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Abstract
Long-term use of zoledronic acid (ZA) increases the risk of medication-related osteonecrosis of the jaw (MRONJ). This may be attributed to ZA-mediated reduction of viable mesenchymal stem cells (MSCs). ZA inhibits protein geranylgeranylation, thus suppressing cell viability and proliferation. Geranylgeraniol (GGOH), which is a naturally found intermediate compound in the mevalonate pathway, has positive effects against ZA. However, precise mechanisms by which GGOH may help preserve stem cell viability against ZA are not fully understood. The objective of this study was to investigate the cytoprotective mechanisms of GGOH against ZA. The results showed that while ZA dramatically decreased the number of viable MSCs, GGOH prevented this negative effect. GGOH-rescued ZA-exposed MSCs formed mineralization comparable to that produced by normal MSCs. Mechanistically, GGOH preserved the number of viable MSCs by its reversal of ZA-mediated Ki67+ MSC number reduction, cell cycle arrest and apoptosis. Moreover, GGOH prevented ZA-suppressed RhoA activity and YAP activation. The results also established the involvement of Rho-dependent YAP and YAP-mediated CDK6 in the cytoprotective ability of GGOH against ZA. In conclusion, GGOH preserves a pool of viable MSCs with osteogenic potency against ZA by rescuing the activity of Rho-dependent YAP activation, suggesting GGOH as a promising agent and YAP as a potential therapeutic target for MRONJ.
Highlights
In patients receiving antiresorptive drugs, prevention and treatment of complications, including medication-related osteonecrosis of the jaw (MRONJ) [1], have become major concerns in current dental practice, especially involved in the management of osteonecrosis of alveolar socket bone after tooth extraction
The effect of GGOH on mesenchymal stem cells (MSCs) viability was first determined and the results showed that GGOH at concentrations less than 100 μM and 75 μM appeared to have no discernible effects on MSC viability and proliferation, whereas the higher doses tested significantly retarded the proliferation of MSCs
The concentration of zoledronic acid (ZA) used in this study was based on our previous report [8] and on the level detected in bone from patients with existing osteonecrosis (0.4–4.6 μM) [6]
Summary
In patients receiving antiresorptive drugs, prevention and treatment of complications, including medication-related osteonecrosis of the jaw (MRONJ) [1], have become major concerns in current dental practice, especially involved in the management of osteonecrosis of alveolar socket bone after tooth extraction. The increasingly accumulated N-BPs in the long-term use of N-BPs may be expected in the bone of patients, and the high level released during bone remodelling is considered to increase the risk of developing MRONJ [4,5,6]. Our previous in vitro study further supports the inhibitory effect on osteoblastic lineage cells by showing that while low-dose ZA inhibited osteoblast differentiation of mesenchymal stem cells (MSCs), high-dose ZA suppressed the viability of MSCs [8]. These findings support the involvement of high-dose N-BP cytotoxicity to osteoblast lineage cells in MRONJ. There is a lack of evidence to support effective prevention and treatment of MRONJ due to N-BPs [9], prompting the investigation to better understand their molecular targets in osteogenic cells beyond osteoclasts and identify key molecules that help protect cells against N-BP cytotoxicity
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