The flavonol glycoside icariin promotes bone formation in growing rats by activating the cAMP signaling pathway in primary cilia of osteoblasts

doi:10.1074/jbc.M117.809517

	The flavonol glycoside icariin promotes bone formation in growing rats by activating the cAMP signaling pathway in primary cilia of osteoblasts
	Wei, Zhenlong 4; Ma, Huiping 3; Xian, Cory J.2; Wang, Jufang1 ; Chen, Keming 4; Shi, Wengui 4; Gao, Yuhai 4; Wang, Yuanyuan 4; Zhou, Jian 4; Ma, Xiaoni 4
刊名	JOURNAL OF BIOLOGICAL CHEMISTRY
	2017-12-22
卷号	292 页码:20883-20896
ISSN号	0021-9258
DOI	10.1074/jbc.M117.809517
英文摘要	Icariin, a prenylated flavonol glycoside isolated from the herb Epimedium, has been considered as a potential alternative therapy for osteoporosis. Previous research has shown that, unlike other flavonoids, icariin is unlikely to act via the estrogen receptor, but its exact mechanism of action is unknown. In this study, using rat calvarial osteoblast culture and rat bone growth models, we demonstrated that icariin promotes bone formation by activating the cAMP/protein kinase A (PKA)/cAMP response element-binding protein (CREB) pathway requiring functional primary cilia of osteoblasts. We found that icariin increases the peak bone mass attained by young rats and promotes the maturation and mineralization of rat calvarial osteoblasts. Icariin activated cAMP/PKA/CREB signaling of the osteoblasts by increasing intracellular cAMP levels and facilitating phosphorylation of both PKA and CREB. Blocking cAMP/PKA/CREB signaling with inhibitors of the cAMP-synthesizing adenylyl cyclase (AC) and PKA inhibitors significantly inhibited the osteogenic effect of icariin in the osteoblasts. Icariin-activated cAMP/PKA/CREB signaling was localized to primary cilia, as indicated by localization of soluble AC and phosphorylated PKA. Furthermore, blocking ciliogenesis via siRNA knockdown of a cilium assembly protein, IFT88, inhibited icariin-induced PKA and CREB phosphorylation and also abolished icariin's osteogenic effect. Finally, several of these outcomes were validated in icariin-treated rats. Together, these results provide new insights into icariin function and its mechanisms of action and strengthen existing ties between cAMP-mediated signaling and osteogenesis.
资助项目	National Natural Sciences Foundation of China[81270963] ; National Natural Sciences Foundation of China[81471090] ; National Natural Sciences Foundation of China[81770879] ; International Science & Technology Cooperation Program of China[2015DFR30940] ; Natural Sciences Foundation of Gansu province[1506RJZA307] ; Science and Technology Research Project of Gansu Province[145RTSA012] ; Science and Technology Research Project of Gansu Province[17JR5RA307] ; National Health and Medical Research Council (NHMRC) Australia Senior Research Fellowship[1042105]
WOS关键词	SOLUBLE ADENYLYL-CYCLASE ; ESTROGEN-RECEPTOR-ALPHA ; MARROW STROMAL CELLS ; OSTEOGENIC DIFFERENTIATION ; IN-VITRO ; OSTEOCLAST FORMATION ; HERBA-EPIMEDII ; CYCLIC-AMP ; MINERALIZATION ; OSTEOPOROSIS
WOS研究方向	Biochemistry & Molecular Biology
语种	英语
出版者	AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
WOS记录号	WOS:000418453400007
资助机构	National Natural Sciences Foundation of China ; International Science & Technology Cooperation Program of China ; Natural Sciences Foundation of Gansu province ; Science and Technology Research Project of Gansu Province ; National Health and Medical Research Council (NHMRC) Australia Senior Research Fellowship
内容类型	期刊论文
源URL	[http://119.78.100.186/handle/113462/46178]
专题	近代物理研究所_生物物理研究室
通讯作者	Wang, Jufang; Chen, Keming
作者单位	1.Chinese Acad Sci, Inst Modern Phys, Key Lab Space Radiobiol Gansu Prov, Lanzhou 730000, Gansu, Peoples R China 2.Univ South Australia, Sch Pharm & Med Sci, Sansom Inst Hlth Res, Adelaide, SA 5001, Australia 3.CPLA, Lanzhou Gen Hosp, Dept Pharm, Lanzhou 730050, Gansu, Peoples R China 4.CPLA, Lanzhou Gen Hosp, Inst Orthopaed, Lanzhou 730050, Gansu, Peoples R China
推荐引用方式 GB/T 7714	Wei, Zhenlong,Ma, Huiping,Xian, Cory J.,et al. The flavonol glycoside icariin promotes bone formation in growing rats by activating the cAMP signaling pathway in primary cilia of osteoblasts[J]. JOURNAL OF BIOLOGICAL CHEMISTRY,2017,292:20883-20896.
APA	Wei, Zhenlong.,Ma, Huiping.,Xian, Cory J..,Wang, Jufang.,Chen, Keming.,...&Ma, Xiaoni.(2017).The flavonol glycoside icariin promotes bone formation in growing rats by activating the cAMP signaling pathway in primary cilia of osteoblasts.JOURNAL OF BIOLOGICAL CHEMISTRY,292,20883-20896.
MLA	Wei, Zhenlong,et al."The flavonol glycoside icariin promotes bone formation in growing rats by activating the cAMP signaling pathway in primary cilia of osteoblasts".JOURNAL OF BIOLOGICAL CHEMISTRY 292(2017):20883-20896.