Inhibition of osteoclast differentiation and collagen antibody-induced arthritis by CTHRC1

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dc.contributor.authorJin, Yong-Ri
dc.contributor.authorStohn, J. Patrizia
dc.contributor.authorWang, Qiaozeng
dc.contributor.authorNagano, Kenichi
dc.contributor.authorBaron, Roland
dc.contributor.authorBouxsein, Mary L.
dc.contributor.authorRosen, Clifford J.
dc.contributor.authorAdarichev, Vyacheslav A.
dc.contributor.authorLindner, Volkhard
dc.creatorYong-Ri, Jin
dc.date.accessioned2018-01-04T05:56:13Z
dc.date.available2018-01-04T05:56:13Z
dc.date.issued2017-04-01
dc.description.abstractAbstract Collagen triple helix repeat-containing1 (Cthrc1) has previously been implicated in osteogenic differentiation and positive regulation of bone mass, however, the underlying mechanisms remain unclear. Here we characterized the bone phenotype of a novel Cthrc1 null mouse strain using bone histomorphometry, μCT analysis and functional readouts for bone strength. In male Cthrc1 null mice both trabecular bone as well as cortical bone formation was impaired, whereas in female Cthrc1 null mice only trabecular bone parameters were altered. Novel and highly specific monoclonal antibodies revealed that CTHRC1 is expressed by osteocytes and osteoblasts, but not osteoclasts. Furthermore, Cthrc1 null mice exhibited increased bone resorption with increased number of osteoclast and increased osteoclast activity together with enhanced expression of osteoclastogenic genes such as c-Fos, Rankl, Trap, and Nfatc1. Differentiation of bone marrow-derived monocytes isolated from Cthrc1 null mice differentiated into osteoclasts as effectively as those from wildtype mice. In the presence of CTHRC1 osteoclastogenic differentiation of bone marrow-derived monocytes was dramatically inhibited as was functional bone resorption by osteoclasts. This process was accompanied by downregulation of osteoclastogenic marker genes, indicating that extrinsically derived CTHRC1 is required for such activity. In vitro, CTHRC1 had no effect on osteogenic differentiation of bone marrow stromal cells, however, calvarial osteoblasts from Cthrc1 null mice exhibited reduced osteogenic differentiation compared to osteoblasts from wildtypes. In a collagen antibody-induced arthritis model Cthrc1 null mice suffered significantly more severe inflammation and joint destruction than wildtypes, suggesting that CTHRC1 expressed by the activated synoviocytes has anti-inflammatory effects. Mechanistically, we found that CTHRC1 inhibited NFκB activation by preventing IκBα degradation while also inhibiting ERK1/2 activation. Collectively our studies demonstrate that CTHRC1 secreted from osteocytes and osteoblasts functions as an inhibitor of osteoclast differentiation via inhibition of NFκB-dependent signaling. Furthermore, our data suggest that CTHRC1 has potent anti-inflammatory properties that limit arthritic joint destruction.en_US
dc.identifierDOI:10.1016/j.bone.2017.01.022
dc.identifier.citationYong-Ri Jin, J. Patrizia Stohn, Qiaozeng Wang, Kenichi Nagano, Roland Baron, Mary L. Bouxsein, Clifford J. Rosen, Vyacheslav A. Adarichev, Volkhard Lindner, Inhibition of osteoclast differentiation and collagen antibody-induced arthritis by CTHRC1, In Bone, Volume 97, 2017, Pages 153-167en_US
dc.identifier.issn87563282
dc.identifier.urihttps://www.sciencedirect.com/science/article/pii/S8756328217300224
dc.identifier.urihttp://nur.nu.edu.kz/handle/123456789/3083
dc.language.isoenen_US
dc.publisherBoneen_US
dc.relation.ispartofBone
dc.rights.license© 2017 Elsevier Inc. All rights reserved.
dc.subjectOsteoclastogenesisen_US
dc.subjectArthritisen_US
dc.subjectBone strengthen_US
dc.subjectCTHRC1en_US
dc.subjectNFκBen_US
dc.titleInhibition of osteoclast differentiation and collagen antibody-induced arthritis by CTHRC1en_US
dc.typeArticleen_US
elsevier.aggregationtypeJournal
elsevier.coverdate2017-04-01
elsevier.coverdisplaydateApril 2017
elsevier.endingpage167
elsevier.identifier.doi10.1016/j.bone.2017.01.022
elsevier.identifier.eid1-s2.0-S8756328217300224
elsevier.identifier.piiS8756-3282(17)30022-4
elsevier.identifier.scopusid85010297648
elsevier.openaccess0
elsevier.openaccessarticlefalse
elsevier.openarchivearticlefalse
elsevier.startingpage153
elsevier.teaserCollagen triple helix repeat-containing1 (Cthrc1) has previously been implicated in osteogenic differentiation and positive regulation of bone mass, however, the underlying mechanisms remain unclear....
elsevier.volume97
workflow.import.sourcescience

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