{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,29]],"date-time":"2026-07-29T00:18:05Z","timestamp":1785284285385,"version":"3.55.0"},"reference-count":58,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2017,1,20]],"date-time":"2017-01-20T00:00:00Z","timestamp":1484870400000},"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>The most frequent disease of the locomotor system is osteoarthritis (OA), which, as a chronic joint disease, might benefit more from nutrition than acute illnesses. Collagen hydrolysates (CHs) are peptidic mixtures that are often used as nutraceuticals for OA. Three CHs were characterized biochemically and pharmacologically. Our biophysical (MALDI-TOF-MS, NMR, AFM) and fluorescence assays revealed marked differences between CHs of fish (Peptan\u00ae F 5000, Peptan\u00ae F 2000) and porcine (Mobiforte\u00ae) origin with respect to the total number of peptides and common peptides between them. Using a novel dual radiolabeling procedure, no CH modulated collagen biosynthesis in human knee cartilage explants. Peptan\u00ae F 2000 enhanced the activities of the aggrecanase ADMATS4 and ADMATS5 in vitro without loss of proteoglycan from cartilage explants; the opposite effect was observed with Mobiforte\u00ae. Interleukin (IL)-6, matrix metalloproteinase (MMP)-1, -3 and -13 levels were elevated in explants that were treated with Mobiforte\u00ae and Peptan\u00ae F 5000, but not with Peptan\u00ae F 2000. In conclusion, the heterogeneous peptide composition and disparate pharmacological effects between CHs suggest that the effect of a CH preparation cannot be extrapolated to other formulations. Thus, the declaration of a CH as a safe and effective nutraceutical requires a thorough examination of its pleiotropic effects.<\/jats:p>","DOI":"10.3390\/ijms18010207","type":"journal-article","created":{"date-parts":[[2017,1,20]],"date-time":"2017-01-20T10:10:12Z","timestamp":1484907012000},"page":"207","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":44,"title":["Metabolic Response of Human Osteoarthritic Cartilage to Biochemically Characterized Collagen Hydrolysates"],"prefix":"10.3390","volume":"18","author":[{"given":"Saskia","family":"Schadow","sequence":"first","affiliation":[{"name":"Laboratory for Experimental Orthopaedics, Department of Orthopaedics, Justus Liebig University Giessen, Paul-Meimberg-Str. 3, 35392 Giessen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Viktor","family":"Simons","sequence":"additional","affiliation":[{"name":"Laboratory for Experimental Orthopaedics, Department of Orthopaedics, Justus Liebig University Giessen, Paul-Meimberg-Str. 3, 35392 Giessen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0377-395X","authenticated-orcid":false,"given":"Guenter","family":"Lochnit","sequence":"additional","affiliation":[{"name":"Protein Analytics, Department of Biochemistry, Faculty of Medicine, Justus Liebig University Giessen, Friedrichstr. 24, 35392 Giessen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jens","family":"Kordelle","sequence":"additional","affiliation":[{"name":"Laboratory for Experimental Orthopaedics, Department of Orthopaedics, Justus Liebig University Giessen, Paul-Meimberg-Str. 3, 35392 Giessen, Germany"},{"name":"Agaplesion Evangelical Hospital Mittelhessen, Paul-Zipp-Str. 171, 35398 Giessen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zuzana","family":"Gazova","sequence":"additional","affiliation":[{"name":"Institute of Experimental Physics, Department of Biophysics, Slovak Academy of Sciences, Watsonova 47, 040 01 Ko\u0161ice, Slovakia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hans-Christian","family":"Siebert","sequence":"additional","affiliation":[{"name":"RI-B-NT Research Institute of Bioinformatics and Nanotechnology, Franziusallee 177, 24148 Kiel, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juergen","family":"Steinmeyer","sequence":"additional","affiliation":[{"name":"Laboratory for Experimental Orthopaedics, Department of Orthopaedics, Justus Liebig University Giessen, Paul-Meimberg-Str. 3, 35392 Giessen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2017,1,20]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"168","DOI":"10.1016\/j.addr.2006.01.007","article-title":"Oral treatment options for degenerative joint disease-presence and future","volume":"58","author":"Steinmeyer","year":"2006","journal-title":"Adv. Drug Deliv. Rev."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Schadow, S., Siebert, H.-C., Lochnit, G., Kordelle, J., Rickert, M., and Steinmeyer, J. (2013). Collagen metabolism of human osteoarthritic articular cartilage as modulated by bovine collagen hydrolysates. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0053955"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.joca.2010.10.017","article-title":"Nutraceuticals: Do they represent a new era in the management of osteoarthritis? A narrative review from the lessons taken with five products","volume":"19","author":"Henrotin","year":"2011","journal-title":"Osteoarthr. Cartil."},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"EFSA Panel on Dietetic Products, Nutrition and Allergies (2011). Scientific Opinion on the substantiation of a health claim related to collagen hydrolysate and maintenance of joints pursuant to Article 13(5) of Regulation (EC) No 1924\/2006. EFSA J., 9, 2291.","DOI":"10.2903\/j.efsa.2011.2291"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"535","DOI":"10.1016\/j.berh.2007.12.010","article-title":"Dietary manipulation in musculoskeletal conditions","volume":"22","author":"Rayman","year":"2008","journal-title":"Best Pract. Res. Clin. Rheumatol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"809","DOI":"10.1016\/j.joca.2012.04.008","article-title":"Symptomatic and chondroprotective treatment with collagen derivatives in osteoarthritis: A systematic review","volume":"20","author":"Luijsterburg","year":"2012","journal-title":"Osteoarthr. Cartil."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"218","DOI":"10.6000\/1929-5634.2013.02.04.6","article-title":"Biomedical and pharmaceutical application of fish collagen and gelatin: A review","volume":"2","author":"Jeevithan","year":"2013","journal-title":"J. Nutr. Ther."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"291","DOI":"10.1111\/jocd.12174","article-title":"The effect of oral collagen peptide supplementation on skin moisture and the dermal collagen network: Evidence from an ex vivo model and randomized, placebo-controlled clinical trials","volume":"14","author":"Asserin","year":"2015","journal-title":"J. Cosmet. Dermatol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1002\/jemt.22609","article-title":"Emerging therapy in arthritis: Modulation of markers of the inflammatory process","volume":"79","author":"Mortarino","year":"2016","journal-title":"Microsc. Res. Technol."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Comblain, F., Sanchez, C., Lesponne, I., Balligand, M., Serisier, S., and Henrotin, Y. (2015). Curcuminoids extract, hydrolyzed collagen and green tea extract synergically inhibit inflammatory and catabolic mediator\u00b4s synthesis by normal bovine and osteoarthritic human chondrocytes in monolayer. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0121654"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"393","DOI":"10.1007\/s00441-003-0702-8","article-title":"Stimulation of type II collagen biosynthesis and secretion in bovine chondrocytes cultured with degraded collagen","volume":"311","author":"Oesser","year":"2003","journal-title":"Cell Tissue Res."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"545","DOI":"10.1007\/s00418-010-0760-4","article-title":"Hydrolyzed fish collagen induced chondrogenic differentiation of equine adipose tissue-derived stromal cells","volume":"134","author":"Raabe","year":"2010","journal-title":"Histochem. Cell Biol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"436","DOI":"10.1021\/bm401780v","article-title":"Potential application of hydrolyzed fish collagen for inducing the multidirectional differentiation of rat bone marrow mesenchymal stem cells","volume":"15","author":"Liu","year":"2014","journal-title":"Biomacromolecules"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"385","DOI":"10.17219\/acem\/31704","article-title":"An estimation of the biological properties of fish collagen in an experimental in vitro study","volume":"24","author":"Kuzan","year":"2015","journal-title":"Adv. Clin. Exp. Med."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"393","DOI":"10.1007\/s13238-010-0038-6","article-title":"Interaction of the \u03b12A domain of integrin with small collagen fragments","volume":"1","author":"Siebert","year":"2010","journal-title":"Protein Cell"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"3117","DOI":"10.1002\/cphc.201200284","article-title":"Molecular organization of different collagen hydrolysates and collagen fragments as revealed by a combination of Atomic Force Microscopy (AFM) and Diffusion Ordered NMR Spectroscopy (DOSY)","volume":"13","author":"Schurink","year":"2012","journal-title":"ChemPhysChem"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"463","DOI":"10.1016\/j.procbio.2014.11.015","article-title":"Physico-chemical, antioxidant and intestinal adsorption properties of whale shark type-II collagen based on its solubility with acid and pepsin","volume":"50","author":"Jeevithan","year":"2015","journal-title":"Process Biochem."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1891","DOI":"10.1093\/jn\/129.10.1891","article-title":"Oral administration of 14C-labeled gelatin hydrolysate leads to an accumulation of radioactivity in cartilage of mice (C57\/BL)","volume":"129","author":"Oesser","year":"1999","journal-title":"J. Nutr."},{"key":"ref_19","first-page":"139","article-title":"The regulation of the ADAMTS4 and ADAMTS5 aggrecanases in osteoarthritis: A review","volume":"26","author":"Bondeson","year":"2008","journal-title":"Clin. Exp. Rheumatol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"703","DOI":"10.1111\/j.1440-1827.2007.02167.x","article-title":"Expression of ADAMTS4 (aggreacanse-1) in human osteoarthritic cartilage","volume":"57","author":"Naito","year":"2007","journal-title":"Pathol. Int."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1110\/ps.073287008","article-title":"Crystal structures of the two major aggrecan degrading enzymes, ADAMTS4 and ADAMTS5","volume":"17","author":"Mosyak","year":"2008","journal-title":"Protein Sci."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"735","DOI":"10.1002\/pro.606","article-title":"Structure analysis reveals the flexibility of the ADAMTS5 active site","volume":"20","author":"Shieh","year":"2011","journal-title":"Protein Sci."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"5334","DOI":"10.1073\/pnas.0407106102","article-title":"Conformational variability of matrix metalloproteinases: Beyond a single 3D structure","volume":"102","author":"Bertini","year":"2005","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1197","DOI":"10.1007\/s00775-007-0288-9","article-title":"Matrix metallo-proteinase-inhibitor interaction: The solution structure of the catalytic domain of human matrix metalloproteinase-3 with different inhibitors","volume":"12","author":"Alcaraz","year":"2007","journal-title":"J. Biol. Inorg. Chem."},{"key":"ref_25","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 Rheumatol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"289","DOI":"10.1097\/BOR.0000000000000162","article-title":"Biologic basis of osteoarthritis: State of the evidence","volume":"27","author":"Malemud","year":"2015","journal-title":"Curr. Opin. Rheumatol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"463","DOI":"10.1016\/j.matbio.2009.07.005","article-title":"The C-terminal domains of ADAMTS-4 and ADAMTS-5 promote association with N-TIMP-3","volume":"28","author":"Troeberg","year":"2009","journal-title":"Matrix Biol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"71","DOI":"10.3109\/03008200109014250","article-title":"The effect of collagen fragments on the extracellular matrix metabolism of bovine and human chondrocytes","volume":"42","author":"Jennings","year":"2001","journal-title":"Connect Tissue Res."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1002\/jor.20001","article-title":"Collagen degradation products modulate matrix metalloproteinase expression in cultured articular chondrocytes","volume":"24","author":"Fichter","year":"2006","journal-title":"J. Orthop. Res."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1053\/joca.2001.0488","article-title":"Osteoarthritis or osteoarthrosis: The definition of inflammation becomes a semantic issue in the genomic era of molecular medicine","volume":"10","author":"Attur","year":"2002","journal-title":"Osteoarthr. Cartil."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"535","DOI":"10.1136\/annrheumdis-2011-201047","article-title":"Associations between serum levels of inflammatory markers and change in knee pain over 5 years in older adults: A prospective cohort study","volume":"72","author":"Stannus","year":"2013","journal-title":"Ann. Rheum. Dis."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1179","DOI":"10.1016\/j.joca.2013.05.014","article-title":"The factors associated with pain severity in patients with knee osteoarthritis vary according to the radiographic disease severity: A cross-sectional study","volume":"21","author":"Shimura","year":"2013","journal-title":"Osteoarthr. Cartil."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1441","DOI":"10.1016\/j.joca.2010.08.016","article-title":"Circulating levels of IL-6 and TNF-\u03b1 are associated with knee radiographic osteoarthritis and knee cartilage loss in older adults","volume":"18","author":"Stannus","year":"2010","journal-title":"Osteoarthr. Cartil."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"2037","DOI":"10.1002\/art.24598","article-title":"Interleukin-6 is a significant predictor of radiographic knee osteoarthritis: The Chingford Study","volume":"60","author":"Livshits","year":"2009","journal-title":"Arthritis Rheumatol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1620","DOI":"10.1002\/1529-0131(200107)44:7<1620::AID-ART285>3.0.CO;2-B","article-title":"Synergistic effects of glycoprotein 130 binding cytokines in combination with interleukin-1 on cartilage collagen breakdown","volume":"44","author":"Rowan","year":"2001","journal-title":"Arthritis Rheumatol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"549","DOI":"10.1016\/S0945-053X(00)00111-6","article-title":"IL-6 and its soluble receptor augment aggrecanase-mediated proteoglycan catabolism in articular cartilage","volume":"19","author":"Flannery","year":"2000","journal-title":"Matrix Biol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"2985","DOI":"10.1002\/art.24857","article-title":"Mechanical injury potentiate proteoglycan catabolism induced by interleukin-6 with soluble interleukin-6 receptor and tumor necrosis factor \u03b1 in immature bovine and adult human articular cartilage","volume":"60","author":"Sui","year":"2009","journal-title":"Arthritis Rheumatol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"787","DOI":"10.1016\/j.beem.2015.07.001","article-title":"The soluble interleukin-6 receptor and related proteins","volume":"29","year":"2015","journal-title":"Best Pract. Res. Clin. Endocrinol. Metab."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"160","DOI":"10.1046\/j.1432-1327.2001.01867.x","article-title":"Soluble gp130 is the natural inhibitor of soluble interlukin-6 receptor transsignaling responses","volume":"268","author":"Jostock","year":"2001","journal-title":"Eur. J. Biochem."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.ijpharm.2004.11.014","article-title":"Protein aggregation and its inhibition in biopharmaceutics","volume":"289","author":"Wang","year":"2005","journal-title":"Int. J. Pharm."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"136","DOI":"10.1002\/art.20725","article-title":"Freshly isolated osteoarthritic chondrocytes are catabolically more active than normal chondrocytes, but less responsive to catabolic stimulation with interleukin-1beta","volume":"52","author":"Fan","year":"2005","journal-title":"Arthritis Rheumatol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"325","DOI":"10.2174\/138945007779940070","article-title":"Osteoarthritis: Aging of matrix and cells-going for a remedy","volume":"8","author":"Aigner","year":"2007","journal-title":"Curr. Drug Targets"},{"key":"ref_43","first-page":"25","article-title":"The transcript level of interleukin-6 in the cartilage of idiopathic ostoarthritis of knees","volume":"161","author":"Moktar","year":"2010","journal-title":"Clin. Ther."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"683","DOI":"10.1042\/bj1760683","article-title":"Age-related changes in the composition and structure of human articular cartilage proteoglycans","volume":"176","author":"Bayliss","year":"1979","journal-title":"Biochem. J."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"328","DOI":"10.1016\/j.foodchem.2014.02.091","article-title":"Dose-dependent changes in the levels of free and peptide forms of hydroxyproline in human plasma after collagen hydrolysate ingestion","volume":"159","author":"Shigemura","year":"2014","journal-title":"Food Chem."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"3752","DOI":"10.1021\/jf5057502","article-title":"Bioavailability and bioavailable forms of collagen after oral administration to rats","volume":"63","author":"Wang","year":"2015","journal-title":"J. Agric. Food Chem."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"154","DOI":"10.1002\/art.23175","article-title":"Regional differences in chondrocyte metabolism in osteoarthritis: A detailed analysis by laser capture microdissection","volume":"58","author":"Fukui","year":"2008","journal-title":"Arthritis Rheumatol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"269","DOI":"10.1016\/j.joca.2004.10.023","article-title":"Analysis of ADAMTS4 and MT4-MMP indicates that both are involved in aggrecanolysis in interleukin-1-treated bovine cartilage","volume":"13","author":"Patwari","year":"2005","journal-title":"Osteoarthr. Cartil."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"2065","DOI":"10.1002\/art.1780401120","article-title":"Osteoarthritic lesions: Involvement of three different collagenases","volume":"40","author":"Shlopov","year":"1997","journal-title":"Arthritis Rheumatol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"798","DOI":"10.1177\/1535370213480740","article-title":"Collagen hydrolysate inhibits zymosan-induced inflammation","volume":"238","author":"Hartog","year":"2013","journal-title":"Exp. Biol. Med."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"208","DOI":"10.3177\/jnsv.56.208","article-title":"Chicken collagen hydrolysate reduces proinflammatory cytokine production in C57BL\/6. KOR-ApoEsh1 mice","volume":"56","author":"Zhang","year":"2010","journal-title":"J. Nutr. Sci. Vitaminol."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"S45","DOI":"10.1016\/S1063-4584(08)60119-3","article-title":"Prophylactic treatment with a special collagen hydrolysate decreases cartilage tissue degeneration in the knee joints","volume":"16","author":"Oesser","year":"2008","journal-title":"Osteoarthr. Cartil."},{"key":"ref_53","unstructured":"Collins, D.H. (1949). The Pathology of Articular and Spinal Diseases, Edward Arnold and Co."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"828","DOI":"10.1002\/jor.21026","article-title":"In vitro inhibition of aggrecanase activity by tetracyclines and proteoglycan loss from osteoarthritic human articular cartilage","volume":"28","author":"Steinmeyer","year":"2010","journal-title":"J. Orthop. Res."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"1263","DOI":"10.1016\/j.joca.2008.02.011","article-title":"Dual proline labeling protocol for individual \u201cbaseline\u201d and \u201cresponse\u201d biosynthesis measurements in human articular cartilage","volume":"16","author":"Goodwin","year":"2008","journal-title":"Osteoarthr. Cartil."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1016\/0304-4165(86)90306-5","article-title":"Improved quantitation and discrimination of sulphated glycosaminoglycans by use of dimethylmethylene blue","volume":"83","author":"Farndale","year":"1986","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1016\/0003-2697(82)90118-X","article-title":"Analysis of nitrate, nitrite, and [15N]nitrate in biological fluids","volume":"126","author":"Green","year":"1982","journal-title":"Anal. Biochem."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1186\/s13075-015-0586-5","article-title":"Detecting cathepsin activity in human osteoarthritis via activity-based probes","volume":"17","author":"Merquiol","year":"2015","journal-title":"Arthritis Res. Ther."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/18\/1\/207\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T18:26:37Z","timestamp":1760207197000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/18\/1\/207"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2017,1,20]]},"references-count":58,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2017,1]]}},"alternative-id":["ijms18010207"],"URL":"https:\/\/doi.org\/10.3390\/ijms18010207","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2017,1,20]]}}}