近日，药学院病毒免疫药物药理学课题组刘叔文教授和抗炎免疫药理学课题组李晓娟教授以共同通讯作者在Biochem Pharmacol上发表了题为“Artesunate suppresses RANKL-induced osteoclastogenesis through inhibition of PLCγ1-Ca2+-NFATc1 signaling pathway and prevents ovariectomy-induced bone loss.”的研究论文。靶向破骨细胞过度激活可用于治疗相关骨破坏疾病包含骨质疏松、类风湿性关节炎、骨转移肿瘤等。 抗疟药物青蒿琥酯是半合成的青蒿素的衍生物，近年在临床被用于类风湿性关节炎的治疗，但是其对破骨细胞的影响未有研究报导。 我们发现青蒿琥酯体外能够直接抑制RANKL诱导破骨细胞形成、骨吸收活性。进一步机制研究发现，青蒿琥酯在其抑制破骨细胞生成的剂量下对RANKL诱导的破骨前体细胞NF-κB通路的激活无显著作用，但却能够显著降低RANKL上调的NFATc1基因蛋白表达、PLCγ1活化、钙离子内流、钙调神经磷酸酶 (PP2B-Aα) 表达。此外，青蒿琥酯能够显著抑制卵巢切除小鼠的骨破坏，并降低血清RANKL、RANKL/OPG、TRAP5b。研究表明青蒿琥酯可通过抑制PLCγ1-Ca2+-NFATc1信号通路抑制RANKL诱导的破骨细胞形成和骨吸收，并提示其可用于治疗RANKL介导的骨破坏疾病。
Zeng X, Zhang Y, Wang S, Wang K, Tao L, Zou M, Chen N, Xu J, Liu S, Li X. Artesunate suppresses RANKL-induced osteoclastogenesis through inhibition of PLCγ1-Ca2+-NFATc1 signaling pathway and prevents ovariectomy-induced bone loss. Biochem Pharmacol. 2016 Oct 24. pii: S0006-2952(16)30376-8. doi: 10.1016/j.bcp.2016.10.007. [Epub ahead of print]
Bone lytic diseases including osteoporosis, rheumatoid arthritis, and bone metastatic tumors affect hundreds of millions people worldwide. Targeting over-activated osteoclasts as an anti-resorptive treatment becomes an important strategy to treat osteolytic diseases. Artesunate is a compound derived from artemisinin (qinghaosu) and has been used to treat malaria and rheumatoid arthritis clinically in China, but its role in osteolysis is unknown. Here, we found that artesunate could suppress RANKL-induced osteoclastogenesis and bone resorption from 1.56 to 12.5μM. Artesunate obviously reduced RANKL-induced NF-κB-luc activity at 50μM, but had no effects on RANKL-induced NF-κB activation (NF-κB luciferase activity, IκB-α degradation and nuclear NF-κB p65 protein level) from 3.125 to 12.5μM in pre-osteoclastic RAW264.7 cells. Interestingly, artesunate could significantly inhibit RANKL-induced NFATc1 activation measured by NFAT luciferase activity, NFATc1 mRNA and nuclear NFATc1 protein levels from 3.125 to 12.5μM. Further study revealed that artesunate inhibited RANKL up-regulated PLCγ1 activation, intracellular calcium, and calcineurin (PP2B-Aα) protein expression from 3.125 to 12.5μM. In addition, the NFATc1 targeted osteoclast-specific genes expression including cathepsin K, MMP-9, and TRAP was reduced by artesunate. Finally, we showed that artesunate was able to reverse the bone loss in an ovariectomized mouse model in vivo accompanied with reduced RANKL, RANKL/OPG, and TRAP-5b levels. This study indicates that artesunate inhibits RANKL-induced osteoclastogenesis and bone loss by inhibiting PLCγ1-Ca2+-calcineurin-NFATc1 pathway. Collectively, our data suggest that artesunate is a potential treatment option against RANKL-mediated osteolytic bone disease.