title: Lipoprotein receptor-related protein 6 is required for parathyroid hormone-induced Sost suppression.
abstract: Parathyroid hormone (PTH) suppresses the expression of the bone formation inhibitor sclerostin (Sost) in osteocytes by inducing nuclear accumulation of histone deacetylases (HDACs) to inhibit the myocyte enhancer factor 2 (MEF2)-dependent Sost bone enhancer. Previous studies revealed that lipoprotein receptor-related protein 6 (LRP6) mediates the intracellular signaling activation and the anabolic bone effect of PTH. Here, we investigated whether LRP6 mediates the inhibitory effect of PTH on Sost using an osteoblast-specific Lrp6-knockout (LRP6-KO) mouse model. An increased level of Sost mRNA expression was detected in femur tissue from LRP6-KO mice, compared to wild-type littermates. The number of osteocytes expressing sclerostin protein was also increased in bone tissue of LRP6-KO littermates, indicating a negative regulatory role of LRP6 on Sost/sclerostin. In wild-type littermates, intermittent PTH treatment significantly suppressed Sost mRNA expression in bone and the number of sclerostin(+) osteocytes, while the effect of PTH was much less significant in LRP6-KO mice. Additionally, PTH-induced downregulation of MEF2C and 2D, as well as HDAC changes in osteocytes, were abrogated in LRP6-KO mice. These data indicate that LRP6 is required for PTH suppression of Sost expression.
authors.affiliation: Department of Orthopaedic Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland.|Institute of Endocrinology and Metabolism, Second Xiangya Hospital, Central South University, Changsha, Hunan, China.
authors.forename: Changjun
authors.initials: C
authors.lastname: Li
authors.affiliation: Department of Orthopaedics, Medical College of Shihezi University, Shihezi, Xinjiang, China.
authors.forename: Weishan
authors.initials: W
authors.lastname: Wang
authors.affiliation: Department of Orthopaedic Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland.|State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, China.
authors.forename: Liang
authors.initials: L
authors.lastname: Xie
authors.affiliation: Institute of Endocrinology and Metabolism, Second Xiangya Hospital, Central South University, Changsha, Hunan, China.
authors.forename: Xianghang
authors.initials: X
authors.lastname: Luo
authors.affiliation: Department of Orthopaedic Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Xu
authors.initials: X
authors.lastname: Cao
authors.affiliation: Department of Orthopaedic Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Mei
authors.initials: M
authors.lastname: Wan
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D001842:Bone and Bones / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D003433:Crosses, Genetic; D005269:Femur; D005786:Gene Expression Regulation / Q000187:drug effects; D006023:Glycoproteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D056464:Histone Deacetylase 2 / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D006655:Histone Deacetylases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007279:Injections, Subcutaneous; D036341:Intercellular Signaling Peptides and Proteins; D060488:Low Density Lipoprotein Receptor-Related Protein-6 / Q000235:genetics / Q000378:metabolism*; D064326:MEF2 Transcription Factors / Q000819:agonists / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D010281:Parathyroid Hormone / Q000008:administration & dosage / Q000378:metabolism* / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D011897:Random Allocation; D000099186:Histone Deacetylase 3
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D006023:Glycoproteins; D056464:Histone Deacetylase 2; D006655:Histone Deacetylases; D036341:Intercellular Signaling Peptides and Proteins; D060488:Low Density Lipoprotein Receptor-Related Protein-6; D064326:MEF2 Transcription Factors; D010281:Parathyroid Hormone; D012333:RNA, Messenger; D000099186:Histone Deacetylase 3; C555476:Lrp6 protein, mouse; C578041:Mef2c protein, mouse; C578044:Mef2d protein, mouse; C486030:Sost protein, mouse; C533424:Hdac2 protein, mouse
keywords: HDAC; LRP6; Li, C., W. Wang, L. Xie, X. Luo, X. Cao & M. Wan. Lipoprotein receptor-related protein 6 is required for parathyroid hormone-induced Sost suppression. In “MARROW,” ed. by M. Zaidi. Ann. N.Y. Acad. Sci. 1364: 62-73.; MEF2; PTH; Sost; osteocyte; sclerostin
references.citation: Science. 1991 Nov 15;254(5034):1024-6
references.pmid: 1658941
references.citation: Proc Natl Acad Sci U S A. 2008 May 20;105(20):7281-6
references.pmid: 18490653
references.citation: J Biol Chem. 2006 Aug 18;281(33):23698-711
references.pmid: 16790443
references.citation: Osteoporos Int. 2014 Dec;25(12):2743-54
references.pmid: 25074352
references.citation: Expert Opin Biol Ther. 2014 May;14(5):697-707
references.pmid: 24665957
references.citation: Trends Endocrinol Metab. 2004 Mar;15(2):60-5
references.pmid: 15036251
references.citation: Proc Natl Acad Sci U S A. 1992 Apr 1;89(7):2732-6
references.pmid: 1313566
references.citation: Bone. 2012 Mar;50(3):663-9
references.pmid: 22155511
references.citation: Am J Hum Genet. 2001 Mar;68(3):577-89
references.pmid: 11179006
references.citation: Cell Mol Life Sci. 2005 Mar;62(5):551-77
references.pmid: 15747061
references.citation: J Clin Endocrinol Metab. 2010 Apr;95(4):1991-7
references.pmid: 20156921
references.citation: PLoS One. 2011;6(3):e17772
references.pmid: 21436889
references.citation: Bone. 2013 Jun;54(2):250-7
references.pmid: 23017659
references.citation: Proc Natl Acad Sci U S A. 2012 Aug 28;109(35):14092-7
references.pmid: 22886088
references.citation: J Bone Miner Res. 2011 May;26(5):1035-46
references.pmid: 21140374
references.citation: J Bone Miner Res. 2008 Jun;23(6):860-9
references.pmid: 18269310
references.citation: J Biol Chem. 2014 Sep 5;289(36):24995-5009
references.pmid: 25012661
references.citation: J Biol Chem. 1998 Mar 27;273(13):7547-53
references.pmid: 9516456
references.citation: J Bone Miner Res. 1997 Mar;12(3):384-92
references.pmid: 9076581
references.citation: J Cell Biol. 2014 Jun 23;205(6):771-80
references.pmid: 24934156
references.citation: J Bone Joint Surg Am. 2014 Oct 1;96(19):1659-68
references.pmid: 25274791
references.citation: J Bone Miner Res. 2015 Feb;30(2):274-85
references.pmid: 25088803
references.citation: Dev Biol. 2011 Nov 15;359(2):222-9
references.pmid: 21924256
references.citation: J Endocrinol. 2011 Apr;209(1):21-32
references.pmid: 21220409
references.citation: J Biol Chem. 2005 May 20;280(20):19883-7
references.pmid: 15778503
references.citation: J Exp Med. 2004 Mar 15;199(6):805-14
references.pmid: 15024046
references.citation: Trends Endocrinol Metab. 2010 Apr;21(4):237-44
references.pmid: 20074973
references.citation: Endocrinology. 2005 Nov;146(11):4577-83
references.pmid: 16081646
references.citation: Cell Stem Cell. 2010 Nov 5;7(5):571-80
references.pmid: 21040899
references.citation: J Bone Miner Res. 2015 Mar;30(3):400-11
references.pmid: 25271055
references.citation: Proc Natl Acad Sci U S A. 2012 Sep 11;109(37):15048-53
references.pmid: 22927401
references.citation: J Bone Miner Res. 2012 Sep;27(9):2001-14
references.pmid: 22589223
references.citation: Discov Med. 2011 Oct;12(65):263-73
references.pmid: 22031665
references.citation: J Bone Miner Res. 2007 Mar;22(3):394-402
references.pmid: 17147489
references.citation: J Mol Histol. 2007 Aug;38(4):261-9
references.pmid: 17549589
references.citation: EMBO J. 2003 Dec 1;22(23):6267-76
references.pmid: 14633986
references.citation: Genes Dev. 2008 Nov 1;22(21):2968-79
references.pmid: 18981475
references.citation: Bone. 2005 Aug;37(2):148-58
references.pmid: 15946907
references.citation: Ann N Y Acad Sci. 2011 Nov;1237:39-46
references.pmid: 22082363
references.citation: Nat Rev Mol Cell Biol. 2002 Sep;3(9):639-50
references.pmid: 12209124
references.citation: J Biol Chem. 2002 Nov 15;277(46):44005-12
references.pmid: 12215457
references.citation: PLoS One. 2009;4(11):e7930
references.pmid: 19936252
references.citation: Bone Res. 2014 Apr 29;2:14006
references.pmid: 26273519
references.citation: J Bone Miner Res. 2013 Oct;28(10):2094-108
references.pmid: 23609180
references.citation: Nat Genet. 2009 Nov;41(11):1199-206
references.pmid: 19801982
references.citation: PLoS One. 2008;3(8):e2942
references.pmid: 18698360
references.citation: J Bone Miner Res. 2007 Dec;22(12):1957-67
references.pmid: 17696759
references.citation: Expert Opin Biol Ther. 2011 Jan;11(1):117-27
references.pmid: 21114421
references.citation: J Musculoskelet Neuronal Interact. 2008 Oct-Dec;8(4):291-3
references.pmid: 19147944
references.citation: Nat Med. 2009 Jul;15(7):757-65
references.pmid: 19584867
references.citation: J Biol Chem. 2005 Jul 22;280(29):26770-5
references.pmid: 15908424
references.citation: Endocrinology. 2010 Aug;151(8):3502-13
references.pmid: 20501677
references.citation: Sci Signal. 2011;4(164):ra15
references.pmid: 21406690
references.citation: J Bone Miner Res. 2012 Feb;27(2):360-73
references.pmid: 22161640
references.citation: J Clin Endocrinol Metab. 2010 Nov;95(11):5056-62
references.pmid: 20631014
references.citation: Science. 2009 Aug 14;325(5942):834-40
references.pmid: 19608861
references.citation: Bone. 2007 Jun;40(6):1434-46
references.pmid: 17517365
references.citation: Bone. 2010 Jun;46(6):1486-97
references.pmid: 20188226
references.citation: Genome Res. 2005 Jul;15(7):928-35
references.pmid: 15965026
references.citation: Endocr Rev. 2005 Feb;26(1):78-113
references.pmid: 15689574
references.citation: Ann N Y Acad Sci. 2007 Nov;1117:196-208
references.pmid: 18056044
references.citation: Hum Mol Genet. 2001 Mar 1;10(5):537-43
references.pmid: 11181578
references.citation: J Cell Biochem. 1994 Jul;55(3):287-99
references.pmid: 7962159
references.citation: Nat Med. 2012 Jul;18(7):1095-101
references.pmid: 22729283
references.citation: Cell Metab. 2010 Feb 3;11(2):161-71
references.pmid: 20142103
references.citation: J Bone Miner Res. 1995 Dec;10(12):1935-43
references.pmid: 8619374
references.citation: Development. 2007 Dec;134(23):4131-40
references.pmid: 17959722
references.citation: J Bone Miner Res. 2011 Feb;26(2):229-38
references.pmid: 21254230
references.citation: J Bone Miner Res. 2012 Oct;27(10):2075-84
references.pmid: 22623172