Department of Orthopedics, The First Affiliated Hospital of Soochow University, 188 Shizi Street, Suzhou, 215006, Jiangsu, China.
Department of Orthopedics, Wuxi 9th People's Hospital Affiliated to Soochow University, Wuxi, 214000, Jiangsu, China.
Cell Commun Signal. 2024 Mar 4;22(1):160. doi: 10.1186/s12964-024-01525-w.
Estrogen deficiency-mediated hyperactive osteoclast represents the leading role during the onset of postmenopausal osteoporosis. The activation of a series of signaling cascades triggered by RANKL-RANK interaction is crucial mechanism underlying osteoclastogenesis. Vorinostat (SAHA) is a broad-spectrum pan-histone deacetylase inhibitor (HDACi) and its effect on osteoporosis remains elusive.
The effects of SAHA on osteoclast maturation and bone resorptive activity were evaluated using in vitro osteoclastogenesis assay. To investigate the effect of SAHA on the osteoclast gene networks during osteoclast differentiation, we performed high-throughput transcriptome sequencing. Molecular docking and the assessment of RANKL-induced signaling cascades were conducted to confirm the underlying regulatory mechanism of SAHA on the action of RANKL-activated osteoclasts. Finally, we took advantage of a mouse model of estrogen-deficient osteoporosis to explore the clinical potential of SAHA.
We showed here that SAHA suppressed RANKL-induced osteoclast differentiation concentration-dependently and disrupted osteoclastic bone resorption in vitro. Mechanistically, SAHA specifically bound to the predicted binding site of RANKL and blunt the interaction between RANKL and RANK. Then, by interfering with downstream NF-κB and MAPK signaling pathway activation, SAHA negatively regulated the activity of NFATc1, thus resulting in a significant reduction of osteoclast-specific gene transcripts and functional osteoclast-related protein expression. Moreover, we found a significant anti-osteoporotic role of SAHA in ovariectomized mice, which was probably realized through the inhibition of osteoclast formation and hyperactivation.
These data reveal a high affinity between SAHA and RANKL, which results in blockade of RANKL-RANK interaction and thereby interferes with RANKL-induced signaling cascades and osteoclastic bone resorption, supporting a novel strategy for SAHA application as a promising therapeutic agent for osteoporosis.
雌激素缺乏介导的破骨细胞活性亢进是绝经后骨质疏松症发病的主要原因。核因子 κB 受体活化因子配体（RANKL）与核因子 κB 受体（RANK）相互作用激活一系列信号级联反应是破骨细胞分化的关键机制。伏立诺他（SAHA）是一种广谱的组蛋白去乙酰化酶抑制剂（HDACi），但其在骨质疏松症中的作用仍不清楚。
通过体外破骨细胞生成实验评估 SAHA 对破骨细胞成熟和骨吸收活性的影响。为了研究 SAHA 对破骨细胞分化过程中破骨细胞基因网络的影响，我们进行了高通量转录组测序。采用分子对接和 RANKL 诱导的信号级联反应评估，以确认 SAHA 对 RANKL 激活的破骨细胞作用的潜在调节机制。最后，我们利用雌激素缺乏性骨质疏松症小鼠模型探索了 SAHA 的临床潜力。
我们发现 SAHA 浓度依赖性地抑制 RANKL 诱导的破骨细胞分化，并在体外破坏破骨细胞的骨吸收作用。机制上，SAHA 特异性结合 RANKL 的预测结合位点，削弱 RANKL 与 RANK 的相互作用。然后，通过干扰下游 NF-κB 和 MAPK 信号通路的激活，SAHA 负调控 NFATc1 的活性，从而导致破骨细胞特异性基因转录物和功能性破骨细胞相关蛋白表达显著减少。此外，我们发现 SAHA 在去卵巢小鼠中具有显著的抗骨质疏松作用，这可能是通过抑制破骨细胞形成和过度激活来实现的。
这些数据揭示了 SAHA 与 RANKL 之间的高亲和力，导致 RANKL-RANK 相互作用的阻断，并干扰 RANKL 诱导的信号级联反应和破骨细胞骨吸收，为 SAHA 作为一种有前途的骨质疏松症治疗药物的应用提供了新的策略。
