Synovium-Derived MicroRNAs Regulate Bone Pathways in Rheumatoid Arthritis.
Articular bone erosion in rheumatoid arthritis (RA) is mediated by the interaction between inflammation and pathways regulating bone metabolism. Inflammation promotes osteoclastogenesis and also inhibits osteoblast function, further contributing to the persistence of erosions. MicroRNAs (miRNAs) are important regulators of skeletal remodeling and play a role in RA pathogenesis. We therefore determined the expression of miRNAs in inflamed synovial tissue and the role they play in pathways regulating osteoblast and osteoclast function. Using the serum transfer mouse model of RA in C57BL/6 mice, we performed Fluidigm high-throughput qPCR-based screening of miRNAs from nonarthritic and arthritic mice. Global gene expression profiling was also performed on Affymetrix microarrays from these same synovial samples. miRNA and mRNA expression profiles were subjected to comparative bioinformatics. A total of 536 upregulated genes and 417 downregulated genes were identified that are predicted targets of miRNAs with reciprocal expression changes. Gene ontology analysis of these genes revealed significant enrichment in skeletal pathways. Of the 22 miRNAs whose expression was most significantly changed (p < 0.01) between nonarthritic and arthritic mice, we identified their targets that both inhibit and promote bone formation. These miRNAs are predicted to target Wnt and BMP signaling pathway components. We validated miRNA array findings and demonstrated that secretion of miR-221-3p in exosomes was upregulated by synovial fibroblasts treated with the proinflammatory cytokine TNF. Overexpression of miR-221-3p suppressed calvarial osteoblast differentiation and mineralization in vitro. These results suggest that miRNAs derived from inflamed synovial tissues may regulate signaling pathways at erosion sites that affect bone loss and potentially also compensatory bone formation. © 2016 American Society for Bone and Mineral Research.
Department of Medicine, University of Massachusetts Medical School, Worcester, MA, USA.
Yukiko
Y
Maeda
Department of Biochemistry, University of Vermont, Burlington, VT, USA.
Nicholas H
NH
Farina
Department of Medicine, University of Massachusetts Medical School, Worcester, MA, USA.
Melissa M
MM
Matzelle
Department of Orthopedic Surgery and Physical Rehabilitation, University of Massachusetts Medical School, Worcester, MA, USA.
Paul J
PJ
Fanning
Department of Biochemistry, University of Vermont, Burlington, VT, USA.|Department of Orthopedic Surgery and Physical Rehabilitation, University of Massachusetts Medical School, Worcester, MA, USA.
Jane B
JB
Lian
Department of Medicine, University of Massachusetts Medical School, Worcester, MA, USA.
Ellen M
EM
Gravallese
D000818:Animals; D001172:Arthritis, Rheumatoid / Q000235:genetics* / Q000473:pathology; D001842:Bone and Bones / Q000378:metabolism* / Q000473:pathology; D002454:Cell Differentiation / Q000235:genetics; D002478:Cells, Cultured; D015536:Down-Regulation / Q000235:genetics; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology; D020869:Gene Expression Profiling; D008297:Male; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D010006:Osteoblasts / Q000378:metabolism / Q000473:pathology; D015398:Signal Transduction / Q000235:genetics*; D013583:Synovial Membrane / Q000378:metabolism* / Q000473:pathology; D000070918:Synoviocytes / Q000378:metabolism
D035683:MicroRNAs
BONE; MICRORNA; OSTEOBLAST; RHEUMATOID ARTHRITIS; SYNOVIUM
Nat Clin Pract Rheumatol. 2008 Sep;4(9):473-80
18756273
J Bone Miner Res. 2009 Sep;24(9):1572-85
19338457
J Clin Invest. 2013 Apr;123(4):1542-55
23454749
Science. 1999 Sep 17;285(5435):1923-6
10489374
Nat Med. 2012 Jul;18(7):1077-86
22660635
J Biol Chem. 2012 Jan 6;287(2):916-24
22102413
Ann Rheum Dis. 2013 Oct;72(10):1732-6
23666928
Ann Rheum Dis. 2008 Dec;67 Suppl 3:iii50-5
19022814
Nature. 2012 May 3;485(7396):69-74
22522930
Mol Cell Biochem. 2015 Oct;408(1-2):283-93
26160280
Nat Genet. 2005 Sep;37(9):945-52
16056226
Cancer Res. 1999 Aug 1;59(15):3705-11
10446985
J Clin Invest. 2007 Jun;117(6):1616-26
17549257
Methods. 2001 Dec;25(4):402-8
11846609
Curr Osteoporos Rep. 2014 Mar;12(1):90-7
24488619
J Biochem. 2012 Mar;151(3):247-54
22253449
Int J Cancer. 2015 Sep 15;137(6):1352-61
25704289
J Clin Invest. 2012 Oct;122(10 ):3563-78
23006329
Mol Cell Biol. 2011 Jan;31(1):203-14
21041476
Front Genet. 2013 Nov 12;4:214
24273550
J Cell Biochem. 2010 Apr 1;109 (5):866-75
20039311
Endocrinology. 2002 Jun;143(6):2349-56
12021200
Nat Med. 2013 Feb;19(2):179-92
23389618
JAKSTAT. 2013 Jul 1;2(3):e23930
24069548
J Clin Invest. 2004 May;113(9):1334-43
15124025
Immunity. 1999 Apr;10(4):451-61
10229188
Ann Rheum Dis. 2000 Aug;59(8):647-9
10913064
Nat Commun. 2011;2:282
21505438
Cancer Res. 2008 Apr 15;68(8):2773-80
18413744
Am J Cancer Res. 2013 Nov 01;3(5):465-77
24224124
Proc Natl Acad Sci U S A. 2013 Jul 9;110(28):11499-504
23798430
Nat Rev Clin Oncol. 2011 Jun 07;8(8):467-77
21647195
Arthritis Rheum. 2011 Feb;63(2):373-81
21279994
Arthritis Res Ther. 2015 Jul 28;17:192
26215036
Ann Rheum Dis. 2014 Oct;73(10):1898-904
23897768
J Biol Chem. 2002 Nov 15;277(46):44005-12
12215457
Cell. 2000 Dec 22;103(7):1085-97
11163184
Nat Commun. 2016 Mar 07;7:10872
26947250
Proc Natl Acad Sci U S A. 2010 Jan 5;107(1):264-9
20018759
FEBS Lett. 2013 Sep 17;587(18):3027-31
23886710
BMC Genomics. 2011 Mar 09;12:144
21388556
Oncogene. 2008 Sep 25;27(43):5651-61
18521080
Nature. 1999 Feb 18;397(6720):617-21
10050855
Swiss Med Wkly. 2011 Mar 18;141:w13175
21416408
Dev Biol. 2010 Apr 1;340(1):10-21
20079730
J Biol Chem. 2001 Apr 6;276(14):10700-5
11152674
Cancer Res. 2003 Sep 1;63(17):5357-62
14500368
Proc Natl Acad Sci U S A. 2008 Feb 12;105(6):1949-54
18238902
Mol Cell Biol. 2009 Aug;29(15):4201-19
19487464
Arthritis Rheum. 2012 May;64(5):1540-50
22139865
Traffic. 2011 Dec;12(12):1659-68
21645191
Arthritis Rheum. 1999 Dec;42(12):2517-23
10615996
Nat Rev Endocrinol. 2012 Jan 31;8(4):212-27
22290358
Nucleic Acids Res. 2008 Jan;36(Database issue):D154-8
17991681
Arthritis Rheum. 2012 Oct;64(10):3240-5
22674011
J Biol Chem. 2008 Oct 17;283(42):28274-86
18682393
Nat Med. 2007 Feb;13(2):156-63
17237793
Proc Natl Acad Sci U S A. 2008 Sep 16;105(37):13906-11
18784367
Nat Protoc. 2009;4(1):44-57
19131956
Development. 2003 Sep;130(17):4123-33
12874132
Clin Exp Immunol. 2013 Jan;171(1):91-9
23199328
Mol Med Rep. 2015 Aug;12(2):2395-401
25891943
Genes Dev. 2001 Nov 1;15(21):2865-76
11691837
Proc Natl Acad Sci U S A. 2011 Jun 14;108(24):9863-8
21628588
Proc Natl Acad Sci U S A. 2011 Jul 5;108(27):11193-8
21690378
Ann Rheum Dis. 2012 Oct;71(10):1716-23
22562984
ScientificWorldJournal. 2010 Apr 13;10:624-32
20419275
Am J Respir Crit Care Med. 2012 Dec 1;186(11):1168-79
23065014