Department of Orthopaedic Surgery, Sir Run Run Shaw Hospital, Medical College of Zhejiang University, Hangzhou, Zhejiang 310016, China; School of Biomedical Sciences, University of Western Australia, Perth, Western Australia 6009, Australia.
School of Biomedical Sciences, University of Western Australia, Perth, Western Australia 6009, Australia.
Biomed Pharmacother. 2022 Oct;154:113622. doi: 10.1016/j.biopha.2022.113622. Epub 2022 Sep 7.
Osteoclasts play an important role in maintaining the relative stability of bone mass. Abnormal number and function of osteoclasts are closely related to osteoporosis and osteolytic diseases. Thiaplakortone B (TPB), a natural compound derived from the Great Barrier Reef sponge Plakortis lita, has been reported to inhibit the growth of the malaria parasite, Plasmodium falciparum, but its effect on osteoclastogenesis has not been previously investigated. In our study, we found that TPB suppresses the receptor activator of nuclear factor-κB (NF-κB) ligand (RANKL)-induced osteoclast formation and resorption activity by tartrate-resistant acid phosphatase (TRAcP) staining, immunofluorescence staining of F-actin belts and hydroxyapatite resorption assay. Furthermore, using quantitative real-time polymerase chain reaction (qRT-PCR) and Western blotting analysis, we discovered that TPB inhibits osteoclast-specific genes and proteins expression. Mechanistically, TPB blocks multiple upstream pathways including calcium oscillation, NF-κB, mitogen-activated protein kinase (MAPK) and nuclear factor of activated T cells 1(NFATc1) signaling pathways. In vivo, TPB could dampen bone loss in an ovariectomy (OVX) mouse model by micro-CT assessment and histological staining. Therefore, TPB may serve as a potential therapeutic candidate for the treatment of osteoporosis and osteolysis.
破骨细胞在维持骨量的相对稳定方面发挥着重要作用。破骨细胞数量和功能的异常与骨质疏松症和溶骨性疾病密切相关。Thiaplakortone B（TPB）是一种从大堡礁海绵 Plakortis lita 中提取的天然化合物，已被报道可抑制疟原虫（Plasmodium falciparum）的生长，但它对破骨细胞生成的影响尚未被研究过。在我们的研究中，我们发现 TPB 通过抗酒石酸酸性磷酸酶（TRAcP）染色、F-肌动蛋白带的免疫荧光染色和羟磷灰石吸收测定，抑制核因子-κB（NF-κB）配体（RANKL）诱导的破骨细胞形成和吸收活性。此外，通过定量实时聚合酶链反应（qRT-PCR）和 Western blot 分析，我们发现 TPB 抑制破骨细胞特异性基因和蛋白的表达。从机制上讲，TPB 阻断了多个上游通路，包括钙震荡、NF-κB、丝裂原活化蛋白激酶（MAPK）和激活 T 细胞的核因子 1（NFATc1）信号通路。在体内，TPB 通过 micro-CT 评估和组织学染色，可抑制去卵巢（OVX）小鼠模型中的骨丢失。因此，TPB 可能成为治疗骨质疏松症和溶骨性疾病的潜在治疗候选药物。
