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Homocysteine (Hcys) inhibits collagen cross\u2010linking and consequently decreases bone extracellular matrix (ECM) quality. Serum amyloid A (A\u2010SAA), an acute\u2010phase protein family, plays an important role in chronic and inflammatory diseases and up\u2010regulates MMP13, which plays an important role in bone development and remodeling. Here, we investigate the effect of Hcys on expression of SAA3, a member of the A\u2010SAA gene family, in osteoblasts characterizing underlying mechanisms and possible consequences on bone metabolism. MC3T3\u2010E1 osteoblast\u2010like cells were cultured up to 21 d with Hcys (low millimolar range) or reseeded onto ECM resulting from untreated or Hcys\u2010treated MC3T3\u2010E1 cells. Fourier\u2010transformed infrared spectroscopy and a discriminative antibody were used to characterize the resulting ECM. Gene expression and signaling pathways were analyzed by gene chip, quantitative RT\u2010PCR, and immunoblotting. Transcriptional regulation of\n                    <jats:italic>Saa3<\/jats:italic>\n                    was studied by promoter transfection assays, chromatin immunoprecipitation, and immunofluorescence microscopy. Hcys treatment resulted in reduced collagen cross\u2010linking, uncovering of RGD\u2010motifs, and activation of the PTK2\u2010PXN\u2010CTNNB1 pathway followed by RELA activation. These signaling events led to increased SAA3 expression followed by the production of\n                    <jats:italic>MMP13<\/jats:italic>\n                    and several chemokines, including\n                    <jats:italic>Ccl5, Ccl2, Cxcl10<\/jats:italic>\n                    , and\n                    <jats:italic>Il6.<\/jats:italic>\n                    Our data suggest\n                    <jats:italic>Saa3<\/jats:italic>\n                    as link between hyperhomocysteinemia and development of osteoporosis.\u2014Thaler, R., Zwerina, J., Rumpler, M., Spitzer, S., Gamsjaeger, S., Paschalis, E. P., Klaushofer, K., Varga, F. Homocysteine induces serum amyloid A3 in osteoblasts\n                    <jats:italic>via<\/jats:italic>\n                    unlocking RGD motifs in collagen.\n                    <jats:italic>FASEB J.<\/jats:italic>\n                    27, 446\u2013463 (2013).\n                    <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"http:\/\/www.fasebj.org\">www.fasebj.org<\/jats:ext-link>\n                  <\/jats:p>","DOI":"10.1096\/fj.12-208058","type":"journal-article","created":{"date-parts":[[2012,10,20]],"date-time":"2012-10-20T02:36:11Z","timestamp":1350700571000},"page":"446-463","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":34,"title":["Homocysteine induces serum amyloid A3 in osteoblasts\n                    <i>via<\/i>\n                    unlocking RGD\u2010motifs in collagen"],"prefix":"10.1096","volume":"27","author":[{"given":"Roman","family":"Thaler","sequence":"first","affiliation":[{"name":"Ludwig Boltzmann Institute of Osteology at the Hanusch Hospital of Wiener Gebietskrankenkasse (WGKK) Allgemeine Unfallversicherungsanstalt (AUVA) Trauma Center Meidling, 1st Medical Department Hanusch Hospital Vienna Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jochen","family":"Zwerina","sequence":"additional","affiliation":[{"name":"Ludwig Boltzmann Institute of Osteology at the Hanusch Hospital of Wiener Gebietskrankenkasse (WGKK) Allgemeine Unfallversicherungsanstalt (AUVA) Trauma Center Meidling, 1st Medical Department Hanusch Hospital Vienna Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Monika","family":"Rumpler","sequence":"additional","affiliation":[{"name":"Ludwig Boltzmann Institute of Osteology at the Hanusch Hospital of Wiener Gebietskrankenkasse (WGKK) Allgemeine Unfallversicherungsanstalt (AUVA) Trauma Center Meidling, 1st Medical Department Hanusch Hospital Vienna Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Silvia","family":"Spitzer","sequence":"additional","affiliation":[{"name":"Ludwig Boltzmann Institute of Osteology at the Hanusch Hospital of Wiener Gebietskrankenkasse (WGKK) Allgemeine Unfallversicherungsanstalt (AUVA) Trauma Center Meidling, 1st Medical Department Hanusch Hospital Vienna Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sonja","family":"Gamsjaeger","sequence":"additional","affiliation":[{"name":"Ludwig Boltzmann Institute of Osteology at the Hanusch Hospital of Wiener Gebietskrankenkasse (WGKK) Allgemeine Unfallversicherungsanstalt (AUVA) Trauma Center Meidling, 1st Medical Department Hanusch Hospital Vienna Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eleftherios P.","family":"Paschalis","sequence":"additional","affiliation":[{"name":"Ludwig Boltzmann Institute of Osteology at the Hanusch Hospital of Wiener Gebietskrankenkasse (WGKK) Allgemeine Unfallversicherungsanstalt (AUVA) Trauma Center Meidling, 1st Medical Department Hanusch Hospital Vienna Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Klaus","family":"Klaushofer","sequence":"additional","affiliation":[{"name":"Ludwig Boltzmann Institute of Osteology at the Hanusch Hospital of Wiener Gebietskrankenkasse (WGKK) Allgemeine Unfallversicherungsanstalt (AUVA) Trauma Center Meidling, 1st Medical Department Hanusch Hospital Vienna Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Franz","family":"Varga","sequence":"additional","affiliation":[{"name":"Ludwig Boltzmann Institute of Osteology at the Hanusch Hospital of Wiener Gebietskrankenkasse (WGKK) Allgemeine Unfallversicherungsanstalt (AUVA) Trauma Center Meidling, 1st Medical Department Hanusch Hospital Vienna Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2012,10,19]]},"reference":[{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11154-006-9001-5"},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.96.1.191"},{"key":"e_1_2_7_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1065-6995(03)00037-4"},{"key":"e_1_2_7_5_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M110.166181"},{"key":"e_1_2_7_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.biomaterials.2009.12.051"},{"key":"e_1_2_7_7_1","doi-asserted-by":"publisher","DOI":"10.1002\/jbm.a.30876"},{"key":"e_1_2_7_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bone.2008.12.023"},{"key":"e_1_2_7_9_1","doi-asserted-by":"publisher","DOI":"10.1002\/jcb.10413"},{"key":"e_1_2_7_10_1","doi-asserted-by":"publisher","DOI":"10.1590\/S0100-879X2009007500021"},{"key":"e_1_2_7_11_1","doi-asserted-by":"publisher","DOI":"10.1515\/CCLM.2007.067"},{"key":"e_1_2_7_12_1","doi-asserted-by":"publisher","DOI":"10.2174\/092986710791959783"},{"key":"e_1_2_7_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.archger.2008.03.009"},{"key":"e_1_2_7_14_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMe048030"},{"key":"e_1_2_7_15_1","doi-asserted-by":"publisher","DOI":"10.1359\/jbmr.070210"},{"key":"e_1_2_7_16_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa032739"},{"key":"e_1_2_7_17_1","doi-asserted-by":"publisher","DOI":"10.1046\/j.1432-1327.1999.00657.x"},{"key":"e_1_2_7_18_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.89.17.7949"},{"key":"e_1_2_7_19_1","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.166.4.2801"},{"key":"e_1_2_7_20_1","doi-asserted-by":"publisher","DOI":"10.1046\/j.1365-2362.1996.159291.x"},{"key":"e_1_2_7_21_1","first-page":"14","article-title":"Rheumatoid 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