WSS25, a sulfated polysaccharide, inhibits RANKL-induced mouse osteoclast formation by blocking SMAD/ID1 signaling

doi:10.1038/aps.2015.65

CORC > 上海药物研究所 > 中国科学院上海药物研究所 > 药理学第三研究室

	WSS25, a sulfated polysaccharide, inhibits RANKL-induced mouse osteoclast formation by blocking SMAD/ID1 signaling
	Chen, Cheng 1,2; Qin, Yi 2; Fang, Jian-ping 2; Ni, Xin-yan 2; Yao, Jian 2; Wang, Hai-ying 1; Ding, Kan2
刊名	ACTA PHARMACOLOGICA SINICA
	2015-09
卷号	36 期号:9 页码:1053-1064
关键词	WSS25 polysaccharides osteoclast RANKL BMP-2 Smad1/5/8 Id1 ovariectomized mice osteoporosis
ISSN号	1671-4083
DOI	10.1038/aps.2015.65
文献子类	Article
英文摘要	Aim: WSS25 is a sulfated polysaccharide extracted from the rhizome of Gastrodia elata BI, which has been found to bind to bone morphogenetic protein 2 (BMP-2) in hepatocellular cancer cells. Since BMP-2 may regulate both osteoclasts and osteoblasts, here we investigated the effects of WSS25 on osteoclastogenesis in vitro and bone loss in ovariectomized mice. Methods: RAW264.7 cells or mouse bone marrow macrophages (BMMs) were treated with RANKL to induce osteoclastogenesis, which was assessed using TRAP staining, actin ring formation and pit formation assays, as well as bone resorption assay. Cell viability was detected with MTT assay. The mRNA levels of osteoclastogenesis-related genetic markers (TRAP, NFATc1, MMP-9 and cathepsin K) were detected using RT-PCR, while the protein levels of p-Smad1/5/8 and Id1 were measure with Western blotting. WSS25 was administered to ovariectomized mice (100 mg.kg(-1).d(-1), po) for 3 months. After the mice were euthanized, total bone mineral density and cortical bone density were measured. Results: In RAW264.7 cells and BMMs, WSS25 (2.5, 5, 10 mu g/mL) did not affect the cell viability, but dose-dependently inhibited RANKL-induced osteoclastogenesis. Furthermore, WSS25 potently suppressed RANKL-induced expression of TRAP, NFATc1, MMP-9 and cathepsin K in RAW264.7 cells. Treatment of RAW264.7 cells with RANKL increased BMP-2 expression, Smad1/5/8 phosphorylation and Id1 expression, which triggered osteoclast differentiation, whereas co-treatment with WSS25 or the endogenous BMP-2 antagonist noggin suppressed the BMP-2/Smad/Id1 signaling pathway. In RAW264.7 cells, knockdown of Id1 attenuated RANKL-induced osteoclast differentiation, which was partially rescued by Id1 overexpression. In conformity to the in vitro experiments, chronic administration of WSS25 significantly reduced the bone loss in ovariectomized mice. Conclusion: WSS25 inhibits RANKL-induced osteoclast formation in RAW264.7 cells and BMMs by blocking the BMP-2/Smad/Id1 signaling pathway. WSS25 administration reduces bone loss in ovariectomized mice, suggesting that it may be a promising therapeutic agent for osteoporosis.
资助项目	National Natural Science Foundation of China (NSFC)[31230022] ; National Science Fund for Distinguished Young Scholars[81125025] ; New Drug Creation and Manufacturing Program[2012ZX09301001-003]
WOS关键词	KAPPA-B LIGAND ; BONE-FORMATION ; RECEPTOR ACTIVATOR ; CATHEPSIN-K ; T-CELLS ; DIFFERENTIATION ; RESORPTION ; OSTEOPOROSIS ; PROTEINS ; MICE
WOS研究方向	Chemistry ; Pharmacology & Pharmacy
语种	英语
CSCD记录号	CSCD:5510632
出版者	ACTA PHARMACOLOGICA SINICA
WOS记录号	WOS:000360840200003
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/276416]
专题	药理学第三研究室上海药物代谢研究中心
通讯作者	Wang, Hai-ying
作者单位	1.Shanghai Univ Tradit Chinese Med, Inst Tradit Chinese Med, Shanghai 201203, Peoples R China 2.Chinese Acad Sci, Shanghai Inst Mat Med, Glycochem & Glycobiol Lab, Shanghai 201203, Peoples R China;
推荐引用方式 GB/T 7714	Chen, Cheng,Qin, Yi,Fang, Jian-ping,et al. WSS25, a sulfated polysaccharide, inhibits RANKL-induced mouse osteoclast formation by blocking SMAD/ID1 signaling[J]. ACTA PHARMACOLOGICA SINICA,2015,36(9):1053-1064.
APA	Chen, Cheng.,Qin, Yi.,Fang, Jian-ping.,Ni, Xin-yan.,Yao, Jian.,...&Ding, Kan.(2015).WSS25, a sulfated polysaccharide, inhibits RANKL-induced mouse osteoclast formation by blocking SMAD/ID1 signaling.ACTA PHARMACOLOGICA SINICA,36(9),1053-1064.
MLA	Chen, Cheng,et al."WSS25, a sulfated polysaccharide, inhibits RANKL-induced mouse osteoclast formation by blocking SMAD/ID1 signaling".ACTA PHARMACOLOGICA SINICA 36.9(2015):1053-1064.