Cell Biology and Toxicology ( IF 5.3 ) Pub Date : 2021-01-09 , DOI: 10.1007/s10565-020-09578-6 Xiang Li 1 , Yuxin Wang 1 , Liangping Li 2 , Shengji Zhou 1 , Fengchao Zhao 1
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Osteoclasts are crucial cellular components of bone and are the cause of various bone problems like osteoporosis. Various biological activities such as anti-tumorous, anti-inflammatory, antibacterial, and immunomodulatory function are influenced by Sclareol, as a natural diterpene compound. However, studies on the effect and mechanism of Sclareol on osteoporosis are rare. In the current research, the influence of Sclareol on osteoclastogenesis and osteoblastogenesis was targeted to be discovered in ovariectomy (OVX)-induced animal models and in vitro. The expression levels of osteoclast-related genes such as c-Fos, NFATc1, and CTSK were detected by RT-qPCR and western blotting to understand the inhibition of Sclareol on the creation of osteoclast. The influence of Sclareol on osteoblastogenesis and the expression of osteoblastogenic markers were also examined. Sclareol inhibited the osteoclastogenesis caused by receptor activator of nuclear factor-κB ligand (RANKL) which promoted osteoblastogenesis through upregulating the expression of cysteine-rich protein 61 (CYR61/CCN1), which is a matricellular protein of the CCN family. The p-ERK and p-P38 protein expression levels were considerably downregulated by Sclareol. Furthermore, CCN1 overexpression partially mimicked the inhibitory effect of Sclareol, while the opposite results were obtained after CCN1 silencing. Additionally, Sclareol protected against loss of bones in an osteoporosis mouse model generated by OVX. The acquired results indicated that Sclareol represses RANKL-induced osteoclastogenesis and promotes osteoblastogenesis via promoting the expression of CCN1 by constraining the mitogen-activated protein kinase (MAPK) pathway. Our findings proposed that for the avoidance and treatment of osteoclast-linked disorders, Sclareol is a potentially effective drug.
Graphical abstract
中文翻译：
香紫苏醇抑制 RANKL 诱导的破骨细胞生成并通过抑制 MAPK 通路促进 CCN1 表达促进成骨细胞生成
破骨细胞是骨骼的重要细胞成分，是各种骨骼问题（如骨质疏松症）的原因。作为一种天然二萜化合物，香紫苏醇影响各种生物活性，例如抗肿瘤、抗炎、抗菌和免疫调节功能。然而，关于香紫苏醇对骨质疏松的作用和机制的研究却很少。在目前的研究中，Sclareol 对破骨细胞生成和成骨细胞生成的影响有针对性地在卵巢切除术 (OVX) 诱导的动物模型和体外发现。通过RT-qPCR和蛋白质印迹检测破骨细胞相关基因如c-Fos、NFATc1和CTSK的表达水平，以了解香紫苏醇对破骨细胞产生的抑制作用。还检查了香紫苏醇对成骨细胞生成和成骨细胞标记物表达的影响。香紫苏醇抑制由核因子-κB 配体 (RANKL) 受体激活剂引起的破骨细胞生成，RANKL 通过上调富含半胱氨酸的蛋白 61 (CYR61/CCN1) 的表达来促进成骨细胞生成，该蛋白是 CCN 家族的一种基质细胞蛋白。香紫苏显着下调了 p-ERK 和 p-P38 蛋白表达水平。此外，CCN1 过表达部分模拟了香紫苏的抑制作用，而在 CCN1 沉默后获得了相反的结果。此外，在由 OVX 生成的骨质疏松症小鼠模型中，香紫苏醇可防止骨骼丢失。获得的结果表明，Sclareol 抑制 RANKL 诱导的破骨细胞生成，并通过限制丝裂原活化蛋白激酶 (MAPK) 途径促进 CCN1 的表达来促进成骨细胞生成。我们的研究结果表明，为了避免和治疗破骨细胞相关疾病，香紫苏是一种潜在有效的药物。
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