R Fliefel1, A El Ashwah2, S Entekhabi3, J Kumbrink4, M Ehrenfeld5, S Otto6. 1. Experimental Surgery and Regenerative Medicine (ExperiMed), Ludwig-Maximilians-University, Nussbaumstrasse 20, 80336 Munich, Germany; Department of Oral and Maxillofacial Surgery and Facial Plastic Surgery, Ludwig-Maximilians-University, Lindwurmstrasse 2a, 80337 Munich, Germany; Department of Oral and Maxillofacial Surgery, Alexandria-University, Champollion Street, 21500 Alexandria, Egypt. Electronic address: riham.fliefel@med.uni-muenchen.de. 2. Department of Oral and Maxillofacial Surgery, Alexandria-University, Champollion Street, 21500 Alexandria, Egypt. 3. Experimental Surgery and Regenerative Medicine (ExperiMed), Ludwig-Maximilians-University, Nussbaumstrasse 20, 80336 Munich, Germany. 4. Institute of Pathology, Medical Faculty, Ludwig-Maximilians-University, 36,Thalkirchner street, 80337 Munich Germany. 5. Department of Oral and Maxillofacial Surgery and Facial Plastic Surgery, Ludwig-Maximilians-University, Lindwurmstrasse 2a, 80337 Munich, Germany. 6. Experimental Surgery and Regenerative Medicine (ExperiMed), Ludwig-Maximilians-University, Nussbaumstrasse 20, 80336 Munich, Germany; Department of Oral and Maxillofacial Surgery and Facial Plastic Surgery, Ludwig-Maximilians-University, Lindwurmstrasse 2a, 80337 Munich, Germany.
Abstract
BACKGROUND: Treatment of massive bone defects is a great challenge. Mesenchymal stem cells (MSCs) enhance bone regeneration by differentiating into osteoblasts. Bisphosphonates (BPs) are antiresorptives reducing bone resorption. Despite Medication-related osteonecrosis of the jaw (MRONJ) is a known side effect of antiresorptives, evidences suggest that BPs have positive effect on bone formation. The aims of this study were to investigate the effect of zoledronic acid (ZA) and geranylgeraniol (GGOH) on human mesenchymal stem cells (hMSCs) being a part of the bone microenvironment and evaluate whether low dose of bisphosphonate has enhanced osteogenic differentiation of hMSCs. MATERIALS AND METHODS: The effect of ZA and GGOH on MSCs was investigated in addition to the effect of low doses of ZA on osteogenic differentiation of MSCs and analysed by WST-1, Live/Dead staining and coefficient of drug index (CDI). The osteogenic differentiation of the cells was confirmed by ALP activity, xylenol orange and alizarin red staining, microarray and PCR with levels of statistical significance indicated at *P<0.05, **P<0.01 and ***P<0.0001. MAIN FINDINGS: Although, high concentration of ZA had significantly decreased the cell viability in MSCs, GGOH reversed the action of ZA on the cells while at very high concentration; it caused severe reduction in the cell viability. CDI showed antagonism or synergism depending on the concentrations of ZA and GGOH. CONCLUSION: The treatment of cells with ZA has increased the mineralization and osteogenic differentiation of MSCs. Our study supported the hypothesis that zoledronic acid plays a bifunctional role depending on the concentration.
BACKGROUND: Treatment of massive bone defects is a great challenge. Mesenchymal stem cells (MSCs) enhance bone regeneration by differentiating into osteoblasts. Bisphosphonates (BPs) are antiresorptives reducing bone resorption. Despite Medication-related osteonecrosis of the jaw (MRONJ) is a known side effect of antiresorptives, evidences suggest that BPs have positive effect on bone formation. The aims of this study were to investigate the effect of zoledronic acid (ZA) and geranylgeraniol (GGOH) on human mesenchymal stem cells (hMSCs) being a part of the bone microenvironment and evaluate whether low dose of bisphosphonate has enhanced osteogenic differentiation of hMSCs. MATERIALS AND METHODS: The effect of ZA and GGOH on MSCs was investigated in addition to the effect of low doses of ZA on osteogenic differentiation of MSCs and analysed by WST-1, Live/Dead staining and coefficient of drug index (CDI). The osteogenic differentiation of the cells was confirmed by ALP activity, xylenol orange and alizarin red staining, microarray and PCR with levels of statistical significance indicated at *P<0.05, **P<0.01 and ***P<0.0001. MAIN FINDINGS: Although, high concentration of ZA had significantly decreased the cell viability in MSCs, GGOH reversed the action of ZA on the cells while at very high concentration; it caused severe reduction in the cell viability. CDI showed antagonism or synergism depending on the concentrations of ZA and GGOH. CONCLUSION: The treatment of cells with ZA has increased the mineralization and osteogenic differentiation of MSCs. Our study supported the hypothesis that zoledronic acid plays a bifunctional role depending on the concentration.