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Mechanical stimulation induces bone growth and remodeling by the secondary messenger, cyclic guanosine 3', 5'-monophosphate (cGMP), in osteoblasts. However, the role of cGMP in the regulation of estrogen biosynthesis, whose deficiency is a major cause of osteoporosis, remains unclear. Here, we found that the prenylated flavonoids, 3- O -methoxymethyl-7- O -benzylicaritin (13), 7- O -benzylicaritin (14), and 4'- O -methyl-8-isopentylkaempferol (15), which were synthesized using icariin analogs, promoted estrogen biosynthesis in osteoblastic UMR106 cells, with calculated EC 50 values of 1.53, 3.45, and 10.57 µM, respectively. 14 and 15 increased the expression level of the bone specific promoter I.4-driven aromatase, the only enzyme that catalyzes estrogen formation by using androgens as substrates, in osteoblastic cells. 14 inhibited phosphodiesterase 5 (PDE5), stimulated intracellular cGMP level and promoted osteoblast cell differentiation. Inhibition of cGMP dependent-protein kinase G (PKG) abolished the stimulatory effect of 14 on estrogen biosynthesis and osteoblast cell differentiation. Further, PKG activation by 14 stimulated the activity of SHP2 (Src homology 2 domain-containing tyrosine phosphatase 2), thereby activating Src and ERK (extracellular signal-regulated kinase) signaling and increasing ERK-dependent aromatase expression in osteoblasts. Our findings reveal a previously unknown role of cGMP in the regulation of estrogen biosynthesis in the bone. These results support the further development of 14 as a PKG-activating drug to mimic the anabolic effects of mechanical stimulation of bone in the treatment of osteoporosis.

Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Titel:	Inhibition of Phosphodiesterase 5 Promotes the Aromatase-Mediated Estrogen Biosynthesis in Osteoblastic Cells by Activation of cGMP/PKG/SHP2 Pathway.
Autor/in / Beteiligte Person:	Wisanwattana, W ; Wongkrajang, K ; Cao, DY ; Shi, XK ; Zhang, ZH ; Zhou, ZY ; Li, F ; Mei, QG ; Wang, C ; Suksamrarn, A ; Zhang, GL ; Wang, F
Link:	Zum Volltext
Zeitschrift:	Frontiers in endocrinology, Jg. 12 (2021-03-12), S. 636784
Veröffentlichung:	[Lausanne : Frontiers Research Foundation], 2021
Medientyp:	academicJournal
ISSN:	1664-2392 (print)
DOI:	10.3389/fendo.2021.636784
Schlagwort:	3T3 Cells Animals Cell Differentiation Cell Line Cell Survival Cyclic AMP metabolism Cyclic GMP metabolism Cyclic GMP-Dependent Protein Kinases metabolism Flavonoids chemistry HEK293 Cells Humans Mice Molecular Docking Simulation Osteoblasts cytology Osteoporosis Protein Tyrosine Phosphatase, Non-Receptor Type 11 metabolism Stress, Mechanical Aromatase metabolism Cyclic Nucleotide Phosphodiesterases, Type 5 metabolism Estrogens metabolism Osteoblasts metabolism
Sonstiges:	Nachgewiesen in: MEDLINE Sprachen: English Publication Type: Journal Article; Research Support, Non-U.S. Gov't Language: English [Front Endocrinol (Lausanne)] 2021 Mar 12; Vol. 12, pp. 636784. <i>Date of Electronic Publication: </i>2021 Mar 12 (<i>Print Publication: </i>2021). MeSH Terms: Aromatase / metabolism ; Cyclic Nucleotide Phosphodiesterases, Type 5 / metabolism ; Estrogens / metabolism ; Osteoblasts / metabolism ; 3T3 Cells ; Animals ; Cell Differentiation ; Cell Line ; Cell Survival ; Cyclic AMP / metabolism ; Cyclic GMP / metabolism ; Cyclic GMP-Dependent Protein Kinases / metabolism ; Flavonoids / chemistry ; HEK293 Cells ; Humans ; Mice ; Molecular Docking Simulation ; Osteoblasts / cytology ; Osteoporosis ; Protein Tyrosine Phosphatase, Non-Receptor Type 11 / metabolism ; Stress, Mechanical References: J Biol Chem. 2012 Jan 6;287(2):978-88. (PMID: 22117068) ; Mol Cell Endocrinol. 1998 Apr 30;139(1-2):117-29. (PMID: 9705080) ; Cancer Sci. 2009 Oct;100(10):1786-93. (PMID: 19622105) ; Nature. 2003 Sep 4;425(6953):98-102. (PMID: 12955149) ; Phytomedicine. 2009 Apr;16(4):320-6. (PMID: 19269147) ; Cell Death Dis. 2014 Nov 27;5:e1544. (PMID: 25429621) ; J Biol Chem. 2001 Apr 27;276(17):14443-50. (PMID: 11278600) ; Trends Mol Med. 2013 Mar;19(3):197-209. (PMID: 23348042) ; J Ethnopharmacol. 2011 Apr 12;134(3):519-41. (PMID: 21215308) ; Beilstein J Org Chem. 2015 Jul 20;11:1220-5. (PMID: 26425179) ; Bone. 2020 Jun;135:115305. (PMID: 32126313) ; J Bone Miner Res. 2009 Mar;24(3):411-24. (PMID: 19016591) ; Bioorg Med Chem Lett. 2016 Nov 15;26(22):5497-5500. (PMID: 27765509) ; J Ethnopharmacol. 2013 Feb 13;145(3):715-21. (PMID: 23261485) ; IUBMB Life. 2009 Oct;61(10):979-86. (PMID: 19787703) ; Arch Pharm Res. 2008 Dec;31(12):1534-9. (PMID: 19099220) ; Oncotarget. 2017 Nov 20;8(69):113734-113748. (PMID: 29371942) ; Cell. 2003 Mar 21;112(6):737-40. (PMID: 12654240) ; Br J Pharmacol. 2010 Feb;159(4):939-49. (PMID: 20128811) ; Joint Bone Spine. 2006 Jan;73(1):37-42. (PMID: 16213769) ; Phytomedicine. 2010 May;17(6):414-23. (PMID: 19747809) ; Sci Signal. 2010 Dec 21;3(153):ra91. (PMID: 21177494) ; Nat Protoc. 2014 Sep;9(9):2100-22. (PMID: 25101824) ; Mol Endocrinol. 2009 Oct;23(10):1634-45. (PMID: 19556341) ; Eur J Pharmacol. 2012 Sep 15;691(1-3):275-82. (PMID: 22796452) ; J Bone Miner Res. 1998 May;13(5):763-73. (PMID: 9610739) ; Nitric Oxide. 2018 Jun 1;76:62-70. (PMID: 29550520) ; Phytomedicine. 2008 Jan;15(1-2):55-61. (PMID: 17482445) ; Annu Rev Physiol. 2002;64:93-127. (PMID: 11826265) ; Chin Med. 2012 Apr 30;7:10. (PMID: 22546174) ; J Bone Miner Res. 1998 Jun;13(6):996-1004. (PMID: 9626631) ; Beilstein J Org Chem. 2015 Feb 25;11:288-93. (PMID: 25815082) ; Eur J Endocrinol. 2005 Dec;153(6):981-8. (PMID: 16322405) ; Endocrinology. 2013 Mar;154(3):1202-14. (PMID: 23389955) ; J Med Chem. 2016 Oct 13;59(19):8967-9004. (PMID: 27606546) ; Mol Cell Biol. 2012 May;32(10):1867-78. (PMID: 22431513) ; Semin Reprod Med. 2004 Feb;22(1):11-23. (PMID: 15083377) ; Phytomedicine. 2005 Mar;12(3):189-93. (PMID: 15830840) ; Annu Rev Biochem. 1999;68:821-61. (PMID: 10872467) ; Sci Rep. 2017 Aug 10;7(1):7760. (PMID: 28798396) ; J Nat Prod. 2008 Sep;71(9):1513-7. (PMID: 18778098) ; Biochem Biophys Res Commun. 2000 Nov 2;277(3):604-10. (PMID: 11062001) ; Nat Rev Rheumatol. 2010 Jan;6(1):50-9. (PMID: 20046206) ; J Ethnopharmacol. 2011 May 17;135(2):553-60. (PMID: 21463675) ; Proc Natl Acad Sci U S A. 2020 Jun 23;117(25):14386-14394. (PMID: 32513693) ; Bone. 1998 Mar;22(3):201-9. (PMID: 9514212) ; J Gerontol A Biol Sci Med Sci. 2012 Nov;67(11):1140-52. (PMID: 22451474) ; Med Sci Monit Basic Res. 2018 Mar 13;24:47-58. (PMID: 29557941) ; Exp Biol Med (Maywood). 2017 May;242(10):1051-1061. (PMID: 28399643) ; J Sex Med. 2011 Mar;8(3):696-704. (PMID: 21176111) ; J Cell Biol. 2007 Feb 26;176(5):709-18. (PMID: 17325210) Contributed Indexing: Keywords: PDE5; aromatase; estrogen biosynthesis; icariin analogs; osteoblast Substance Nomenclature: 0 (Estrogens) ; 0 (Flavonoids) ; E0399OZS9N (Cyclic AMP) ; EC 1.14.14.1 (Aromatase) ; EC 2.7.11.12 (Cyclic GMP-Dependent Protein Kinases) ; EC 3.1.3.48 (Protein Tyrosine Phosphatase, Non-Receptor Type 11) ; EC 3.1.3.48 (Ptpn11 protein, mouse) ; EC 3.1.4.35 (Cyclic Nucleotide Phosphodiesterases, Type 5) ; EC 3.1.4.35 (Pde5a protein, mouse) ; H2D2X058MU (Cyclic GMP) ; VNM47R2QSQ (icariin) Entry Date(s): Date Created: 20210329 Date Completed: 20211221 Latest Revision: 20211221 Update Code: 20240513 PubMed Central ID: PMC7995890

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Inhibition of Phosphodiesterase 5 Promotes the Aromatase-Mediated Estrogen Biosynthesis in Osteoblastic Cells by Activation of cGMP/PKG/SHP2 Pathway.