title: Myocilin stimulates osteogenic differentiation of mesenchymal stem cells through mitogen-activated protein kinase signaling.
abstract: Myocilin is a secreted glycoprotein that is expressed in ocular and non-ocular tissues. Mutations in the MYOCILIN gene may lead to juvenile- and adult-onset primary open-angle glaucoma. Here we report that myocilin is expressed in bone marrow-derived mesenchymal stem cells (MSCs) and plays a role in their differentiation into osteoblasts in vitro and in osteogenesis in vivo. Expression of myocilin was detected in MSCs derived from mouse, rat, and human bone marrow, with human MSCs exhibiting the highest level of myocilin expression. Expression of myocilin rose during the course of human MSC differentiation into osteoblasts but not into adipocytes, and treatment with exogenous myocilin further enhanced osteogenesis. MSCs derived from Myoc-null mice had a reduced ability to differentiate into the osteoblastic lineage, which was partially rescued by exogenous extracellular myocilin treatment. Myocilin also stimulated osteogenic differentiation of wild-type MSCs, which was associated with activation of the p38, Erk1/2, and JNK MAP kinase signaling pathways as well as up-regulated expression of the osteogenic transcription factors Runx2 and Dlx5. Finally, cortical bone thickness and trabecular volume, as well as the expression level of osteopontin, a known factor of bone remodeling and osteoblast differentiation, were reduced dramatically in the femurs of Myoc-null mice compared with wild-type mice. These data suggest that myocilin should be considered as a target for improving the bone regenerative potential of MSCs and may identify a new role for myocilin in bone formation and/or maintenance in vivo.
authors: Section of Retinal Ganglion Cell Biology, Laboratory of Retinal Cell and Molecular Biology, National Eye Institute, National Institutes of Health, Bethesda, Maryland 20892.
authors: Heung Sun
authors: HS
authors: Kwon
authors: Section of Retinal Ganglion Cell Biology, Laboratory of Retinal Cell and Molecular Biology, National Eye Institute, National Institutes of Health, Bethesda, Maryland 20892.
authors: Thomas V
authors: TV
authors: Johnson
authors: Section of Retinal Ganglion Cell Biology, Laboratory of Retinal Cell and Molecular Biology, National Eye Institute, National Institutes of Health, Bethesda, Maryland 20892. Electronic address: tomarevs@nei.nih.gov.
authors: Stanislav I
authors: SI
authors: Tomarev
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000502:physiology*; D002478:Cells, Cultured; D050659:Core Binding Factor Alpha 1 Subunit / Q000096:biosynthesis / Q000235:genetics; D003598:Cytoskeletal Proteins / Q000235:genetics / Q000378:metabolism*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000235:genetics / Q000378:metabolism; D005136:Eye Proteins / Q000235:genetics / Q000378:metabolism*; D006023:Glycoproteins / Q000235:genetics / Q000378:metabolism*; D018398:Homeodomain Proteins / Q000096:biosynthesis / Q000235:genetics; D006801:Humans; D020935:MAP Kinase Signaling System / Q000502:physiology*; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000378:metabolism*; D051379:Mice; D008817:Mice, Mutant Strains; D010006:Osteoblasts / Q000166:cytology / Q000378:metabolism*; D010012:Osteogenesis / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014157:Transcription Factors / Q000096:biosynthesis / Q000235:genetics; D015854:Up-Regulation / Q000502:physiology; D000099179:Myocilin
chemical_list: D050659:Core Binding Factor Alpha 1 Subunit; D003598:Cytoskeletal Proteins; D048049:Extracellular Signal-Regulated MAP Kinases; D005136:Eye Proteins; D006023:Glycoproteins; D018398:Homeodomain Proteins; D014157:Transcription Factors; D000099179:Myocilin; C100596:DLX5 protein, human; C088334:Distal-less homeobox proteins; C501120:Dlx5 protein, mouse; C493709:RUNX2 protein, human; C493716:Runx2 protein, mouse; C493717:Runx2 protein, rat
keywords: Differentiation; Glycoprotein Secretion; MAP Kinases (MAPKs); Mesenchymal Stem Cells; Myocilin; Osteogenesis; Signaling
references: Invest Ophthalmol Vis Sci. 2003 Jun;44(6):2588-96
references: 12766061
references: J Clin Invest. 2011 Sep;121(9):3542-53
references: 21821918
references: Invest Ophthalmol Vis Sci. 2008 May;49(5):1932-9
references: 18436825
references: Nature. 2002 Jul 4;418(6893):41-9
references: 12077603
references: Proc Natl Acad Sci U S A. 2008 Oct 28;105(43):16809-13
references: 18922779
references: Science. 1997 Jan 31;275(5300):668-70
references: 9005853
references: Rheumatology (Oxford). 2008 Dec;47(12):1775-9
references: 18854347
references: J Clin Invest. 2010 Jul;120(7):2457-73
references: 20551513
references: Science. 1999 Apr 2;284(5411):143-7
references: 10102814
references: Science. 2005 Jun 3;308(5727):1472-7
references: 15933201
references: Tissue Eng. 1998 Winter;4(4):415-28
references: 9916173
references: J Biol Chem. 2005 Sep 9;280(36):31353-9
references: 16000303
references: Exp Cell Res. 2008 Apr 15;314(7):1495-506
references: 18313048
references: N Engl J Med. 2009 Mar 12;360(11):1113-24
references: 19279343
references: Exp Cell Res. 1998 Jan 10;238(1):265-72
references: 9457080
references: ACS Nano. 2010 Nov 23;4(11):6439-48
references: 21028783
references: J Biol Chem. 2008 Feb 15;283(7):3816-26
references: 18056716
references: Crit Rev Oral Biol Med. 2000;11(3):279-303
references: 11021631
references: Invest Ophthalmol Vis Sci. 2000 Nov;41(12):3678-93
references: 11053263
references: J Biomed Biotechnol. 2010;2010:795385
references: 20182548
references: Nat Protoc. 2009;4(1):102-6
references: 19131962
references: Biochem J. 2007 Dec 15;408(3):297-315
references: 17850214
references: J Neurosci. 2006 Nov 15;26(46):11903-14
references: 17108164
references: Endocrinology. 2003 Jun;144(6):2588-96
references: 12746322
references: J Cell Biochem. 2011 Dec;112(12):3491-501
references: 21793042
references: Nat Struct Biol. 2002 Apr;9(4):268-72
references: 11896401
references: J Cell Physiol. 2007 Nov;213(2):341-7
references: 17620285
references: Mol Cell Biol. 2006 Nov;26(22):8427-36
references: 16954374
references: J Biol Chem. 2004 Jan 2;279(1):259-64
references: 14573624
references: J Cell Commun Signal. 2009 Dec;3(3-4):227-38
references: 19862642
references: Invest Ophthalmol Vis Sci. 2011 Jan 05;52(1):179-89
references: 20926826
references: Surv Ophthalmol. 2002 Nov-Dec;47(6):547-61
references: 12504739
references: Proc Natl Acad Sci U S A. 2009 Nov 3;106(44):18587-91
references: 19843692
references: Exp Eye Res. 2009 Apr;88(4):738-46
references: 19084518
references: Biochem Biophys Res Commun. 2003 Dec 19;312(3):592-600
references: 14680806
references: J Biol Chem. 1998 Mar 13;273(11):6341-50
references: 9497363
references: Biochim Biophys Acta. 2008 Jan;1784(1):76-93
references: 17964301
references: Biochem Biophys Res Commun. 2003 Sep 26;309(3):689-94
references: 12963046
references: Invest Ophthalmol Vis Sci. 2001 Dec;42(13):3173-81
references: 11726619
references: Biochem Biophys Res Commun. 1998 Apr 28;245(3):887-93
references: 9588210
references: Mol Cell Biol. 2009 Apr;29(8):2139-54
references: 19188438
references: Invest Ophthalmol Vis Sci. 2006 Jan;47(1):206-12
references: 16384964
references: Biochim Biophys Acta. 2007 Aug;1773(8):1358-75
references: 17481747
references: Mol Cell Biol. 2001 Nov;21(22):7707-13
references: 11604506
references: Invest Ophthalmol Vis Sci. 2010 Apr;51(4):2051-9
references: 19933193
references: Am J Pathol. 2010 Jun;176(6):2880-90
references: 20382707
references: Nature. 1994 Dec 22-29;372(6508):739-46
references: 7997261
references: J Cell Mol Med. 2010 Sep;14(9):2190-9
references: 20716123
references: Hum Mol Genet. 1997 Nov;6(12):2091-7
references: 9328473
references: J Bone Joint Surg Br. 2011 Apr;93(4):427-34
references: 21464477
references: J Biol Chem. 2012 Apr 13;287(16):13216-27
references: 22371502
references: Hum Mol Genet. 1999 May;8(5):899-905
references: 10196380
references: Invest Ophthalmol Vis Sci. 2000 Nov;41(12):3842-9
references: 11053284
references: J Med Genet. 2006 Aug;43(8):691-8
references: 16611749
references: Cell Stem Cell. 2010 Oct 8;7(4):431-42
references: 20887949
references: Exp Cell Res. 2005 Feb 15;303(2):218-28
references: 15652337
references: J Cell Biol. 2007 Feb 26;176(5):709-18
references: 17325210