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.

长期使用唑来膦酸（ZA）会增加药物相关性颌骨坏死（MRONJ）的风险。这可能归因于 ZA 介导的活间充质干细胞 (MSC) 的减少。 ZA 抑制蛋白质香叶基香叶基化，从而抑制细胞活力和增殖。香叶基香叶醇 (GGOH) 是甲羟戊酸途径中天然发现的中间化合物，对 ZA 具有积极作用。然而，GGOH 帮助保持干细胞抵抗 ZA 的活力的精确机制尚不完全清楚。本研究的目的是研究 GGOH 对 ZA 的细胞保护机制。结果表明，虽然 ZA 显着减少了存活 MSC 的数量，但 GGOH 却阻止了这种负面影响。 GGOH 拯救的暴露于 ZA 的 MSC 形成的矿化与正常 MSC 产生的矿化相当。从机制上讲，GGOH 通过逆转 ZA 介导的 Ki67 ⁺ MSC 数量减少、细胞周期停滞和细胞凋亡来保留存活的 MSC 数量。此外，GGOH 还可阻止 ZA 抑制的 RhoA 活性和 YAP 激活。结果还确定了 Rho 依赖性 YAP 和 YAP 介导的 CDK6 参与 GGOH 针对 ZA 的细胞保护能力。总之，GGOH 通过挽救 Rho 依赖性 YAP 激活的活性，保留了一批具有抗 ZA 成骨功效的活 MSC，表明 GGOH 是一种有前景的药物，YAP 是 MRONJ 的潜在治疗靶点。