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In OA, articular chondrocytes (AC) and synovial fibroblasts (SF) release innate-derived immune mediators that initiate and perpetuate inflammation, inducing cartilage extracellular matrix (ECM) degradation. Given the lack of therapies for the treatment of OA, in this study, we explore biomarkers that enable the development of new therapeutical approaches. We analyze the set of secreted proteins in AC and SF co-cultures by stable isotope labeling with amino acids (SILAC). We describe, for the first time, 115 proteins detected in SF-AC co-cultures stimulated by fibronectin fragments (Fn-fs). We also study the role of the vasoactive intestinal peptide (VIP) in this secretome, providing new proteins involved in the main events of OA, confirmed by ELISA and multiplex analyses. VIP decreases proteins involved in the inflammatory process (CHI3L1, PTX3), complement activation (C1r, C3), and cartilage ECM degradation (DCN, CTSB and MMP2), key events in the initiation and progression of OA. Our results support the anti-inflammatory and anti-catabolic properties of VIP in rheumatic diseases and provide potential new targets for OA treatment.<\/jats:p>","DOI":"10.3390\/ijms22126441","type":"journal-article","created":{"date-parts":[[2021,6,16]],"date-time":"2021-06-16T10:27:07Z","timestamp":1623839227000},"page":"6441","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["Proteomic Analysis of Synovial Fibroblasts and Articular Chondrocytes Co-Cultures Reveals Valuable VIP-Modulated Inflammatory and Degradative Proteins in Osteoarthritis"],"prefix":"10.3390","volume":"22","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4500-8132","authenticated-orcid":false,"given":"Selene","family":"P\u00e9rez-Garc\u00eda","sequence":"first","affiliation":[{"name":"Department of Cell Biology, Faculty of Biology and Faculty of Medicine, Complutense University of Madrid (UCM), 28040 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valentina","family":"Calamia","sequence":"additional","affiliation":[{"name":"Rheumatology Research Group, INIBIC-Biomedical Research Institute, CICA-University of A Coru\u00f1a, 15006 A Coru\u00f1a, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tamara","family":"Hermida-G\u00f3mez","sequence":"additional","affiliation":[{"name":"Rheumatology Research Group, INIBIC-Biomedical Research Institute, CICA-University of A Coru\u00f1a, 15006 A Coru\u00f1a, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0678-3619","authenticated-orcid":false,"given":"Irene","family":"Guti\u00e9rrez-Ca\u00f1as","sequence":"additional","affiliation":[{"name":"Department of Cell Biology, Faculty of Biology and Faculty of Medicine, Complutense University of Madrid (UCM), 28040 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5480-9417","authenticated-orcid":false,"given":"Mar","family":"Carri\u00f3n","sequence":"additional","affiliation":[{"name":"Department of Cell Biology, Faculty of Biology and Faculty of Medicine, Complutense University of Madrid (UCM), 28040 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9001-2413","authenticated-orcid":false,"given":"Ra\u00fal","family":"Villanueva-Romero","sequence":"additional","affiliation":[{"name":"Department of Cell Biology, Faculty of Biology and Faculty of Medicine, Complutense University of Madrid (UCM), 28040 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2446-5075","authenticated-orcid":false,"given":"David","family":"Castro","sequence":"additional","affiliation":[{"name":"Department of Cell Biology, Faculty of Biology and Faculty of Medicine, Complutense University of Madrid (UCM), 28040 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carmen","family":"Mart\u00ednez","sequence":"additional","affiliation":[{"name":"Department of Cell Biology, Faculty of Biology and Faculty of Medicine, Complutense University of Madrid (UCM), 28040 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5886-8273","authenticated-orcid":false,"given":"Yasmina","family":"Juarranz","sequence":"additional","affiliation":[{"name":"Department of Cell Biology, Faculty of Biology and Faculty of Medicine, Complutense University of Madrid (UCM), 28040 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9821-7635","authenticated-orcid":false,"given":"Francisco J.","family":"Blanco","sequence":"additional","affiliation":[{"name":"Rheumatology Research Group, INIBIC-Biomedical Research Institute, CICA-University of A Coru\u00f1a, 15006 A Coru\u00f1a, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2839-1923","authenticated-orcid":false,"given":"Rosa P.","family":"Gomariz","sequence":"additional","affiliation":[{"name":"Department of Cell Biology, Faculty of Biology and Faculty of Medicine, Complutense University of Madrid (UCM), 28040 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,6,16]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1697","DOI":"10.1002\/art.34453","article-title":"Osteoarthritis: A disease of the joint as an organ","volume":"64","author":"Loeser","year":"2012","journal-title":"Arthritis Rheum."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"293","DOI":"10.1016\/j.mcna.2019.10.007","article-title":"Osteoarthritis: Pathology, Diagnosis, and Treatment Options","volume":"104","author":"Abramoff","year":"2020","journal-title":"Med. Clin. N. Am."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"136","DOI":"10.1080\/03008207.2018.1470167","article-title":"Conditioned media from human osteoarthritic synovium induces inflammation in a synoviocyte cell line","volume":"60","author":"Belluzzi","year":"2018","journal-title":"Connect. Tissue Res."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"22","DOI":"10.3389\/fbioe.2018.00022","article-title":"Interplay of Inflammatory Mediators with Epigenetics and Cartilage Modifi-cations in Osteoarthritis","volume":"6","author":"Raman","year":"2018","journal-title":"Front Bioeng. Biotechnol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"2115","DOI":"10.1016\/S0140-6736(11)60243-2","article-title":"Osteoarthritis: An update with relevance for clinical practice","volume":"377","author":"Bijlsma","year":"2011","journal-title":"Lancet"},{"key":"ref_6","unstructured":"Monfort, J. (2010). Artrosis: Fisiopatolog\u00eda, Diagn\u00f3stico y Tratamiento, M\u00e9dica Panamericana."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"2449","DOI":"10.1016\/j.ajpath.2016.05.017","article-title":"Healthy and Osteoarthritic Synovial Fibroblasts Produce a Disintegrin and Metalloproteinase with Thrombospondin Motifs 4, 5, 7, and 12","volume":"186","author":"Seoane","year":"2016","journal-title":"Am. J. Pathol."},{"key":"ref_8","first-page":"18","article-title":"Urokinase Plasminogen Activator System in Synovial Fibroblasts from Osteoarthritis Patients: Modulation by Inflammatory Mediators and Neuropeptides","volume":"52","author":"Jimeno","year":"2013","journal-title":"J. Mol. Neurosci."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"3974","DOI":"10.1111\/jcmm.14283","article-title":"Wnt and RUNX2 mediate cartilage breakdown by osteoarthritis synovial fibro-blast-derived ADAMTS-7 and -12","volume":"23","author":"Carrion","year":"2019","journal-title":"J. Cell Mol. Med."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"130","DOI":"10.2174\/1381612820666140825122036","article-title":"Role of Synovial Fibroblasts in Rheumatoid Arthritis","volume":"21","author":"Lefevre","year":"2014","journal-title":"Curr. Pharm. Des."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"4195","DOI":"10.1242\/jcs.023820","article-title":"The extracellular matrix at a glance","volume":"123 Pt 24","author":"Frantz","year":"2010","journal-title":"J. Cell Sci."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"2830","DOI":"10.1111\/febs.14818","article-title":"The extracellular matrix as a multitasking player in disease","volume":"286","author":"Theocharis","year":"2019","journal-title":"FEBS J."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"a005058","DOI":"10.1101\/cshperspect.a005058","article-title":"Extracellular Matrix Degradation and Remodeling in Development and Disease","volume":"3","author":"Lu","year":"2011","journal-title":"Cold Spring Harb. Perspect. Biol."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Geurts, J., Juri\u0107, D., M\u00fcller, M., Sch\u00e4ren, S., and Netzer, C. (2018). Novel Ex Vivo Human Osteochondral Explant Model of Knee and Spine Osteoarthritis Enables Assessment of Inflammatory and Drug Treatment Responses. Int. J. Mol. Sci., 19.","DOI":"10.3390\/ijms19051314"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"120555","DOI":"10.1016\/j.biomaterials.2020.120555","article-title":"The regulation of cartilage extracellular matrix homeostasis in joint cartilage degeneration and regeneration","volume":"268","author":"Peng","year":"2021","journal-title":"Biomaterials"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"197","DOI":"10.3109\/s10165-006-0490-6","article-title":"Cartilage destruction by matrix degradation products","volume":"16","author":"Yasuda","year":"2006","journal-title":"Mod. Rheumatol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1038\/nrrheum.2010.196","article-title":"Role of proinflammatory cytokines in the pathophysiology of osteoarthritis","volume":"7","author":"Kapoor","year":"2010","journal-title":"Nat. Rev. Rheumatol."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Perez-Garcia, S., Carrion, M., Gutierrez-Canas, I., Villanueva-Romero, R., Castro, D., Martinez, C., Gonzalez-Alvaro, I., Blanco, F.J., Juarranz, Y., and Gomariz, R.P. (2019). Profile of Matrix-Remodeling Proteinases in Osteoarthritis: Impact of Fibron-ectin. Cells, 9.","DOI":"10.3390\/cells9010040"},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Gr\u00e4ssel, S., and Muschter, D. (2018). Do Neuroendocrine Peptides and Their Receptors Qualify as Novel Therapeutic Targets in Osteoarthritis?. Int. J. Mol. Sci., 19.","DOI":"10.3390\/ijms19020367"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"729","DOI":"10.3389\/fendo.2019.00729","article-title":"An Overview of VPAC Receptors in Rheumatoid Arthritis: Biological Role and Clinical Significance","volume":"10","author":"Gomariz","year":"2019","journal-title":"Front. Endocrinol."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Mart\u00ednez, C., Juarranz, Y., Guti\u00e9rrez-Ca\u00f1as, I., Carri\u00f3n, M., P\u00e9rez-Garc\u00eda, S., Villanueva-Romero, R., Castro, D., Lamana, A., Mellado, M., and Gonz\u00e1lez-\u00c1lvaro, I. (2019). A Clinical Approach for the Use of VIP Axis in Inflammatory and Autoimmune Diseases. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21010065"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1086","DOI":"10.1002\/art.23403","article-title":"Differential expression of vaso-active intestinal peptide and its functional receptors in human osteoarthritic and rheumatoid synovial fibroblasts","volume":"58","author":"Juarranz","year":"2008","journal-title":"Arthritis Rheum"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1186\/s12929-016-0280-1","article-title":"Role of vasoactive intestinal peptide in osteoarthritis","volume":"23","author":"Jiang","year":"2016","journal-title":"J. Biomed. Sci."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1607","DOI":"10.1016\/j.clinbiochem.2012.08.020","article-title":"Expression of synovial fluid and articular cartilage VIP in human osteoarthritic knee: A new indicator of disease severity?","volume":"45","author":"Jiang","year":"2012","journal-title":"Clin. Biochem."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"R202","DOI":"10.1186\/ar4040","article-title":"Secretome analysis of chondroitin sulfate-treated chondrocytes reveals anti-angiogenic, anti-inflammatory and anti-catabolic properties","volume":"14","author":"Calamia","year":"2012","journal-title":"Arthritis Res. Ther."},{"key":"ref_26","first-page":"552","article-title":"Proteomic analysis of synovial fibro-blast-like synoviocytes from rheumatoid arthritis","volume":"31","author":"Li","year":"2013","journal-title":"Clini. Exp. Rheumatol."},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Sanchez, C., Mazzucchelli, G., Lambert, C., Comblain, F., Depauw, E., and Henrotin, Y. (2018). Comparison of secretome from osteoblasts derived from sclerotic versus non-sclerotic subchondral bone in OA: A pilot study. PLoS ONE, 13.","DOI":"10.1371\/journal.pone.0194591"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"455","DOI":"10.1007\/s00296-018-3988-2","article-title":"Cartilage turnover and intra-articular corticosteroid injec-tions in knee osteoarthritis","volume":"38","author":"Klocke","year":"2018","journal-title":"Rheumatol. Int."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"260","DOI":"10.1111\/j.1365-2249.2007.03561.x","article-title":"High serum YKL-40 level in a cohort of octogenarians is associated with increased risk of all-cause mortality","volume":"151","author":"Johansen","year":"2007","journal-title":"Clin. Exp. Immunol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1042\/bj20020075","article-title":"The chitinase 3-like protein human cartilage glycoprotein 39 (HC-gp39) stimulates proliferation of human connective-tissue cells and activates both extracellular signal-regulated kinase- and protein kinase B-mediated signalling pathways","volume":"365","author":"Recklies","year":"2002","journal-title":"Biochem. J."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"128","DOI":"10.1177\/117727190700200023","article-title":"Human Chitinases and Chitinase-Like Proteins as Indicators for Inflammation and Cancer","volume":"2","author":"Kzhyshkowska","year":"2007","journal-title":"Biomark. Insights"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"2650","DOI":"10.3109\/10428194.2015.1004168","article-title":"Serum YKL-40: A new independent prognostic marker for skeletal complications in patients with multiple myeloma","volume":"56","author":"Mylin","year":"2015","journal-title":"Leuk. Lymphoma"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"479","DOI":"10.1146\/annurev-physiol-012110-142250","article-title":"Role of Chitin and Chitinase\/Chitinase-Like Proteins in Inflammation, Tissue Remodeling, and Injury","volume":"73","author":"Lee","year":"2011","journal-title":"Annu. Rev. Physiol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"171","DOI":"10.1136\/postgradmedj-2013-203726rep","article-title":"Republished: Value of biomarkers in osteoarthritis: Current status and perspectives","volume":"90","author":"Lotz","year":"2014","journal-title":"Postgrad. Med. J."},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"V\u00e4\u00e4n\u00e4nen, T., Vuolteenaho, K., Kautiainen, H., Nieminen, R., Mottonen, T., Hannonen, P., Korpela, M., Kauppi, M.J., Laiho, K., and Kaipiainen-Sepp\u00e4nen, O. (2017). Glycoprotein YKL-40: A potential biomarker of disease activity in rheumatoid arthritis during intensive treatment with csDMARDs and infliximab. Evidence from the randomised controlled NEO-RACo trial. PLoS ONE, 12.","DOI":"10.1371\/journal.pone.0183294"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1452","DOI":"10.1016\/j.joca.2013.08.012","article-title":"Osteoarthritis year 2013 in review: Biomarkers; reflecting before moving forward, one step at a time","volume":"21","author":"Lafeber","year":"2013","journal-title":"Osteoarthr. Cartil."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1165","DOI":"10.1007\/s00264-009-0747-8","article-title":"Human cartilage glycoprotein 39\u2014Biomarker of joint damage in knee osteoarthritis","volume":"33","author":"Rackov","year":"2009","journal-title":"Int. Orthop."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"224","DOI":"10.1186\/ar2592","article-title":"Cartilage homeostasis in health and rheumatic diseases","volume":"11","author":"Goldring","year":"2009","journal-title":"Arthritis Res. Ther."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"220","DOI":"10.1186\/ar2292","article-title":"Cells of the synovium in rheumatoid arthritis. Chondrocytes","volume":"9","author":"Otero","year":"2007","journal-title":"Arthritis Res. Ther."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"991","DOI":"10.7754\/Clin.Lab.2015.150135","article-title":"Increased Synovial Fluid YKL-40 Levels are Linked with Symptomatic Severity in Knee Osteoarthritis Patients","volume":"61","author":"Guan","year":"2015","journal-title":"Clin. Lab."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"828","DOI":"10.1136\/ard.59.10.828","article-title":"Serum levels of YKL-40 and C reactive protein in patients with hip osteoarthritis and healthy subjects: A cross sectional study","volume":"59","author":"Conrozier","year":"2000","journal-title":"Ann. Rheum. Dis."},{"key":"ref_42","first-page":"1","article-title":"YKL-40 as a Novel Factor Associated with Inflammation and Catabolic Mechanisms in Osteoarthritic Joints","volume":"2014","author":"Koskinen","year":"2014","journal-title":"Mediat. Inflamm."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"9538451","DOI":"10.1155\/2017\/9538451","article-title":"Chitinase-3-Like Protein 1 (YKL-40) Is a New Bi-omarker of Inflammation in Psoriasis","volume":"2017","author":"Salomon","year":"2017","journal-title":"Mediat. Inflamm."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"485","DOI":"10.5114\/ada.2018.77239","article-title":"Chitinase-3-like protein 1 (YKL-40) is a biomarker of severity of joint involvement in psoriatic arthritis","volume":"35","author":"Salomon","year":"2018","journal-title":"Adv. Dermatol. Allergol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1016\/j.cca.2018.01.035","article-title":"Acute phase reactant, Pentraxin 3, as a novel marker for the diagnosis of rheumatoid arthritis","volume":"480","author":"Sharma","year":"2018","journal-title":"Clin. Chim. Acta"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"e3125","DOI":"10.1038\/cddis.2017.514","article-title":"Impairment of PTX3 expression in osteoblasts: A key element for osteoporosis","volume":"8","author":"Scimeca","year":"2017","journal-title":"Cell Death Dis."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"28","DOI":"10.3109\/s10165-012-0630-0","article-title":"Serum amyloid A (SAA) induces pentraxin 3 (PTX3) production in rheumatoid synoviocytes","volume":"23","author":"Satomura","year":"2013","journal-title":"Mod. Rheumatol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"196","DOI":"10.1046\/j.1365-2249.2000.01110.x","article-title":"Expression and production of the long pentraxin PTX3 in rheumatoid arthritis (RA)","volume":"119","author":"Luchetti","year":"2000","journal-title":"Clin. Exp. Immunol."},{"key":"ref_49","first-page":"2423","article-title":"Expression of CHI3L1 and CHIT1 in os-teoarthritic rat cartilage model. A morphological study","volume":"58","author":"Szychlinska","year":"2014","journal-title":"Eur. J. Histochem."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"89","DOI":"10.2174\/1381612013398374","article-title":"Immunology of VIP: A review and therapeutical per-spectives","volume":"7","author":"Gomariz","year":"2001","journal-title":"Curr. Pharm. Des."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1196\/annals.1317.031","article-title":"VIP-PACAP System in Immunity: New Insights for Multitarget Therapy","volume":"1070","author":"Gomariz","year":"2006","journal-title":"Ann. N. Y. Acad. Sci."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1007\/s00726-011-1184-8","article-title":"Vasoactive intestinal peptide: A neuropeptide with pleiotropic immune functions","volume":"45","author":"Delgado","year":"2013","journal-title":"Amino Acids"},{"key":"ref_53","doi-asserted-by":"crossref","unstructured":"Galindo-Izquierdo, M., and Alvarez, J.L.P. (2021). Complement as a Therapeutic Target in Systemic Autoimmune Diseases. Cells, 10.","DOI":"10.3390\/cells10010148"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"1179544117751430","DOI":"10.1177\/1179544117751430","article-title":"Osteoarthritis and the Complement Cascade","volume":"11","author":"Silawal","year":"2018","journal-title":"Clin. Med. Insights Arthritis Musculoskelet. Disord."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"3574","DOI":"10.1002\/art.27720","article-title":"Regulation of complement by cartilage oligomeric matrix protein allows for a novel molecular diagnostic principle in rheumatoid arthritis","volume":"62","author":"Happonen","year":"2010","journal-title":"Arthritis Rheum."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"R15","DOI":"10.1186\/ar3694","article-title":"Serum COMP-C3b complexes in rheumatic diseases and relation to anti-TNF-\u03b1 treatment","volume":"14","author":"Happonen","year":"2012","journal-title":"Arthritis Res. Ther."},{"key":"ref_57","doi-asserted-by":"crossref","unstructured":"Melin Furst, C., Morgelin, M., Vadstrup, K., Heinegard, D., Aspberg, A., and Blom, A.M. (2013). The C-type lectin of the aggrecan G3 domain activates complement. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0061407"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"830","DOI":"10.1016\/j.molimm.2008.09.018","article-title":"Short leucine-rich glycoproteins of the extracellular matrix display diverse patterns of complement interaction and activation","volume":"46","author":"Manderson","year":"2009","journal-title":"Mol. Immunol."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"252","DOI":"10.1016\/S0049-0172(00)80012-8","article-title":"Fibronectin fragments and their role in inflammatory arthritis","volume":"29","author":"Barilla","year":"2000","journal-title":"Semin. Arthritis Rheum."},{"key":"ref_60","first-page":"37","article-title":"Interaction between fibronectin and C1q in rheumatoid synovial fluid and normal plasma","volume":"72","author":"Carsons","year":"1988","journal-title":"Clin. Exp. Immunol."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"535010","DOI":"10.3389\/fimmu.2020.535010","article-title":"Complement Expression and Activation in Osteoarthritis Joint Compartments","volume":"11","author":"Assirelli","year":"2020","journal-title":"Front. Immunol."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1007\/BF00302666","article-title":"Expression of the components and regulatory proteins of the classical pathway of complement in normal and diseased synovium","volume":"14","author":"Gulati","year":"1994","journal-title":"Rheumatol. Int."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"139","DOI":"10.1007\/BF00301260","article-title":"Expression of the components and regulatory proteins of the alternative complement pathway and the membrane attack complex in normal and diseased synovium","volume":"13","author":"Guc","year":"1993","journal-title":"Rheumatol. Int."},{"key":"ref_64","first-page":"648","article-title":"Synthesis of classical pathway complement components by chondrocytes","volume":"88","author":"Bradley","year":"1996","journal-title":"Immunology"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"675","DOI":"10.1016\/j.joca.2019.09.007","article-title":"Complement component C1q is produced by isolated articular chondrocytes","volume":"28","author":"Lubbers","year":"2020","journal-title":"Osteoarthr. Cartil."},{"key":"ref_66","first-page":"9","article-title":"Multi-omics analysis of synovial fluid: A promising ap-proach in the study of osteoarthritis","volume":"32","author":"Vicenti","year":"2018","journal-title":"J. Biol. Regul. Homeost. Agents"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"223","DOI":"10.1186\/s13075-016-1123-x","article-title":"The complement system is activated in synovial fluid from subjects with knee injury and from patients with osteoarthritis","volume":"18","author":"Struglics","year":"2016","journal-title":"Arthritis Res. Ther."},{"key":"ref_68","first-page":"43","article-title":"Classical Complement Pathway Components C1r and C1s: Purification from Human Serum and in Recombinant Form and Functional Characterization","volume":"1100","author":"Rossi","year":"2013","journal-title":"Adv. Struct. Saf. Stud."},{"key":"ref_69","first-page":"2827","article-title":"Proteomic analysis of synovial fluid in osteoarthritis using SWATH-mass spectrometry","volume":"17","author":"Liao","year":"2017","journal-title":"Mol. Med. Rep."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1016\/0022-1759(90)90420-Z","article-title":"Trimer and tetramer complexes containing C1 esterase inhibitor, C1r and C1s, in serum and synovial fluid of patients with rheumatic disease","volume":"129","author":"Laurell","year":"1990","journal-title":"J. Immunol. Methods"},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1159\/000233956","article-title":"C1 Activation, with C1q in Excess of Functional C1 in Synovial Fluid from Patients with Rheumatoid Arthritis","volume":"79","author":"Berglund","year":"1986","journal-title":"Int. Arch. Allergy Immunol."},{"key":"ref_72","doi-asserted-by":"crossref","unstructured":"Hengartner, N.-E., Fiedler, J., Schrezenmeier, H., Huber-Lang, M., and Brenner, R.E. (2015). Crucial Role of IL1beta and C3a in the In Vitro-Response of Multipotent Mesenchymal Stromal Cells to Inflammatory Mediators of Polytrauma. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0116772"},{"key":"ref_73","doi-asserted-by":"crossref","unstructured":"Ourradi, K., Xu, Y., De Seny, M., Kirwan, J., Blom, A., and Sharif, M. (2017). Development and validation of novel biomarker assays for osteoarthritis. PLoS ONE, 12.","DOI":"10.1371\/journal.pone.0181334"},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"1144","DOI":"10.1136\/ard.2010.135541","article-title":"Discovery and biochemical characterisation of four novel biomarkers for osteoarthritis","volume":"70","author":"Sharif","year":"2011","journal-title":"Ann. Rheum. Dis."},{"key":"ref_75","first-page":"29","article-title":"C3f is a potential tool for the staging of osteoarthritis","volume":"31","author":"Corigliano","year":"2017","journal-title":"J. Boil. Regul. Homeost. Agents"},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"170","DOI":"10.1016\/j.talanta.2017.03.078","article-title":"Validation of a new method by nano-liquid chromatography on chip tandem mass spectrometry for combined quantitation of C3f and the V65 vitron-ectin fragment as biomarkers of diagnosis and severity of osteoarthritis","volume":"169","author":"Cobraiville","year":"2017","journal-title":"Talanta"},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"569","DOI":"10.1111\/1756-185X.13794","article-title":"Knee synovial fluid com-plement C3-beta chain levels correlate with clinical symptoms of knee osteoarthritis","volume":"23","author":"Cheng","year":"2020","journal-title":"Int. J. Rheum. Dis."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"219","DOI":"10.1111\/sji.12411","article-title":"Activation of Complement Fol-lowing Total Hip Replacement","volume":"83","author":"Thordardottir","year":"2016","journal-title":"Scand. J. Immunol."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"1123","DOI":"10.1136\/ard.51.10.1123","article-title":"Relative contribution of contact and complement activation to inflammatory reactions in arthritic joints","volume":"51","author":"Abbink","year":"1992","journal-title":"Ann. Rheum. Dis."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"442","DOI":"10.1136\/annrheumdis-2016-209319","article-title":"Forced exercise-induced osteoarthritis is attenuated in mice lacking the small leucine-rich proteoglycan decorin","volume":"76","author":"Gronau","year":"2017","journal-title":"Ann. Rheum. Dis."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"40","DOI":"10.1016\/j.matbio.2018.05.008","article-title":"Osteoarthritis as a disease of the cartilage pericellular matrix","volume":"71\u201372","author":"Guilak","year":"2018","journal-title":"Matrix Biol."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"710","DOI":"10.1002\/art.37799","article-title":"Matrix-assisted laser desorption ionization-imaging mass spectrometry: A new methodology to study human osteoarthritic cartilage","volume":"65","author":"Eijkel","year":"2013","journal-title":"Arthritis Rheum."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"37698","DOI":"10.1074\/jbc.M304638200","article-title":"Complexes of Matrilin-1 and Biglycan or Decorin Connect Collagen VI Microfibrils to Both Collagen II and Aggrecan","volume":"278","author":"Wiberg","year":"2003","journal-title":"J. Biol. Chem."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"364","DOI":"10.1016\/S0369-8114(01)00145-6","article-title":"Structure and regulation of articular cartilage proteoglycan expression","volume":"49","author":"Redini","year":"2001","journal-title":"Pathol. Biol."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1006\/scdb.2000.0243","article-title":"Cartilage proteoglycans","volume":"12","author":"Knudson","year":"2001","journal-title":"Semin. Cell Dev. Biol."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"94","DOI":"10.1006\/abio.1999.4379","article-title":"Structural analysis of cartilage proteoglycans and glycoproteins using ma-trix-assisted laser desorption\/ionization time-of-flight mass spectrometry","volume":"277","author":"Zaia","year":"2000","journal-title":"Anal. Biochem."},{"key":"ref_87","first-page":"329","article-title":"New aspects of the pathogenesis of osteoarthritis: The role of fibroblast-like chondrocytes in late stages of the disease","volume":"20","author":"Tesche","year":"2005","journal-title":"Histol. Histopathol."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"379","DOI":"10.1186\/s13075-015-0902-0","article-title":"Soluble biglycan: A potential mediator of cartilage degradation in osteoarthritis","volume":"17","author":"Barreto","year":"2015","journal-title":"Arthritis Res."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"654","DOI":"10.1053\/joca.2001.0420","article-title":"The small proteoglycans decorin and biglycan in human articular cartilage of late-stage osteoarthritis","volume":"9","author":"Bock","year":"2001","journal-title":"Osteoarthr. Cartil."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"R79","DOI":"10.1186\/ar2453","article-title":"Fragmentation of decorin, biglycan, lumican and keratocan is elevated in degenerate human meniscus, knee and hip articular cartilages compared with age-matched macroscopically normal and control tissues","volume":"10","author":"Melrose","year":"2008","journal-title":"Arthritis Res. Ther."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"R852","DOI":"10.1186\/ar1756","article-title":"Regional assessment of articular cartilage gene expression and small proteoglycan metabolism in an animal model of osteoarthritis","volume":"7","author":"Young","year":"2005","journal-title":"Arthritis Res."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"3065","DOI":"10.1016\/j.molimm.2008.03.011","article-title":"VIP reverses the expression profiling of TLR4-stimulated signaling pathway in rheumatoid arthritis synovial fibroblasts","volume":"45","author":"Arranz","year":"2008","journal-title":"Mol. Immunol."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"522","DOI":"10.1093\/rheumatology\/keg168","article-title":"Elevated levels of synovial fluid antibodies reactive with the small proteoglycans biglycan and decorin in patients with rheumatoid arthritis or other joint diseases","volume":"42","author":"Falus","year":"2003","journal-title":"Rheumatology"},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"1387","DOI":"10.1681\/ASN.2014010117","article-title":"Beyond tissue injury-damage-associated molecular patterns, toll-like receptors, and inflam-masomes also drive regeneration and fibrosis","volume":"25","author":"Anders","year":"2014","journal-title":"J. Am. Soc. Nephrol."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"1413","DOI":"10.1002\/jor.20659","article-title":"Autologous synovial fluid enhances migration of mesenchymal stem cells from synovium of osteoarthritis patients in tissue culture system","volume":"26","author":"Zhang","year":"2008","journal-title":"J. Orthop. Res."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"221","DOI":"10.1186\/ar2304","article-title":"Proteinases in the joint: Clinical relevance of proteinases in joint destruction","volume":"9","author":"Rengel","year":"2007","journal-title":"Arthritis Res. Ther."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"133","DOI":"10.1016\/j.bbapap.2011.06.020","article-title":"Proteases involved in cartilage matrix degradation in osteoarthritis","volume":"1824","author":"Troeberg","year":"2012","journal-title":"Biochim. Biophys. Acta (BBA) Proteins Proteom."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"805","DOI":"10.1053\/berh.2001.0195","article-title":"Metalloproteases and inhibitors in arthritic diseases","volume":"15","author":"Welsch","year":"2001","journal-title":"Best Pr. Res. Clin. Rheumatol."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"1043","DOI":"10.1074\/jbc.M704915200","article-title":"Cathepsins B, K, and L are regulated by a defined collagen type II peptide via activation of classical protein kinase C and p38 MAP kinase in articular chondrocytes","volume":"283","author":"Ruettger","year":"2008","journal-title":"J. Biol. Chem."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"571","DOI":"10.1515\/bc.2010.035","article-title":"Expression and activity profiling of selected cysteine cathepsins and matrix metalloproteinases in synovial fluids from patients with rheumatoid arthritis and osteoarthritis","volume":"391","author":"Rozman","year":"2010","journal-title":"Biol. Chem."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"1245","DOI":"10.2174\/138945009789753264","article-title":"Targeting matrix metalloproteinases in inflammatory conditions","volume":"10","author":"Clutterbuck","year":"2009","journal-title":"Curr. Drug Targets"},{"key":"ref_102","first-page":"1970","article-title":"The relative importance of cysteine peptidases in osteoarthritis","volume":"27","author":"Lang","year":"2000","journal-title":"J. Rheumatol."},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"639","DOI":"10.1042\/bj1670639","article-title":"The degradation of cartilage proteoglycans by tissue proteinases. Proteoglycan heterogeneity and the pathway of proteolytic degradation","volume":"167","author":"Roughley","year":"1977","journal-title":"Biochem. J."},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"189","DOI":"10.1016\/0014-5793(90)81151-D","article-title":"Susceptibility of the cartilage collagens types II, IX and XI to degradation by the cysteine proteinases, cathepsins B and L","volume":"269","author":"Maciewicz","year":"1990","journal-title":"FEBS Lett."},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"286","DOI":"10.1016\/S0014-5793(99)00897-2","article-title":"Stimulation of angiogenesis through cathepsin B inactivation of the tissue inhibitors of matrix metalloproteinases","volume":"455","author":"Kostoulas","year":"1999","journal-title":"FEBS Lett."},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1016\/j.semarthrit.2004.03.008","article-title":"Cathepsin B in Osteoarthritis: Uncontrolled Proteolysis in the Wrong Place","volume":"34","author":"Baici","year":"2004","journal-title":"Semin. Arthritis Rheum."},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"363","DOI":"10.1007\/s004180000199","article-title":"Cytoskeletal architecture and cathepsin B trafficking in human articular chondrocytes","volume":"114","author":"Zwicky","year":"2000","journal-title":"Histochem. Cell Biol."},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"1370","DOI":"10.1136\/annrheumdis-2020-217072","article-title":"Serum NT\/CT SIRT1 ratio reflects early osteoarthritis and chondrosenescence","volume":"79","author":"Batshon","year":"2020","journal-title":"Ann. Rheum. Dis."},{"key":"ref_109","first-page":"1265","article-title":"Relationship between cathepsin B and thrombin in rheumatoid arthritis","volume":"31","author":"Mishiro","year":"2004","journal-title":"J. Rheumatol."},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"334","DOI":"10.1006\/bbrc.2001.4787","article-title":"Significance of Cathepsin B Accumulation in Synovial Fluid of Rheumatoid Arthritis","volume":"283","author":"Hashimoto","year":"2001","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_111","first-page":"61","article-title":"Cathepsins B and L in synovial fluids from patients with rheumatoid arthritis and the effect of cathepsin B on the activation of pro-urokinase","volume":"47","author":"Ikeda","year":"2000","journal-title":"J. Med. Investig."},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"1378","DOI":"10.1002\/1529-0131(199808)41:8<1378::AID-ART6>3.0.CO;2-J","article-title":"Differential expression of cathepsins B and L compared with matrix metalloproteinases and their respective inhibitors in rheumatoid arthritis and osteoarthritis: A parallel investigation by semiquantitative reverse transcriptase-polymerase chain reaction and immunohistochemistry","volume":"41","author":"Keyszer","year":"1998","journal-title":"Arthritis Rheum."},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"373","DOI":"10.1080\/03009740701340172","article-title":"Cysteine and serine proteases of synovial tissue in rheumatoid arthritis and osteoarthritis","volume":"36","author":"Zerimech","year":"2007","journal-title":"Scand. J. Rheumatol."},{"key":"ref_114","first-page":"859","article-title":"Cathepsin B and its endogenous inhibitor cystatin C in rheumatoid arthritis synovium","volume":"27","author":"Hansen","year":"2000","journal-title":"J. Rheumatol."},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"149","DOI":"10.1042\/bj1710149","article-title":"Studies on cathepsin B in human articular cartilage","volume":"171","author":"Bayliss","year":"1978","journal-title":"Biochem. J."},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"336","DOI":"10.1002\/jor.1100080305","article-title":"Cathepsin B and cysteine protease inhibitors in human osteoarthritis","volume":"8","author":"Cloutier","year":"1990","journal-title":"J. Orthop. Res."},{"key":"ref_117","doi-asserted-by":"crossref","first-page":"281","DOI":"10.1136\/ard.54.4.281","article-title":"Cathepsin B in osteoarthritis: Zonal variation of enzyme activity in human femoral head cartilage","volume":"54","author":"Baici","year":"1995","journal-title":"Ann. Rheum. Dis."},{"key":"ref_118","doi-asserted-by":"crossref","first-page":"289","DOI":"10.1136\/ard.54.4.289","article-title":"Cathepsin B in osteoarthritis: Cytochemical and histochemical analysis of human femoral head cartilage","volume":"54","author":"Baici","year":"1995","journal-title":"Ann. Rheum. Dis."},{"key":"ref_119","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1186\/s13075-015-0586-5","article-title":"Detecting cathepsin activity in human osteoar-thritis via activity-based probes","volume":"17","author":"Merquiol","year":"2015","journal-title":"Arthritis Res. Ther."},{"key":"ref_120","doi-asserted-by":"crossref","first-page":"1819","DOI":"10.1002\/1529-0131(200108)44:8<1819::AID-ART319>3.0.CO;2-4","article-title":"Alternative messenger RNA splicing and enzyme forms of cathepsin B in human osteoarthritic cartilage and cultured chondrocytes","volume":"44","author":"Berardi","year":"2001","journal-title":"Arthritis Rheum."},{"key":"ref_121","doi-asserted-by":"crossref","first-page":"1007","DOI":"10.1515\/BC.2003.113","article-title":"Exploring the Role of 5\u2032 Alternative Splicing and of the 3\u2032-Untranslated Region of Cathepsin B mRNA","volume":"384","author":"Zwicky","year":"2003","journal-title":"Biol. Chem."},{"key":"ref_122","doi-asserted-by":"crossref","first-page":"S39","DOI":"10.1186\/ar572","article-title":"Matrix metalloproteinases in arthritic disease","volume":"4","author":"Murphy","year":"2002","journal-title":"Arthritis Res."},{"key":"ref_123","doi-asserted-by":"crossref","first-page":"iv44","DOI":"10.1136\/ard.2005.042465","article-title":"What are the roles of metalloproteinases in cartilage and bone damage?","volume":"64","author":"Murphy","year":"2005","journal-title":"Ann. Rheum. Dis."},{"key":"ref_124","doi-asserted-by":"crossref","first-page":"290","DOI":"10.1016\/j.mam.2008.05.002","article-title":"Progress in matrix metalloproteinase research","volume":"29","author":"Murphy","year":"2008","journal-title":"Mol. Asp. Med."},{"key":"ref_125","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1002\/art.11433","article-title":"Expression profiling of metalloproteinases and their inhibitors in cartilage","volume":"50","author":"Kevorkian","year":"2004","journal-title":"Arthritis Rheum."},{"key":"ref_126","doi-asserted-by":"crossref","first-page":"817","DOI":"10.1177\/039463201302600331","article-title":"Expression of Gelatinases (MMP-2, MMP-9) in Human Articular Cartilage","volume":"26","author":"Lipari","year":"2013","journal-title":"Int. J. Immunopathol. Pharmacol."},{"key":"ref_127","first-page":"603","article-title":"MMP-2\/gelatinase A is a gene product of human adult articular chondrocytes and is increased in osteoarthritic cartilage","volume":"22","author":"Duerr","year":"2004","journal-title":"Clin. Exp. Rheumatol."},{"key":"ref_128","doi-asserted-by":"crossref","first-page":"151","DOI":"10.1016\/j.cyto.2007.06.001","article-title":"Increased level of cytokines and matrix metal-loproteinases in osteoarthritic subchondral bone","volume":"38","author":"Hulejova","year":"2007","journal-title":"Cytokine"},{"key":"ref_129","doi-asserted-by":"crossref","first-page":"14811","DOI":"10.4238\/2015.November.18.46","article-title":"High MMP-1, MMP-2, and MMP-9 protein levels in osteoarthritis","volume":"14","author":"Zeng","year":"2015","journal-title":"Genet. Mol. Res."},{"key":"ref_130","doi-asserted-by":"crossref","first-page":"2116","DOI":"10.1160\/TH17-06-0379","article-title":"Platelets Contribute to the Accumulation of Matrix Metalloproteinase Type 2 in Synovial Fluid in Osteoarthritis","volume":"117","author":"Alunno","year":"2017","journal-title":"Thromb. Haemost."},{"key":"ref_131","doi-asserted-by":"crossref","first-page":"1264","DOI":"10.1177\/1071100715611176","article-title":"Inflammatory Cytokines and Matrix Metalloproteinases in the Synovial Fluid After Intra-articular Ankle Fracture","volume":"36","author":"Adams","year":"2015","journal-title":"Foot Ankle Int."},{"key":"ref_132","doi-asserted-by":"crossref","first-page":"42","DOI":"10.1007\/s12291-009-0007-0","article-title":"Multiple matrix metalloproteinases in type II collagen induced arthritis","volume":"24","author":"Sandya","year":"2009","journal-title":"Indian J. Clin. Biochem."},{"key":"ref_133","doi-asserted-by":"crossref","first-page":"22","DOI":"10.1016\/j.tripleo.2005.07.013","article-title":"Expression of matrix metalloproteinases and aggrecanase in the synovial fluids of patients with symptomatic temporomandibular disorders","volume":"102","author":"Yoshida","year":"2006","journal-title":"Oral Surg. Oral Med. Oral Pathol. Oral Radiol. Endodontology"},{"key":"ref_134","doi-asserted-by":"crossref","unstructured":"Yang, C.-C., Lin, C.-Y., Wang, H.-S., and Lyu, S.-R. (2013). Matrix Metalloproteases and Tissue Inhibitors of Metalloproteinases in Medial Plica and Pannus-like Tissue Contribute to Knee Osteoarthritis Progression. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0079662"},{"key":"ref_135","doi-asserted-by":"crossref","first-page":"2270","DOI":"10.1093\/rheumatology\/keu254","article-title":"Endogenous MMP-9 and not MMP-2 promotes rheumatoid synovial fibroblast survival, inflammation and cartilage degradation","volume":"53","author":"Xue","year":"2014","journal-title":"Rheumatology"},{"key":"ref_136","doi-asserted-by":"crossref","first-page":"1393","DOI":"10.1136\/annrheumdis-2011-200867","article-title":"IL-17 and tumour necrosis factor \u03b1 combination induces a HIF-1\u03b1-dependent invasive phenotype in synoviocytes","volume":"71","author":"Hot","year":"2012","journal-title":"Ann. Rheum. Dis."},{"key":"ref_137","doi-asserted-by":"crossref","first-page":"352","DOI":"10.1055\/s-0038-1641592","article-title":"Expression of LOXs and MMP-1, 2, 3 by ACL Fibroblasts and Synoviocytes Impact of Coculture and TNF-\u03b1","volume":"32","author":"Wang","year":"2019","journal-title":"J. Knee Surg."},{"key":"ref_138","doi-asserted-by":"crossref","first-page":"621","DOI":"10.3899\/jrheum.110777","article-title":"Aggravation of ADAMTS and matrix metalloproteinase production and role of ERK1\/2 pathway in the interaction of osteoarthritic subchondral bone osteoblasts and articular cartilage chondrocytes\u2014Possible pathogenic role in osteoarthritis","volume":"39","author":"Prasadam","year":"2012","journal-title":"J. Rheumatol."},{"key":"ref_139","doi-asserted-by":"crossref","unstructured":"Zheng, L., Chen, W., Xian, G., Pan, B., Ye, Y., Gu, M., Ma, Y., Zhang, Z., and Sheng, P. (2021). Identification of abnormally methylated-differentially expressed genes and pathways in osteoarthritis: A comprehensive bioinformatic study. Clin. Rheumatol.","DOI":"10.1007\/s10067-020-05539-w"},{"key":"ref_140","doi-asserted-by":"crossref","first-page":"2245","DOI":"10.1089\/dna.2020.5552","article-title":"Identification of Diagnostic Biomarkers of Osteoarthritis Based on Multi-Chip Integrated Analysis and Machine Learning","volume":"39","author":"Zhang","year":"2020","journal-title":"DNA Cell Biol."},{"key":"ref_141","doi-asserted-by":"crossref","first-page":"275","DOI":"10.3389\/fphys.2019.00275","article-title":"Identification of the Biomarkers and Pathological Process of Osteoarthritis: Weighted Gene Co-expression Network Analysis","volume":"10","author":"Gu","year":"2019","journal-title":"Front. Physiol."},{"key":"ref_142","doi-asserted-by":"crossref","first-page":"1103","DOI":"10.1002\/jor.24802","article-title":"Characterizing correlations among disease severity measures in osteochondral tissues from osteoarthritic knees","volume":"39","author":"Werner","year":"2021","journal-title":"J. Orthop. Res."},{"key":"ref_143","doi-asserted-by":"crossref","first-page":"1076029619828113","DOI":"10.1177\/1076029619828113","article-title":"Matrix Metalloproteinases and Their Inhibitors and Proteoglycan 4 in Patients Undergoing Total Joint Arthroplasty","volume":"25","author":"Thorson","year":"2019","journal-title":"Clin. Appl. Thromb. Hemost."},{"key":"ref_144","doi-asserted-by":"crossref","first-page":"212","DOI":"10.1016\/j.mce.2012.10.021","article-title":"Vasoactive intestinal peptide induces oxidative stress and suppresses metastatic potential in human clear cell renal cell carcinoma","volume":"365","author":"Vacas","year":"2013","journal-title":"Mol. Cell. Endocrinol."},{"key":"ref_145","doi-asserted-by":"crossref","first-page":"678","DOI":"10.1111\/jcmm.12777","article-title":"VIP and CRF reduce ADAMTS expression and function in osteoarthritis synovial fibroblasts","volume":"20","author":"Juarranz","year":"2016","journal-title":"J. Cell. Mol. Med."},{"key":"ref_146","doi-asserted-by":"crossref","first-page":"563","DOI":"10.1038\/87887","article-title":"Vasoactive intestinal peptide prevents experimental arthritis by downregulating both autoimmune and inflammatory components of the disease","volume":"7","author":"Delgado","year":"2001","journal-title":"Nat. Med."},{"key":"ref_147","doi-asserted-by":"crossref","first-page":"R1034","DOI":"10.1186\/ar1779","article-title":"Protective effect of vasoactive intestinal peptide on bone destruction in the collagen-induced arthritis model of rheumatoid arthritis","volume":"7","author":"Juarranz","year":"2005","journal-title":"Arthritis Res."},{"key":"ref_148","doi-asserted-by":"crossref","unstructured":"Mart\u00ednez, C., Ortiz, A.M., Juarranz, Y., Lamana, A., Seoane, I.V., Leceta, J., Garc\u00eda-Vicu\u00f1a, R., Gomariz, R.P., and Gonz\u00e1lez-\u00c1lvaro, I. (2014). Serum Levels of Vasoactive Intestinal Peptide as a Prognostic Marker in Early Arthritis. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0085248"},{"key":"ref_149","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/s41598-018-20400-6","article-title":"Vasoactive intestinal peptide gene polymorphisms, associated with its serum levels, predict treatment requirements in early rheumatoid arthritis","volume":"8","author":"Seoane","year":"2018","journal-title":"Sci. Rep."},{"key":"ref_150","doi-asserted-by":"crossref","first-page":"1155","DOI":"10.1016\/j.joca.2006.04.016","article-title":"Electrophysiological evidence that the vasoactive intestinal peptide receptor antagonist VIP6\u201328 reduces nociception in an animal model of osteoarthritis","volume":"14","author":"Schuelert","year":"2006","journal-title":"Osteoarthr. Cartil."},{"key":"ref_151","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1016\/0167-0115(92)90660-M","article-title":"The regulation of connective tissue metabolism by vasoactive intestinal polypeptide","volume":"37","author":"Rahman","year":"1992","journal-title":"Regul. Pept."},{"key":"ref_152","doi-asserted-by":"crossref","first-page":"1039","DOI":"10.1002\/art.1780290816","article-title":"Development of criteria for the classification and reporting of osteoarthritis: Classification of osteoarthritis of the knee","volume":"29","author":"Altman","year":"1986","journal-title":"Arthritis Rheum."},{"key":"ref_153","doi-asserted-by":"crossref","first-page":"R138","DOI":"10.1186\/ar3077","article-title":"Pharmacoproteomic study of the effects of chondroitin and glucosamine sulfate on human articular chondrocytes","volume":"12","author":"Calamia","year":"2010","journal-title":"Arthritis Res. Ther."},{"key":"ref_154","doi-asserted-by":"crossref","first-page":"3701","DOI":"10.1021\/pr200331k","article-title":"Metabolic labeling of chondro-cytes for the quantitative analysis of the interleukin-1-beta-mediated modulation of their intracellular and extracellular proteomes","volume":"10","author":"Calamia","year":"2011","journal-title":"J. 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