title: Arthritogenic alphaviral infection perturbs osteoblast function and triggers pathologic bone loss.
abstract: Arthritogenic alphaviruses including Ross River virus (RRV), Sindbis virus, and chikungunya virus cause worldwide outbreaks of musculoskeletal disease. The ability of alphaviruses to induce bone pathologies remains poorly defined. Here we show that primary human osteoblasts (hOBs) can be productively infected by RRV. RRV-infected hOBs produced high levels of inflammatory cytokine including IL-6. The RANKL/OPG ratio was disrupted in the synovial fluid of RRV patients, and this was accompanied by an increase in serum Tartrate-resistant acid phosphatase 5b (TRAP5b) levels. Infection of bone cells with RRV was validated using an established RRV murine model. In wild-type mice, infectious virus was detected in the femur, tibia, patella, and foot, together with reduced bone volume in the tibial epiphysis and vertebrae detected by microcomputed tomographic (µCT) analysis. The RANKL/OPG ratio was also disrupted in mice infected with RRV; both this effect and the bone loss were blocked by treatment with an IL-6 neutralizing antibody. Collectively, these findings provide previously unidentified evidence that alphavirus infection induces bone loss and that OBs are capable of producing proinflammatory mediators during alphavirus-induced arthralgia. The perturbed RANKL/OPG ratio in RRV-infected OBs may therefore contribute to bone loss in alphavirus infection.
authors.affiliation: Emerging Viruses and Inflammation Research Group, Institute for Glycomics, Griffith University, Gold Coast, QLD 4222, Australia.
authors.forename: Weiqiang
authors.initials: W
authors.lastname: Chen
authors.forename: Suan-Sin
authors.initials: SS
authors.lastname: Foo
authors.forename: Nestor E
authors.initials: NE
authors.lastname: Rulli
authors.forename: Adam
authors.initials: A
authors.lastname: Taylor
authors.forename: Kuo-Ching
authors.initials: KC
authors.lastname: Sheng
authors.forename: Lara J
authors.initials: LJ
authors.lastname: Herrero
authors.forename: Belinda L
authors.initials: BL
authors.lastname: Herring
authors.forename: Brett A
authors.initials: BA
authors.lastname: Lidbury
authors.forename: Rachel W
authors.initials: RW
authors.lastname: Li
authors.forename: Nicole C
authors.initials: NC
authors.lastname: Walsh
authors.forename: Natalie A
authors.initials: NA
authors.lastname: Sims
authors.forename: Paul N
authors.initials: PN
authors.lastname: Smith
authors.forename: Suresh
authors.initials: S
authors.lastname: Mahalingam
mesh_terms: D000135:Acid Phosphatase / Q000097:blood; D000328:Adult; D018354:Alphavirus Infections / Q000097:blood / Q000473:pathology* / Q000821:virology*; D000818:Animals; D057134:Antibodies, Neutralizing / Q000494:pharmacology; D001168:Arthritis / Q000097:blood / Q000473:pathology / Q000821:virology*; D001862:Bone Resorption / Q000097:blood / Q000473:pathology* / Q000821:virology*; D001842:Bone and Bones / Q000000981:diagnostic imaging / Q000473:pathology / Q000821:virology; D005260:Female; D006132:Growth Plate / Q000187:drug effects / Q000473:pathology / Q000821:virology; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D015850:Interleukin-6 / Q000096:biosynthesis; D007527:Isoenzymes / Q000097:blood; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009500:Neutralization Tests; D010006:Osteoblasts / Q000187:drug effects / Q000473:pathology* / Q000821:virology; D010010:Osteoclasts / Q000187:drug effects / Q000473:pathology / Q000821:virology; D010012:Osteogenesis / Q000187:drug effects; D053244:Osteoprotegerin / Q000378:metabolism; D010641:Phenotype; D053245:RANK Ligand / Q000378:metabolism; D012398:Ross River virus / Q000187:drug effects / Q000502:physiology*; D013582:Synovial Fluid / Q000378:metabolism; D000071681:Tartrate-Resistant Acid Phosphatase; D014779:Virus Replication / Q000187:drug effects; D055114:X-Ray Microtomography
chemical_list: D057134:Antibodies, Neutralizing; D018836:Inflammation Mediators; D015850:Interleukin-6; D007527:Isoenzymes; D053244:Osteoprotegerin; D053245:RANK Ligand; D000135:Acid Phosphatase; D000071681:Tartrate-Resistant Acid Phosphatase
keywords: Interleukin-6; Ross River virus disease; osteoclastogenesis; viral arthritis
references.citation: Immunity. 1997 Mar;6(3):315-25
references.pmid: 9075932
references.citation: Int Immunol. 2011 Nov;23(11):701-12
references.pmid: 21937456
references.citation: BMC Infect Dis. 2009 Dec 10;9:200
references.pmid: 20003320
references.citation: Arthritis Rheum. 2006 Nov;54(11):3551-63
references.pmid: 17075861
references.citation: J Orthop Res. 2010 Oct;28(10):1315-22
references.pmid: 20309870
references.citation: Bone. 2004 Jul;35(1):334-42
references.pmid: 15207775
references.citation: Immunol Rev. 2010 Jan;233(1):301-12
references.pmid: 20193007
references.citation: Immunol Invest. 2013;42(7):555-622
references.pmid: 24004059
references.citation: J Virol. 2006 Jan;80(2):737-49
references.pmid: 16378976
references.citation: Virology. 1991 Jun;182(2):430-41
references.pmid: 1673812
references.citation: J Virol. 2000 Oct;74(19):9294-9
references.pmid: 10982376
references.citation: Endocrinology. 2005 Apr;146(4):1991-8
references.pmid: 15618359
references.citation: Med J Aust. 2002 Oct 7;177(7):352-5
references.pmid: 12358576
references.citation: Clin Exp Rheumatol. 2008 Mar-Apr;26(2):295-304
references.pmid: 18565252
references.citation: BMB Rep. 2010 Aug;43(8):513-23
references.pmid: 20797312
references.citation: Emerg Infect Dis. 2005 Apr;11(4):613-5
references.pmid: 15829203
references.citation: J Infect Dis. 2008 Jun 1;197(11):1585-93
references.pmid: 18433328
references.citation: Cytokine Growth Factor Rev. 2004 Feb;15(1):49-60
references.pmid: 14746813
references.citation: Ann N Y Acad Sci. 2007 Apr;1102:96-108
references.pmid: 17470914
references.citation: J Clin Invest. 1992 Jan;89(1):46-52
references.pmid: 1729280
references.citation: Annu Rev Entomol. 2002;47:1-31
references.pmid: 11729067
references.citation: J Infect Dis. 2012 Aug 1;206(3):455-7: 457-9
references.pmid: 22634878
references.citation: EMBO J. 1994 Mar 1;13(5):1189-96
references.pmid: 8131749
references.citation: Cell Tissue Res. 2006 Feb;323(2):263-71
references.pmid: 16175387
references.citation: Nature. 2003 May 15;423(6937):356-61
references.pmid: 12748655
references.citation: FASEB J. 2002 Sep;16(11):1335-47
references.pmid: 12205025
references.citation: Ann Rheum Dis. 2010 Sep;69(9):1623-8
references.pmid: 20525836
references.citation: Viral Immunol. 2011 Aug;24(4):265-71
references.pmid: 21830898
references.citation: Arthritis Rheum. 2006 Jan;54(1):158-68
references.pmid: 16385511
references.citation: Biochem Biophys Res Commun. 1999 Nov;265(1):144-50
references.pmid: 10548505
references.citation: Mod Rheumatol. 2012 Apr;22(2):167-77
references.pmid: 21953286
references.citation: Microbiol Immunol. 2012 Feb;56(2):134-8
references.pmid: 22188545
references.citation: Proc Natl Acad Sci U S A. 2011 Jul 19;108(29):12048-53
references.pmid: 21730129
references.citation: Rheumatology (Oxford). 2003 May;42 Suppl 2:ii11-6
references.pmid: 12817090
references.citation: Aust N Z J Public Health. 2002 Feb;26(1):69-77
references.pmid: 11895031
references.citation: Mol Immunol. 2012 Oct;52(3-4):273-8
references.pmid: 22750227
references.citation: Trans R Soc Trop Med Hyg. 2010 Jun;104(6):392-9
references.pmid: 20171708
references.citation: Proc Natl Acad Sci U S A. 1998 Mar 31;95(7):3597-602
references.pmid: 9520411
references.citation: J Neurochem. 2005 Jul;94(1):238-48
references.pmid: 15953366
references.citation: Nat Med. 2009 Apr;15(4):417-24
references.pmid: 19330010
references.citation: Clin Exp Rheumatol. 2008 Mar-Apr;26(2):240-6
references.pmid: 18565244
references.citation: Joint Bone Spine. 2009 Dec;76(6):654-7
references.pmid: 19945329
references.citation: Methods Mol Med. 2003;80:19-28
references.pmid: 12728707
references.citation: Arch Biochem Biophys. 2008 May 15;473(2):139-46
references.pmid: 18395508
references.citation: J Infect Dis. 2011 Jan 15;203(2):149-57
references.pmid: 21288813
references.citation: J Infect Dis. 2000 Jan;181(1):27-34
references.pmid: 10608747
references.citation: J Immunol. 2010 May 15;184(10):5914-27
references.pmid: 20404278
references.citation: Intervirology. 2000;43(1):55-60
references.pmid: 10773738