{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,21]],"date-time":"2025-11-21T06:15:17Z","timestamp":1763705717822,"version":"build-2065373602"},"reference-count":55,"publisher":"MDPI AG","issue":"24","license":[{"start":{"date-parts":[[2019,12,7]],"date-time":"2019-12-07T00:00:00Z","timestamp":1575676800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>In systemic sclerosis (SSc), the possible involvement of lymphatic microcirculation and lymphangiogenesis has traditionally been overshadowed by the greater emphasis placed on dysfunctional blood vascular system and angiogenesis. In the present in vitro study, we explore for the first time whether the SSc microenvironment may interfere with lymphangiogenesis, a complex, multi-step process in which lymphatic microvascular endothelial cells (LMVECs) sprout, migrate, and proliferate to generate new lymphatic capillaries. Normal human adult dermal LMVECs from three donors were treated with serum from SSc patients (n = 8), serum from healthy individuals (n = 8), or recombinant human vascular endothelial growth factor (VEGF)-C as a positive control for lymphangiogenesis. Cell proliferation, Boyden chamber Matrigel chemoinvasion, wound healing capacity, and lymphatic capillary morphogenesis on Geltrex were assayed. VEGF-C serum levels were measured by enzyme-linked immunosorbent assay. Gene and protein expression levels of the lymphangiogenic orchestrators VEGF receptor-3 (VEGFR-3)\/Flt-4 and neuropilin-2 (NRP-2) were determined by real-time PCR and Western blotting, respectively. Conditioning with SSc serum significantly inhibited LMVEC proliferation, Matrigel invasion, and wound healing capacity with respect to healthy serum. The ability of LMVECs to form lymphatic tubes on Geltrex was also severely compromised in the presence of SSc serum. VEGF-C levels were comparable in SSc and healthy sera. Treatment with SSc serum resulted in a significant downregulation of both VEGFR-3\/Flt-4 and NRP-2 mRNA and protein levels. In SSc, the pathologic environment severely hampers every lymphangiogenesis step, likely through the reduction of pro-lymphangiogenic VEGFR-3\/NRP-2 co-receptor signaling. The impairment of the lymphangiogenic process opens a new scenario underlying SSc vascular pathophysiology, which is worth investigating further.<\/jats:p>","DOI":"10.3390\/ijms20246189","type":"journal-article","created":{"date-parts":[[2019,12,9]],"date-time":"2019-12-09T05:54:51Z","timestamp":1575870891000},"page":"6189","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Systemic Sclerosis Serum Significantly Impairs the Multi-Step Lymphangiogenic Process: In Vitro Evidence"],"prefix":"10.3390","volume":"20","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3956-8480","authenticated-orcid":false,"given":"Mirko","family":"Manetti","sequence":"first","affiliation":[{"name":"Section of Anatomy and Histology, Department of Experimental and Clinical Medicine, University of Florence, 50134 Florence, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Eloisa","family":"Romano","sequence":"additional","affiliation":[{"name":"Section of Rheumatology, Department of Experimental and Clinical Medicine, University of Florence, 50134 Florence, Italy"},{"name":"Division of Rheumatology and Scleroderma Unit, Department of Geriatric Medicine, Azienda Ospedaliero-Universitaria Careggi (AOUC), 50134 Florence, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6352-0175","authenticated-orcid":false,"given":"Irene","family":"Rosa","sequence":"additional","affiliation":[{"name":"Section of Anatomy and Histology, Department of Experimental and Clinical Medicine, University of Florence, 50134 Florence, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9275-7593","authenticated-orcid":false,"given":"Bianca Saveria","family":"Fioretto","sequence":"additional","affiliation":[{"name":"Section of Rheumatology, Department of Experimental and Clinical Medicine, University of Florence, 50134 Florence, Italy"},{"name":"Division of Rheumatology and Scleroderma Unit, Department of Geriatric Medicine, Azienda Ospedaliero-Universitaria Careggi (AOUC), 50134 Florence, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Serena","family":"Guiducci","sequence":"additional","affiliation":[{"name":"Section of Rheumatology, Department of Experimental and Clinical Medicine, University of Florence, 50134 Florence, Italy"},{"name":"Division of Rheumatology and Scleroderma Unit, Department of Geriatric Medicine, Azienda Ospedaliero-Universitaria Careggi (AOUC), 50134 Florence, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Silvia","family":"Bellando-Randone","sequence":"additional","affiliation":[{"name":"Section of Rheumatology, Department of Experimental and Clinical Medicine, University of Florence, 50134 Florence, Italy"},{"name":"Division of Rheumatology and Scleroderma Unit, Department of Geriatric Medicine, Azienda Ospedaliero-Universitaria Careggi (AOUC), 50134 Florence, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Erika","family":"Pigatto","sequence":"additional","affiliation":[{"name":"Rheumatology Unit, Department of Medicine\u2014DIMED, University of Padova, 35128 Padova, Italy"},{"name":"Internal Medicine Unit, Ospedale Classificato Villa Salus, 30174 Venice, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Franco","family":"Cozzi","sequence":"additional","affiliation":[{"name":"Rheumatology Unit, Department of Medicine\u2014DIMED, University of Padova, 35128 Padova, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lidia","family":"Ibba-Manneschi","sequence":"additional","affiliation":[{"name":"Section of Anatomy and Histology, Department of Experimental and Clinical Medicine, University of Florence, 50134 Florence, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marco","family":"Matucci-Cerinic","sequence":"additional","affiliation":[{"name":"Section of Rheumatology, Department of Experimental and Clinical Medicine, University of Florence, 50134 Florence, Italy"},{"name":"Division of Rheumatology and Scleroderma Unit, Department of Geriatric Medicine, Azienda Ospedaliero-Universitaria Careggi (AOUC), 50134 Florence, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2019,12,7]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"137","DOI":"10.5301\/jsrd.5000249","article-title":"Pathogenesis of systemic sclerosis: Recent insights of molecular and cellular mechanisms and therapeutic opportunities","volume":"2","author":"Varga","year":"2017","journal-title":"J. Scleroderma Relat. Disord."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"15002","DOI":"10.1038\/nrdp.2015.2","article-title":"Systemic sclerosis","volume":"1","author":"Allanore","year":"2015","journal-title":"Nat. Rev. Dis. Primers"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"162","DOI":"10.1002\/art.40377","article-title":"Review: Defining a unified vascular phenotype in systemic sclerosis","volume":"70","author":"Allanore","year":"2018","journal-title":"Arthritis Rheumatol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"314","DOI":"10.1016\/j.autrev.2014.12.001","article-title":"Vascular biomarkers and correlation with peripheral vasculopathy in systemic sclerosis","volume":"14","author":"Chora","year":"2015","journal-title":"Autoimmun. Rev."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"2045","DOI":"10.3389\/fimmu.2018.02045","article-title":"Vascular leaking, a pivotal and early pathogenetic event in systemic sclerosis: Should the door be closed?","volume":"9","author":"Bruni","year":"2018","journal-title":"Front. Immunol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1241","DOI":"10.1111\/j.1582-4934.2010.01027.x","article-title":"Mechanisms in the loss of capillaries in systemic sclerosis: Angiogenesis versus vasculogenesis","volume":"14","author":"Manetti","year":"2010","journal-title":"J. Cell. Mol. Med."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1383","DOI":"10.3389\/fimmu.2018.01383","article-title":"The role of endothelial progenitors in the repair of vascular damage in systemic sclerosis","volume":"9","author":"Pignataro","year":"2018","journal-title":"Front. Immunol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"519","DOI":"10.3389\/fimmu.2019.00519","article-title":"Lymphatic function in autoimmune diseases","volume":"10","author":"Schwartz","year":"2019","journal-title":"Front. Immunol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"221","DOI":"10.1093\/rheumatology\/38.3.221","article-title":"Lymphatic microangiopathy of the skin in systemic sclerosis","volume":"38","author":"Leu","year":"1999","journal-title":"Rheumatology (Oxford)"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"297","DOI":"10.3899\/jrheum.100767","article-title":"Progressive loss of lymphatic vessels in skin of patients with systemic sclerosis","volume":"38","author":"Manetti","year":"2011","journal-title":"J. Rheumatol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"366","DOI":"10.1016\/j.humpath.2009.08.009","article-title":"Lymphatic and blood vessels in scleroderma skin, a morphometric analysis","volume":"41","author":"Rossi","year":"2010","journal-title":"Hum. Pathol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1513","DOI":"10.1002\/art.27406","article-title":"Decreased lymphatic vessel counts in patients with systemic sclerosis: Association with fingertip ulcers","volume":"62","author":"Akhmetshina","year":"2010","journal-title":"Arthritis Rheum."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"575","DOI":"10.1136\/annrheumdis-2018-214240","article-title":"Decreased circulating lymphatic endothelial progenitor cells in digital ulcer-complicated systemic sclerosis","volume":"78","author":"Manetti","year":"2019","journal-title":"Ann. Rheum. Dis."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1615","DOI":"10.1101\/gad.303776.117","article-title":"Lymphangiogenesis guidance by paracrine and pericellular factors","volume":"31","author":"Vaahtomeri","year":"2017","journal-title":"Genes Dev."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"207","DOI":"10.1002\/cphy.c180015","article-title":"Lymphatic vessel network structure and physiology","volume":"9","author":"Breslin","year":"2018","journal-title":"Compr. Physiol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"105562","DOI":"10.1016\/j.biocel.2019.105562","article-title":"Lymphatic and blood systems: Identical or fraternal twins?","volume":"114","author":"Morfoisse","year":"2019","journal-title":"Int. J. Biochem. Cell. Biol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"144","DOI":"10.1016\/j.jaad.2015.03.041","article-title":"Angiogenesis and lymphangiogenesis in inflammatory skin disorders","volume":"73","author":"Varricchi","year":"2015","journal-title":"J. Am. Acad. Dermatol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"176","DOI":"10.1016\/j.canlet.2018.01.040","article-title":"NRP-2 in tumor lymphangiogenesis and lymphatic metastasis","volume":"418","author":"Wang","year":"2018","journal-title":"Cancer Lett."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1727","DOI":"10.1093\/rheumatology\/ken372","article-title":"High circulating levels of VEGF-C suggest abnormal lymphangiogenesis in systemic sclerosis","volume":"47","author":"Chitale","year":"2008","journal-title":"Rheumatology (Oxford)."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"776","DOI":"10.1111\/j.1365-2133.2010.09853.x","article-title":"Impaired lymphangiogenesis due to excess vascular endothelial growth factor-D\/Flt-4 signalling in the skin of patients with systemic sclerosis","volume":"163","author":"Honda","year":"2010","journal-title":"Br. J. Dermatol."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Kanno, Y. (2019). The role of fibrinolytic regulators in vascular dysfunction of systemic sclerosis. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20030619"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"5345673","DOI":"10.1155\/2017\/5345673","article-title":"Angiogenesis dysregulation in the pathogenesis of systemic sclerosis","volume":"2017","author":"Cantatore","year":"2017","journal-title":"BioMed Res. Int."},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Borghini, A., Manetti, M., Nacci, F., Bellando-Randone, S., Guiducci, S., Matucci-Cerinic, M., Ibba-Manneschi, L., and Weber, E. (2015). Systemic sclerosis sera impair angiogenic performance of dermal microvascular endothelial cells: Therapeutic implications of cyclophosphamide. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0130166"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1186\/s13075-017-1233-0","article-title":"Proangiogenic effects of soluble \u03b1-Klotho on systemic sclerosis dermal microvascular endothelial cells","volume":"19","author":"Mazzotta","year":"2017","journal-title":"Arthritis Res. Ther."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1541","DOI":"10.1136\/annrheumdis-2015-207483","article-title":"Decreased expression of neuropilin-1 as a novel key factor contributing to peripheral microvasculopathy and defective angiogenesis in systemic sclerosis","volume":"75","author":"Romano","year":"2016","journal-title":"Ann. Rheum. Dis."},{"key":"ref_26","first-page":"S148","article-title":"Bosentan blocks the antiangiogenic effects of sera from systemic sclerosis patients: An in vitro study","volume":"33","author":"Romano","year":"2015","journal-title":"Clin. Exp. Rheumatol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"4762","DOI":"10.1093\/emboj\/20.17.4762","article-title":"Isolated lymphatic endothelial cells transduce growth, survival and migratory signals via the VEGF-C\/D receptor VEGFR-3","volume":"20","author":"Veikkola","year":"2001","journal-title":"EMBO J."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"728","DOI":"10.1097\/SAP.0000000000000084","article-title":"Adipose-derived stem cells promote proliferation, migration, and tube formation of lymphatic endothelial cells in vitro by secreting lymphangiogenic factors","volume":"74","author":"Takeda","year":"2015","journal-title":"Ann. Plast. Surg."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"4571","DOI":"10.1182\/blood-2007-10-120337","article-title":"Inhibition of endogenous TGF-beta signaling enhances lymphangiogenesis","volume":"111","author":"Oka","year":"2008","journal-title":"Blood"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1083\/jcb.200903137","article-title":"Neuropilin-2 mediates VEGF-C-induced lymphatic sprouting together with VEGFR3","volume":"188","author":"Xu","year":"2010","journal-title":"J. Cell. Biol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"162","DOI":"10.1186\/s13075-017-1370-5","article-title":"The \u201cmyth\u201d of loss of angiogenesis in systemic sclerosis: A pivotal early pathogenetic process or just a late unavoidable event?","volume":"19","author":"Manetti","year":"2017","journal-title":"Arthritis Res. Ther."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1146","DOI":"10.1177\/1947601911423028","article-title":"Lymphangiogenesis and cancer","volume":"2","author":"Christiansen","year":"2011","journal-title":"Genes Cancer"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"460","DOI":"10.1016\/j.cell.2010.01.045","article-title":"Lymphangiogenesis: Molecular mechanisms and future promise","volume":"140","author":"Tammela","year":"2010","journal-title":"Cell"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1016\/0738-081X(94)90260-7","article-title":"Lymphedema and wound healing","volume":"12","author":"Mallon","year":"1994","journal-title":"Clin. Dermatol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1683","DOI":"10.1016\/S0140-6736(06)68737-0","article-title":"Systemic sclerosis: Hypothesis-driven treatment strategies","volume":"367","author":"Charles","year":"2006","journal-title":"Lancet"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"74","DOI":"10.1038\/ni1013","article-title":"Vascular endothelial growth factor C is required for sprouting of the first lymphatic vessels from embryonic veins","volume":"5","author":"Karkkainen","year":"2004","journal-title":"Nat. Immunol."},{"key":"ref_37","first-page":"641","article-title":"Increased but imbalanced expression of VEGF and its receptors has no positive effect on angiogenesis in systemic sclerosis skin","volume":"20","author":"Mackiewicz","year":"2002","journal-title":"Clin. Exp. Rheumatol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"490","DOI":"10.1684\/ejd.2011.1284","article-title":"Expression pattern of VEGFR-1, -2, -3 and D2-40 protein in the skin of patients with systemic sclerosis","volume":"21","author":"Makino","year":"2011","journal-title":"Eur. J. Dermatol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"501","DOI":"10.1016\/j.immuni.2014.01.013","article-title":"Activation of vascular endothelial growth factor receptor-3 in macrophages restrains TLR4-NF-\u03baB signaling and protects against endotoxin shock","volume":"40","author":"Zhang","year":"2014","journal-title":"Immunity"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1016\/S0002-9440(10)63630-9","article-title":"Novel expression of vascular endothelial growth factor receptor (VEGFR)-3 and VEGF-C on corneal dendritic cells","volume":"163","author":"Hamrah","year":"2003","journal-title":"Am. J. Pathol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1243","DOI":"10.1182\/blood-2005-11-4447","article-title":"Neuropilin-2 interacts with VEGFR-2 and VEGFR-3 and promotes human endothelial cell survival and migration","volume":"108","author":"Favier","year":"2006","journal-title":"Blood"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"4797","DOI":"10.1242\/dev.129.20.4797","article-title":"Abnormal lymphatic vessel development in neuropilin 2 mutant mice","volume":"129","author":"Yuan","year":"2002","journal-title":"Development"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1194","DOI":"10.1242\/bio.012302","article-title":"Class 3 semaphorins negatively regulate dermal lymphatic network formation","volume":"4","author":"Uchida","year":"2015","journal-title":"Biol. Open"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"3202","DOI":"10.2353\/ajpath.2010.100594","article-title":"Blockade of transforming growth factor-\u03b21 accelerates lymphatic regeneration during wound repair","volume":"177","author":"Avraham","year":"2010","journal-title":"Am. J. Pathol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"H2113","DOI":"10.1152\/ajpheart.00879.2008","article-title":"TGF-\u03b21 is a negative regulator of lymphatic regeneration during wound repair","volume":"295","author":"Clavin","year":"2008","journal-title":"Am. J. Physiol. Heart Circ. Physiol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"1083","DOI":"10.1084\/jem.20092277","article-title":"Thrombospondin inhibits inflammatory lymphangiogenesis by CD36 ligation on monocytes","volume":"208","author":"Cursiefen","year":"2011","journal-title":"J. Exp. Med."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"11528","DOI":"10.1158\/0008-5472.CAN-07-1458","article-title":"Endostatin overexpression inhibits lymphangiogenesis and lymph node metastasis in mice","volume":"67","author":"Brideau","year":"2007","journal-title":"Cancer Res."},{"key":"ref_48","doi-asserted-by":"crossref","unstructured":"Manetti, M., Romano, E., Rosa, I., Fioretto, B.S., Praino, E., Guiducci, S., Iannone, F., Ibba-Manneschi, L., and Matucci-Cerinic, M. (2019). Systemic sclerosis serum steers the differentiation of adipose-derived stem cells toward profibrotic myofibroblasts: Pathophysiologic implications. J. Clin. Med., 8.","DOI":"10.3390\/jcm8081256"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"201","DOI":"10.1016\/j.it.2004.02.006","article-title":"CXC chemokines: The regulatory link between inflammation and angiogenesis","volume":"25","author":"Romagnani","year":"2004","journal-title":"Trends Immunol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"1845","DOI":"10.1136\/annrheumdis-2018-213257","article-title":"Association of circulating CXCL10 and CXCL11 with systemic sclerosis","volume":"77","author":"Crescioli","year":"2018","journal-title":"Ann. Rheum. Dis."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"505","DOI":"10.1007\/s10456-017-9561-x","article-title":"CXCL10 suppression of hem- and lymph-angiogenesis in inflamed corneas through MMP13","volume":"20","author":"Gao","year":"2017","journal-title":"Angiogenesis"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"555","DOI":"10.1111\/micc.12055","article-title":"IL-27 inhibits lymphatic endothelial cell proliferation by STAT1-regulated gene expression","volume":"20","author":"Nielsen","year":"2013","journal-title":"Microcirculation"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"1747","DOI":"10.1136\/annrheumdis-2013-204424","article-title":"2013 classification criteria for systemic sclerosis: An American college of rheumatology\/European league against rheumatism collaborative initiative","volume":"72","author":"Khanna","year":"2013","journal-title":"Ann. Rheum. Dis."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"1665","DOI":"10.1136\/annrheumdis-2018-213239","article-title":"Slit2\/Robo4 axis may contribute to endothelial cell dysfunction and angiogenesis disturbance in systemic sclerosis","volume":"77","author":"Romano","year":"2018","journal-title":"Ann. Rheum. Dis."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"924","DOI":"10.1136\/annrheumdis-2016-210229","article-title":"Endothelial-to-mesenchymal transition contributes to endothelial dysfunction and dermal fibrosis in systemic sclerosis","volume":"76","author":"Manetti","year":"2017","journal-title":"Ann. Rheum. Dis."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/20\/24\/6189\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T13:40:24Z","timestamp":1760190024000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/20\/24\/6189"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,12,7]]},"references-count":55,"journal-issue":{"issue":"24","published-online":{"date-parts":[[2019,12]]}},"alternative-id":["ijms20246189"],"URL":"https:\/\/doi.org\/10.3390\/ijms20246189","relation":{},"ISSN":["1422-0067"],"issn-type":[{"type":"electronic","value":"1422-0067"}],"subject":[],"published":{"date-parts":[[2019,12,7]]}}}