs proliferation (R = 0.736, p < 0.05 and R = 0.8, p < 0.01, respectively). In-vivo, blood vessels were counted ten days after EPCs transplantation in a subcutaneous mouse model. Mean vessel density was different among donors (p = 0.0001); nevertheless, donors with the lowest vessel densities were higher compared to control (p < 0.05). Finally, using a linear regression model, a mathematical equation was generated to predict blood vessel density relying on: (i) EPCs chemoattractivity, and (ii) VEGFR-2 mRNA levels. Results reveal differences in EPCs functions among healthy individuals, emphasizing the need for a potency assay to pave the way for standardized research and clinical use of human EPCs.
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