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Icariin, a prenylated flavonol glycoside isolated from Epimedii herba, has been found to be a potent stimulator of osteogenic differentiation and has potential application in preventing bone loss. However, the signaling pathway underlying its osteogenic effect remains unclear. We hypothesized that the osteogenic activity of icariin is related to the nitric oxide (NO) signal pathway and PI3K/AKT pathway in its upstream. Rat bone marrow stromal cells (rBMSCs) were cultured in osteogenic medium and treated with icariin or together with L-NAME, ODQ, PDE5, and/or LY294002 (the inhibitor of NOS, sGC, cGMP, and PI3K respectively), and effects were examined on the expression of signal messengers (NOS, NO, sGC, cGMP, PKG and PI3K) and the levels of osteogenic markers (alkaline phosphatase or ALP, osteocalcin and calcified nodules). It was found that icariin dose-dependently increased ALP activity, and treatment at the optimal concentration (10(-5)M) increased NOS activity, iNOS and eNOS expression, NO production, sGC and cGMP contents and PKG expression besides the phosphorylation of AKT. The addition of L-NAME, ODQ and PDE5 significantly inhibited the icariin effects on above markers respectively. The addition of LY294002 decreased the p-AKT level, NOS activity, eNOS expression and NO production significantly, but had no significant effect on iNOS expression. The addition of any of the four inhibitors also abolished the osteogenic effect of icariin on rBMSCs as indicated by ALP activity, osteocalcin synthesis, calcium deposition and the number and areas of calcified nodules. These results suggest that the osteogenic effect of icariin involves the PI3K-AKT-eNOS-NO-cGMP-PKG signal pathway. Furthermore, dosage response studies showed that icariin at 10(-6)M (a physiologically achievable concentration in vivo) also activated this signal pathway.

Titel:	Icariin stimulates the osteogenic differentiation of rat bone marrow stromal cells via activating the PI3K-AKT-eNOS-NO-cGMP-PKG.
Autor/in / Beteiligte Person:	Zhai, YK ; Guo, XY ; Ge, BF ; Zhen, P ; Ma, XN ; Zhou, J ; Ma, HP ; Xian, CJ ; Chen, KM
Link:	Zum Volltext
Zeitschrift:	Bone, Jg. 66 (2014-09-01), S. 189
Veröffentlichung:	New York : Elsevier Science ; <i>Original Publication</i>: Elmsford, NY : Pergamon Press, c1985-, 2014
Medientyp:	academicJournal
ISSN:	1873-2763 (electronic)
DOI:	10.1016/j.bone.2014.06.016
Schlagwort:	Alkaline Phosphatase metabolism Animals Chromones pharmacology Cyclic GMP-Dependent Protein Kinases metabolism Cyclic Nucleotide Phosphodiesterases, Type 5 metabolism Enzyme Activation drug effects Enzyme Inhibitors pharmacology Male Mesenchymal Stem Cells drug effects Morpholines pharmacology NG-Nitroarginine Methyl Ester pharmacology Nitric Oxide Synthase Type III metabolism Osteocalcin metabolism Phenotype Phosphatidylinositol 3-Kinases metabolism Phosphorylation drug effects Proto-Oncogene Proteins c-akt metabolism Rats, Wistar Signal Transduction drug effects Cell Differentiation drug effects Cyclic GMP metabolism Flavonoids pharmacology Mesenchymal Stem Cells cytology Mesenchymal Stem Cells enzymology Nitric Oxide metabolism Osteogenesis drug effects
Sonstiges:	Nachgewiesen in: MEDLINE Sprachen: English Publication Type: Journal Article; Research Support, Non-U.S. Gov't Language: English [Bone] 2014 Sep; Vol. 66, pp. 189-98. <i>Date of Electronic Publication: </i>2014 Jun 20. MeSH Terms: Cell Differentiation / drug effects ; Cyclic GMP / metabolism ; Flavonoids / pharmacology ; Mesenchymal Stem Cells / cytology ; Mesenchymal Stem Cells / enzymology ; Nitric Oxide / metabolism ; Osteogenesis / *drug effects ; Alkaline Phosphatase / metabolism ; Animals ; Chromones / pharmacology ; Cyclic GMP-Dependent Protein Kinases / metabolism ; Cyclic Nucleotide Phosphodiesterases, Type 5 / metabolism ; Enzyme Activation / drug effects ; Enzyme Inhibitors / pharmacology ; Male ; Mesenchymal Stem Cells / drug effects ; Morpholines / pharmacology ; NG-Nitroarginine Methyl Ester / pharmacology ; Nitric Oxide Synthase Type III / metabolism ; Osteocalcin / metabolism ; Phenotype ; Phosphatidylinositol 3-Kinases / metabolism ; Phosphorylation / drug effects ; Proto-Oncogene Proteins c-akt / metabolism ; Rats, Wistar ; Signal Transduction / drug effects Contributed Indexing: Keywords: Bone marrow stromal cells; Icariin; Nitric oxide; Osteogenic differentiation; Signal transduction Substance Nomenclature: 0 (Chromones) ; 0 (Enzyme Inhibitors) ; 0 (Flavonoids) ; 0 (Morpholines) ; 104982-03-8 (Osteocalcin) ; 31C4KY9ESH (Nitric Oxide) ; 31M2U1DVID (2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one) ; EC 1.14.13.39 (Nitric Oxide Synthase Type III) ; EC 2.7.1.- (Phosphatidylinositol 3-Kinases) ; EC 2.7.11.1 (Proto-Oncogene Proteins c-akt) ; EC 2.7.11.12 (Cyclic GMP-Dependent Protein Kinases) ; EC 3.1.3.1 (Alkaline Phosphatase) ; EC 3.1.4.35 (Cyclic Nucleotide Phosphodiesterases, Type 5) ; H2D2X058MU (Cyclic GMP) ; V55S2QJN2X (NG-Nitroarginine Methyl Ester) ; VNM47R2QSQ (icariin) Entry Date(s): Date Created: 20140624 Date Completed: 20150330 Latest Revision: 20220410 Update Code: 20240513

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Icariin stimulates the osteogenic differentiation of rat bone marrow stromal cells via activating the PI3K-AKT-eNOS-NO-cGMP-PKG.