{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,28]],"date-time":"2026-01-28T22:28:24Z","timestamp":1769639304071,"version":"3.49.0"},"reference-count":30,"publisher":"Springer Science and Business Media LLC","issue":"2","license":[{"start":{"date-parts":[[2012,3,12]],"date-time":"2012-03-12T00:00:00Z","timestamp":1331510400000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/2.0\/"},{"start":{"date-parts":[[2012,3,12]],"date-time":"2012-03-12T00:00:00Z","timestamp":1331510400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/2.0\/"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Arthritis Res Ther"],"abstract":"<jats:title>Abstract\n<\/jats:title><jats:sec>\n                        <jats:title>Introduction\n<\/jats:title>\n                        <jats:p>Studies in the spontaneous ankylosis model in aging male DBA\/1 mice and in patients with ankylosing spondylitis provide evidence that inflammation and new tissue formation leading to joint or spine ankylosis are likely linked but largely uncoupled processes. We previously proposed the 'entheseal stress' hypothesis that defines microdamage or cell stress in the enthesis as a trigger for these disease processes. Here, we further investigated the relationship between inflammation and ankylosis by focusing on the early phase of the spontaneous arthritis model.<\/jats:p>\n                     <\/jats:sec><jats:sec>\n                        <jats:title>Methods\n<\/jats:title>\n                        <jats:p>Aging male DBA\/1 mice from different litters were caged together at the age of ten weeks and studied for signs of arthritis. A group of DBA\/1 mice were treated daily with dexamethasone (0.5 \u03bcg\/g body weight). Severity of disease was assessed by histomorphology and by positron emission tomography (PET) using 2-[<jats:sup>18<\/jats:sup>F]fluoro-2-deoxy-D-glucose (<jats:sup>18<\/jats:sup>F-FDG) as a tracer. Bone loss in dexamethasone-treated or control mice was determined by <jats:italic>in vivo<\/jats:italic> dual-energy X-ray absorptiometry. Chemokine gene expression was studied <jats:italic>ex vivo<\/jats:italic> in dissected paws and <jats:italic>in vitro<\/jats:italic> in mesenchymal cells (periosteal and bone marrow stromal cells) by quantitative real-time PCR in the presence or absence of bone morphogenetic protein 2 (BMP2) and dexamethasone.<\/jats:p>\n                     <\/jats:sec><jats:sec>\n                        <jats:title>Results\n<\/jats:title>\n                        <jats:p>Dexamethasone treatment did not affect incidence or severity of ankylosis, but led to an expected reduction in inflammation in the paws at week 15 as measured by PET tracer uptake. Treatment with dexamethasone negatively affected bone mineral density. Chemokines attracting neutrophils and lymphocytes were expressed in affected paws. <jats:italic>In vitro<\/jats:italic>, BMP2 stimulation upregulated chemokines in different mesenchymal joint-associated cell types, an effect that was inhibited by dexamethasone.<\/jats:p>\n                     <\/jats:sec><jats:sec>\n                        <jats:title>Conclusions\n<\/jats:title>\n                        <jats:p>BMP signaling may be a trigger for both inflammation and ankylosis in the spontaneous model of ankylosing enthesitis. The lack of inhibition by glucocorticoids on new bone formation while causing systemic bone loss highlights the paradoxical simultaneous loss and gain of bone in patients with ankylosing spondylitis.<\/jats:p>\n                     <\/jats:sec>","DOI":"10.1186\/ar3772","type":"journal-article","created":{"date-parts":[[2012,3,12]],"date-time":"2012-03-12T15:14:38Z","timestamp":1331565278000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":25,"title":["Inhibition of inflammation but not ankylosis by glucocorticoids in mice: further evidence for the entheseal stress hypothesis"],"prefix":"10.1186","volume":"14","author":[{"given":"Kirsten","family":"Braem","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Christophe M","family":"Deroose","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Frank P","family":"Luyten","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rik J","family":"Lories","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2012,3,12]]},"reference":[{"key":"3516_CR1","doi-asserted-by":"publisher","first-page":"15","DOI":"10.1002\/art.23177","volume":"58","author":"CG Helmick","year":"2008","unstructured":"Helmick CG, Felson DT, Lawrence RC, Gabriel S, Hirsch R, Kwoh CK, Liang MH, Kremers HM, Mayes MD, Merkel PA, Pillemer SR, Reveille JD, Stone JH, National Arthritis Data Workgroup: Estimates of the prevalence of arthritis and other rheumatic conditions in the United States: Part I. Arthritis Rheum. 2008, 58: 15-25. 10.1002\/art.23177.","journal-title":"Arthritis Rheum"},{"key":"3516_CR2","doi-asserted-by":"publisher","first-page":"1379","DOI":"10.1016\/S0140-6736(07)60635-7","volume":"369","author":"J Braun","year":"2007","unstructured":"Braun J, Sieper J: Ankylosing spondylitis. The Lancet. 2007, 369: 1379-1390. 10.1016\/S0140-6736(07)60635-7.","journal-title":"The Lancet"},{"key":"3516_CR3","doi-asserted-by":"publisher","first-page":"1465","DOI":"10.1136\/ard.2009.124206","volume":"69","author":"P Machado","year":"2010","unstructured":"Machado P, Landew\u00e9 R, Braun J, Hermann K-GA, Baker D, van der Heijde D: Both structural damage and inflammation of the spine contribute to impairment of spinal mobility in patients with ankylosing spondylitis. Ann Rheum Dis. 2010, 69: 1465-1470. 10.1136\/ard.2009.124206.","journal-title":"Ann Rheum Dis"},{"key":"3516_CR4","doi-asserted-by":"publisher","first-page":"421","DOI":"10.1007\/s00198-010-1319-x","volume":"22","author":"C Roux","year":"2011","unstructured":"Roux C: Osteoporosis in inflammatory joint diseases. Osteoporos Int. 2011, 22: 421-433. 10.1007\/s00198-010-1319-x.","journal-title":"Osteoporos Int"},{"key":"3516_CR5","doi-asserted-by":"publisher","first-page":"112","DOI":"10.1007\/s11914-011-0058-z","volume":"9","author":"S Carter","year":"2011","unstructured":"Carter S, Lories R: Osteoporosis: a paradox in ankylosing spondylitis. Current Osteoporosis Rep. 2011, 9: 112-115. 10.1007\/s11914-011-0058-z.","journal-title":"Current Osteoporosis Rep"},{"key":"3516_CR6","doi-asserted-by":"publisher","first-page":"221","DOI":"10.1186\/ar2642","volume":"11","author":"R Lories","year":"2009","unstructured":"Lories R, Luyten F, de Vlam K: Progress in spondylarthritis. Mechanisms of new bone formation in spondyloarthritis. Arthritis Res Ther. 2009, 11: 221-10.1186\/ar2642.","journal-title":"Arthritis Res Ther"},{"key":"3516_CR7","doi-asserted-by":"publisher","first-page":"489","DOI":"10.1002\/art.22372","volume":"56","author":"RJU Lories","year":"2007","unstructured":"Lories RJU, Derese I, de Bari C, Luyten FP: Evidence for uncoupling of inflammation and joint remodeling in a mouse model of spondylarthritis. Arthritis Rheum. 2007, 56: 489-497. 10.1002\/art.22372.","journal-title":"Arthritis Rheum"},{"key":"3516_CR8","doi-asserted-by":"publisher","first-page":"3063","DOI":"10.1002\/art.23901","volume":"58","author":"D van der Heijde","year":"2008","unstructured":"van der Heijde D, Landew\u00e9 R, Baraliakos X, Houben H, Tubergen Av, Williamson P, Xu W, Baker D, Goldstein N, Braun J: Radiographic findings following two years of infliximab therapy in patients with ankylosing spondylitis. Arthritis Rheum. 2008, 58: 3063-3070. 10.1002\/art.23901.","journal-title":"Arthritis Rheum"},{"key":"3516_CR9","doi-asserted-by":"publisher","first-page":"1324","DOI":"10.1002\/art.23471","volume":"58","author":"D van der Heijde","year":"2008","unstructured":"van der Heijde D, Landew\u00e9 R, Einstein S, Ory P, Vosse D, Ni L, Lin SL, Tsuji W, Davis JC: Radiographic progression of ankylosing spondylitis after up to two years of treatment with etanercept. Arthritis Rheum. 2008, 58: 1324-1331. 10.1002\/art.23471.","journal-title":"Arthritis Rheum"},{"key":"3516_CR10","doi-asserted-by":"publisher","first-page":"R127","DOI":"10.1186\/ar2794","volume":"11","author":"D van der Heijde","year":"2009","unstructured":"van der Heijde D, Salonen D, Weissman B, Landewe R, Maksymowych W, Kupper H, Ballal S, Gibson E, Wong R, Canadian (M03-606) study group, ATLAS study group: Assessment of radiographic progression in the spines of patients with ankylosing spondylitis treated with adalimumab for up to 2 years. Arthritis Res Ther. 2009, 11: R127-10.1186\/ar2794.","journal-title":"Arthritis Res Ther"},{"key":"3516_CR11","doi-asserted-by":"publisher","first-page":"649","DOI":"10.1002\/art.23260","volume":"58","author":"J Sieper","year":"2008","unstructured":"Sieper J, Appel H, Braun J, Rudwaleit M: Critical appraisal of assessment of structural damage in ankylosing spondylitis: implications for treatment outcomes. Arthritis Rheum. 2008, 58: 649-656. 10.1002\/art.23260.","journal-title":"Arthritis Rheum"},{"key":"3516_CR12","doi-asserted-by":"publisher","first-page":"625","DOI":"10.1016\/j.berh.2010.05.005","volume":"24","author":"RJU Lories","year":"2010","unstructured":"Lories RJU, de Vlam K, Luyten FP: Are current available therapies disease-modifying in spondyloarthritis?. Best Pract Res Clin Rheumatol. 2010, 24: 625-635. 10.1016\/j.berh.2010.05.005.","journal-title":"Best Pract Res Clin Rheumatol"},{"key":"3516_CR13","doi-asserted-by":"publisher","first-page":"595","DOI":"10.1136\/ard.2003.013599","volume":"63","author":"RJU Lories","year":"2004","unstructured":"Lories RJU, Matthys P, de Vlam K, Derese I, Luyten FP: Ankylosing enthesitis, dactylitis, and onychoperiostitis in male DBA\/1 mice: a model of psoriatic arthritis. Ann Rheum Dis. 2004, 63: 595-598. 10.1136\/ard.2003.013599.","journal-title":"Ann Rheum Dis"},{"key":"3516_CR14","doi-asserted-by":"publisher","first-page":"605","DOI":"10.1093\/rheumatology\/ken082","volume":"47","author":"RJU Lories","year":"2008","unstructured":"Lories RJU, Derese I, Luyten FP: Inhibition of osteoclasts does not prevent joint ankylosis in a mouse model of spondyloarthritis. Rheumatology (Oxford). 2008, 47: 605-608. 10.1093\/rheumatology\/ken082.","journal-title":"Rheumatology (Oxford)"},{"key":"3516_CR15","doi-asserted-by":"publisher","first-page":"1571","DOI":"10.1172\/JCI23738","volume":"115","author":"RJU Lories","year":"2005","unstructured":"Lories RJU, Derese I, Luyten FP: Modulation of bone morphogenetic protein signaling inhibits the onset and progression of ankylosing enthesitis. J Clin Invest. 2005, 115: 1571-1579. 10.1172\/JCI23738.","journal-title":"J Clin Invest"},{"key":"3516_CR16","doi-asserted-by":"publisher","first-page":"844","DOI":"10.1002\/1529-0131(200004)43:4<844::AID-ANR15>3.0.CO;2-B","volume":"43","author":"A Corthay","year":"2000","unstructured":"Corthay A, Hansson A-S, Holmdahl R: T lymphocytes are not required for the spontaneous development of entheseal ossification leading to marginal ankylosis in the DBA\/1 mouse. Arthritis Rheum. 2000, 43: 844-851. 10.1002\/1529-0131(200004)43:4<844::AID-ANR15>3.0.CO;2-B.","journal-title":"Arthritis Rheum"},{"key":"3516_CR17","doi-asserted-by":"publisher","first-page":"131","DOI":"10.1162\/153535003322556877","volume":"2","author":"A Loening","year":"2003","unstructured":"Loening A, Gambhir S: AMIDE: a free software tool for multimodality medical image analysis. Mol Imaging. 2003, 2: 131-137. 10.1162\/153535003322556877.","journal-title":"Mol Imaging"},{"key":"3516_CR18","doi-asserted-by":"publisher","first-page":"4095","DOI":"10.1002\/art.23137","volume":"56","author":"RJU Lories","year":"2007","unstructured":"Lories RJU, Peeters J, Bakker A, Tylzanowski P, Derese I, Schrooten J, Thomas JT, Luyten FP: Articular cartilage and biomechanical properties of the long bones in Frzb-knockout mice. Arthritis Rheum. 2007, 56: 4095-4103. 10.1002\/art.23137.","journal-title":"Arthritis Rheum"},{"key":"3516_CR19","doi-asserted-by":"publisher","first-page":"4393","DOI":"10.1016\/j.biomaterials.2011.02.047","volume":"32","author":"SJ Roberts","year":"2011","unstructured":"Roberts SJ, Geris L, Kerckhofs G, Desmet E, Schrooten J, Luyten FP: The combined bone forming capacity of human periosteal derived cells and calcium phosphates. Biomaterials. 2011, 32: 4393-4405. 10.1016\/j.biomaterials.2011.02.047.","journal-title":"Biomaterials"},{"key":"3516_CR20","doi-asserted-by":"publisher","first-page":"729","DOI":"10.1089\/10430340050015626","volume":"11","author":"MKL Chuah","year":"2000","unstructured":"Chuah MKL, Van Damme A, Zwinnen H, Goovaerts I, Vanslembrouck V, Collen D, Vandendriessche T: Long-term persistence of human bone marrow stromal cells transduced with factor VIII-retroviral vectors and transient production of therapeutic levels of human factor VIII in nonmyeloablated immunodeficient mice. Hum Gene Ther. 2000, 11: 729-738. 10.1089\/10430340050015626.","journal-title":"Hum Gene Ther"},{"key":"3516_CR21","doi-asserted-by":"publisher","first-page":"446","DOI":"10.1148\/radiol.2232010914","volume":"223","author":"AH Kaim","year":"2002","unstructured":"Kaim AH, Weber B, Kurrer MO, Gottschalk J, von Schulthess GK, Buck A: Autoradiographic quantification of 18F-FDG uptake in experimental soft-tissue abscesses in rats. Radiology. 2002, 223: 446-451. 10.1148\/radiol.2232010914.","journal-title":"Radiology"},{"key":"3516_CR22","doi-asserted-by":"publisher","first-page":"27229","DOI":"10.1074\/jbc.M603385200","volume":"281","author":"N Fukui","year":"2006","unstructured":"Fukui N, Ikeda Y, Ohnuki T, Hikita A, Tanaka S, Yamane S, Suzuki R, Sandell LJ, Ochi T: Pro-inflammatory cytokine tumor necrosis factor-\u03b1 induces bone morphogenetic protein-2 in chondrocytes via mRNA stabilization and transcriptional up-regulation. J Biol Chem. 2006, 281: 27229-27241. 10.1074\/jbc.M603385200.","journal-title":"J Biol Chem"},{"key":"3516_CR23","doi-asserted-by":"publisher","first-page":"2807","DOI":"10.1002\/art.11389","volume":"48","author":"RJU Lories","year":"2003","unstructured":"Lories RJU, Derese I, Ceuppens JL, Luyten FP: Bone morphogenetic proteins 2 and 6, expressed in arthritic synovium, are regulated by proinflammatory cytokines and differentially modulate fibroblast-like synoviocyte apoptosis. Arthritis Rheum. 2003, 48: 2807-2818. 10.1002\/art.11389.","journal-title":"Arthritis Rheum"},{"key":"3516_CR24","doi-asserted-by":"publisher","first-page":"2203","DOI":"10.1089\/ten.2006.12.2203","volume":"12","author":"J Eyckmans","year":"2006","unstructured":"Eyckmans J, Luyten FP: Species specificity of ectopic bone formation using periosteum-derived mesenchymal progenitor cells. Tissue Eng. 2006, 12: 2203-2213. 10.1089\/ten.2006.12.2203.","journal-title":"Tissue Eng"},{"key":"3516_CR25","doi-asserted-by":"publisher","first-page":"274","DOI":"10.1359\/jbmr.081003","volume":"24","author":"C Colnot","year":"2009","unstructured":"Colnot C: Skeletal cell fate decisions within periosteum and bone marrow during bone regeneration. J Bone Miner Res. 2009, 24: 274-282. 10.1359\/jbmr.081003.","journal-title":"J Bone Miner Res"},{"key":"3516_CR26","doi-asserted-by":"publisher","first-page":"31","DOI":"10.1016\/j.bbrc.2005.03.119","volume":"331","author":"K Taguchi","year":"2005","unstructured":"Taguchi K, Ogawa R, Migita M, Hanawa H, Ito H, Orimo H: The role of bone marrow-derived cells in bone fracture repair in a green fluorescent protein chimeric mouse model. Biochem Biophys Res Commun. 2005, 331: 31-36. 10.1016\/j.bbrc.2005.03.119.","journal-title":"Biochem Biophys Res Commun"},{"key":"3516_CR27","doi-asserted-by":"publisher","first-page":"715","DOI":"10.1136\/ard.62.8.715","volume":"62","author":"JJ Haringman","year":"2003","unstructured":"Haringman JJ, Kraan MC, Smeets TJM, Zwinderman KH, Tak PP: Chemokine blockade and chronic inflammatory disease: proof of concept in patients with rheumatoid arthritis. Ann Rheum Dis. 2003, 62: 715-721. 10.1136\/ard.62.8.715.","journal-title":"Ann Rheum Dis"},{"key":"3516_CR28","doi-asserted-by":"publisher","first-page":"2382","DOI":"10.2353\/ajpath.2009.090093","volume":"175","author":"AT Vieira","year":"2009","unstructured":"Vieira AT, Fagundes CT, Alessandri AL, Castor MG, Guabiraba R, Borges VO, Silveira KD, Vieira EL, Gon\u00e7alves JL, Silva TA, Deruaz M, EI Proudfoot A, Sousa LP, Teixeira MM: Treatment with a novel chemokine-binding protein or eosinophil lineage-ablation protects mice from experimental colitis. Am J Pathol. 2009, 175: 2382-2391. 10.2353\/ajpath.2009.090093.","journal-title":"Am J Pathol"},{"key":"3516_CR29","volume-title":"Ann Rheum Dis","author":"K Braem","year":"2011","unstructured":"Braem K, Luyten FP, Lories RJ: Blocking p38 signaling inhibits chondrogenesis in vitro, but not ankylosis in a model of ankylosing spondylitis in vivo. Ann Rheum Dis. 2011, doi:10.1136\/annrheumdis-2011-200377"},{"key":"3516_CR30","doi-asserted-by":"publisher","first-page":"1756","DOI":"10.1002\/art.21054","volume":"52","author":"A Wanders","year":"2005","unstructured":"Wanders A, Heijde Dvd, Landew\u00e9 R, B\u00e9hier J-M, Calin A, Olivieri I, Zeidler H, Dougados M: Nonsteroidal antiinflammatory drugs reduce radiographic progression in patients with ankylosing spondylitis: A randomized clinical trial. Arthritis Rheum. 2005, 52: 1756-1765. 10.1002\/art.21054.","journal-title":"Arthritis Rheum"}],"container-title":["Arthritis Research &amp; Therapy"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/ar3772.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1186\/ar3772\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/ar3772.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,10,8]],"date-time":"2024-10-08T10:29:45Z","timestamp":1728383385000},"score":1,"resource":{"primary":{"URL":"https:\/\/arthritis-research.biomedcentral.com\/articles\/10.1186\/ar3772"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2012,3,12]]},"references-count":30,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2012,4]]}},"alternative-id":["3516"],"URL":"https:\/\/doi.org\/10.1186\/ar3772","relation":{},"ISSN":["1478-6354"],"issn-type":[{"value":"1478-6354","type":"electronic"}],"subject":[],"published":{"date-parts":[[2012,3,12]]},"assertion":[{"value":"2 December 2011","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"10 February 2012","order":2,"name":"revised","label":"Revised","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"12 March 2012","order":3,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"12 March 2012","order":4,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}}],"article-number":"R59"}}