{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T05:54:21Z","timestamp":1791352461582,"version":"4.3.1"},"reference-count":49,"publisher":"Wiley","issue":"10","license":[{"start":{"date-parts":[[2012,9,28]],"date-time":"2012-09-28T00:00:00Z","timestamp":1348790400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Arthritis &amp; Rheumatism"],"published-print":{"date-parts":[[2012,10]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Objective<\/jats:title><jats:p>Synovial hypervascularity is a prominent pathologic feature in osteoarthritic (OA) joints. Wnt inhibitor Dkk\u20101 contributes to joint remodeling. We undertook this study to investigate whether Dkk\u20101 regulates cartilage destruction activities in OA synovial fibroblasts.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Synovial tissues were harvested from knees of patients with OA and from injured knees of non\u2010OA patients who underwent arthroscopy. Expression of Dkk\u20101, angiogenic factors (stromal cell\u2013derived factor 1 and colony\u2010stimulating factor 1), and cartilage proteinases (ADAMTS\u20105 and matrix metalloproteinase 3 [MMP\u20103]) as well as vascularity in synovium and synovial fluid were quantified using enzyme\u2010linked immunosorbent assay, reverse transcription\u2013polymerase chain reaction, and histomorphometry. Synovial fibroblasts were treated with interleukin\u20101\u03b2 (IL\u20101\u03b2), anti\u2013Dkk\u20101 antibody, and RNA interference to characterize their angiogenic activity. Rats with OA knees were administered Dkk\u20101 antisense oligonucleotide to verify synovial angiogenesis and cartilage integrity.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>OA synovium exhibited increased vascularity and expression of angiogenic factors and proteinases in association with up\u2010regulated Dkk\u20101 levels. Neutralizing Dkk\u20101 reduced the inhibitory effects of OA synovial fluid on aggrecan expression in chondrocyte cultures. IL\u20101\u03b2 induction of Dkk\u20101 increased expression of hypoxia\u2010inducible factor 1\u03b1 (HIF\u20101\u03b1), angiogenic factors, ADAMTS\u20105, and MMP\u20103 in synovial fibroblasts and promoted angiogenesis in vascular endothelial cells. Knockdown of HIF\u20101\u03b1 decreased Dkk\u20101 enhancement of angiogenic factor expression. Stabilization of glycogen synthase kinase 3\u03b2 phosphorylated at Ser<jats:sup>9<\/jats:sup>, \u03b2\u2010catenin, T cell factor 4, and ERK signaling attenuated Dkk\u20101 up\u2010regulation of angiogenic factor and proteinase expression in synovial fibroblasts. In vivo, Dkk\u20101 interference reduced the expression of angiogenic factors and proteinases and ameliorated synovial vascularity and cartilage deterioration in knees of rats with OA.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Dkk\u20101 promoted angiogenic and cartilage degradation activities in synovial fibroblasts, which accelerated synovial angiogenesis and cartilage destruction. Dkk\u20101 blockade has therapeutic potential for reducing OA\u2010induced synovitis and joint deterioration.<\/jats:p><\/jats:sec>","DOI":"10.1002\/art.34602","type":"journal-article","created":{"date-parts":[[2012,6,26]],"date-time":"2012-06-26T22:01:09Z","timestamp":1340748069000},"page":"3267-3277","source":"Crossref","is-referenced-by-count":47,"title":["Dkk\u20101 promotes angiogenic responses and cartilage matrix proteinase secretion in synovial fibroblasts from osteoarthritic joints"],"prefix":"10.1002","volume":"64","author":[{"given":"Lin\u2010Hsiu","family":"Weng","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jih\u2010Yang","family":"Ko","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ching\u2010Jen","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi\u2010Chih","family":"Sun","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Feng\u2010Sheng","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2012,9,28]]},"reference":[{"key":"e_1_2_7_2_2","doi-asserted-by":"publisher","DOI":"10.1002\/art.11094"},{"key":"e_1_2_7_3_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrrheum.2010.196"},{"key":"e_1_2_7_4_2","doi-asserted-by":"publisher","DOI":"10.1097\/BOR.0b013e3283103d12"},{"key":"e_1_2_7_5_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.joca.2007.01.020"},{"key":"e_1_2_7_6_2","doi-asserted-by":"publisher","DOI":"10.1002\/art.34315"},{"key":"e_1_2_7_7_2","doi-asserted-by":"publisher","DOI":"10.1002\/art.27462"},{"key":"e_1_2_7_8_2","doi-asserted-by":"publisher","DOI":"10.1186\/ar2592"},{"key":"e_1_2_7_9_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00296-010-1592-1"},{"key":"e_1_2_7_10_2","doi-asserted-by":"publisher","DOI":"10.1093\/rheumatology\/keq188"},{"key":"e_1_2_7_11_2","doi-asserted-by":"publisher","DOI":"10.1002\/art.22450"},{"key":"e_1_2_7_12_2","doi-asserted-by":"publisher","DOI":"10.1002\/jbmr.377"},{"key":"e_1_2_7_13_2","doi-asserted-by":"publisher","DOI":"10.1359\/jbmr.060311"},{"key":"e_1_2_7_14_2","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.00222-08"},{"key":"e_1_2_7_15_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2009.12.007"},{"key":"e_1_2_7_16_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pmed.0040249"},{"key":"e_1_2_7_17_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa030847"},{"key":"e_1_2_7_18_2","doi-asserted-by":"publisher","DOI":"10.1002\/jbmr.5"},{"key":"e_1_2_7_19_2","doi-asserted-by":"publisher","DOI":"10.1136\/ard.2008.102046"},{"key":"e_1_2_7_20_2","doi-asserted-by":"publisher","DOI":"10.1038\/nm1538"},{"key":"e_1_2_7_21_2","doi-asserted-by":"publisher","DOI":"10.1002\/art.27496"},{"key":"e_1_2_7_22_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bone.2009.10.030"},{"key":"e_1_2_7_23_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.joca.2008.12.008"},{"key":"e_1_2_7_24_2","doi-asserted-by":"publisher","DOI":"10.1002\/art.27357"},{"key":"e_1_2_7_25_2","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-08-3402"},{"key":"e_1_2_7_26_2","doi-asserted-by":"publisher","DOI":"10.2353\/ajpath.2010.090465"},{"key":"e_1_2_7_27_2","doi-asserted-by":"publisher","DOI":"10.1161\/ATVBAHA.110.213751"},{"key":"e_1_2_7_28_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.107.172718"},{"key":"e_1_2_7_29_2","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-05-1021"},{"key":"e_1_2_7_30_2","doi-asserted-by":"publisher","DOI":"10.2106\/00004623-197153030-00009"},{"key":"e_1_2_7_31_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2010-07-295964"},{"key":"e_1_2_7_32_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2010-01-261792"},{"key":"e_1_2_7_33_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M110.113787"},{"key":"e_1_2_7_34_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M109.053926"},{"key":"e_1_2_7_35_2","doi-asserted-by":"publisher","DOI":"10.1101\/gad.1230704"},{"key":"e_1_2_7_36_2","doi-asserted-by":"publisher","DOI":"10.1124\/mol.107.036541"},{"key":"e_1_2_7_37_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ydbio.2010.02.033"},{"key":"e_1_2_7_38_2","doi-asserted-by":"publisher","DOI":"10.1210\/en.2007-0910"},{"key":"e_1_2_7_39_2","doi-asserted-by":"publisher","DOI":"10.1186\/ar3124"},{"key":"e_1_2_7_40_2","doi-asserted-by":"publisher","DOI":"10.1002\/art.24844"},{"key":"e_1_2_7_41_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1008256107"},{"key":"e_1_2_7_42_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbrc.2009.01.086"},{"key":"e_1_2_7_43_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M109.001735"},{"key":"e_1_2_7_44_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ydbio.2008.01.012"},{"key":"e_1_2_7_45_2","doi-asserted-by":"publisher","DOI":"10.3109\/03009742.2010.486767"},{"key":"e_1_2_7_46_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0008284"},{"key":"e_1_2_7_47_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M109.027086"},{"key":"e_1_2_7_48_2","doi-asserted-by":"publisher","DOI":"10.1681\/ASN.2008101059"},{"key":"e_1_2_7_49_2","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2011.03.043"},{"key":"e_1_2_7_50_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2008-03-145169"}],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