{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,3]],"date-time":"2026-10-03T04:18:14Z","timestamp":1791001094798,"version":"4.1.0"},"reference-count":56,"publisher":"MDPI AG","issue":"13","license":[{"start":{"date-parts":[[2021,6,30]],"date-time":"2021-06-30T00:00:00Z","timestamp":1625011200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000069","name":"National Institute of Arthritis and Musculoskeletal and Skin Diseases","doi-asserted-by":"publisher","award":["1R21 AR076604"],"award-info":[{"award-number":["1R21 AR076604"]}],"id":[{"id":"10.13039\/100000069","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Mesenchymal stem cells (MSCs) obtained from various sources, including bone marrow, have been proposed as a therapeutic strategy for the improvement of tissue repair\/regeneration, including the repair of cartilage defects or lesions. Often the highly inflammatory environment after injury or during diseases, however, greatly diminishes the therapeutic and reparative effectiveness of MSCs. Therefore, the identification of novel factors that can protect MSCs against an inflammatory environment may enhance the effectiveness of these cells in repairing tissues, such as articular cartilage. In this study, we investigated whether a peptide (P15-1) that binds to hyaluronan (HA), a major component of the extracellular matrix of cartilage, protects bone-marrow-derived MSCs (BMSCs) in an inflammatory environment. The results showed that P15-1 reduced the mRNA levels of catabolic and inflammatory markers in interleukin-1beta (IL-1\u03b2)-treated human BMSCs. In addition, P15-1 enhanced the attachment of BMSCs to HA-coated tissue culture dishes and stimulated the chondrogenic differentiation of the multipotential murine C3H\/10T1\/2 MSC line in a micromass culture. In conclusion, our findings suggest that P15-1 may increase the capacity of BMSCs to repair cartilage via the protection of these cells in an inflammatory environment and the stimulation of their attachment to an HA-containing matrix and chondrogenic differentiation.<\/jats:p>","DOI":"10.3390\/ijms22137058","type":"journal-article","created":{"date-parts":[[2021,6,30]],"date-time":"2021-06-30T10:03:19Z","timestamp":1625047399000},"page":"7058","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Protective Effects of a Hyaluronan-Binding Peptide (P15-1) on Mesenchymal Stem Cells in an Inflammatory Environment"],"prefix":"10.3390","volume":"22","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0184-9220","authenticated-orcid":false,"given":"Thorsten","family":"Kirsch","sequence":"first","affiliation":[{"name":"Department of Orthopaedic Surgery, New York University Grossman School of Medicine, New York, NY 10010, USA"},{"name":"Department of Biomedical Engineering, New York University Tandon School of Engineering, New York, NY 10010, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fenglin","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Orthopaedic Surgery, New York University Grossman School of Medicine, New York, NY 10010, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Olivia","family":"Braender-Carr","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering, New York University Tandon School of Engineering, New York, NY 10010, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2714-1666","authenticated-orcid":false,"given":"Mary K.","family":"Cowman","sequence":"additional","affiliation":[{"name":"Department of Orthopaedic Surgery, New York University Grossman School of Medicine, New York, NY 10010, USA"},{"name":"Department of Biomedical Engineering, New York University Tandon School of Engineering, New York, NY 10010, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,6,30]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"584","DOI":"10.1038\/nrrheum.2013.109","article-title":"Mesenchymal stem cells in joint disease and repair","volume":"9","author":"Barry","year":"2013","journal-title":"Nat. Rev. Rheumatol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"341","DOI":"10.1002\/jcp.21200","article-title":"Adult mesenchymal stem cells for tissue engineering versus regenerative medicine","volume":"213","author":"Caplan","year":"2007","journal-title":"J. Cell. Physiol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1445","DOI":"10.1002\/sctm.17-0051","article-title":"Mesenchymal stem cells: Time to change the name!","volume":"6","author":"Caplan","year":"2017","journal-title":"Stem Cells Transl. Med."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1","DOI":"10.15283\/ijsc.2008.1.1.1","article-title":"Mesenchymal stem cell delivery routes and fate","volume":"1","author":"Kurtz","year":"2008","journal-title":"Int. J. Stem Cells"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1416","DOI":"10.1007\/s10350-005-0052-6","article-title":"A phase I clinical trial of the treatment of Crohn\u2019s fistula by adipose mesenchymal stem cell transplantation","volume":"48","author":"Herreros","year":"2005","journal-title":"Dis. Colon Rectum"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"245","DOI":"10.1002\/jcp.10260","article-title":"Participation of bone marrow derived cells in cutaneous wound healing","volume":"196","author":"Badiavas","year":"2003","journal-title":"J. Cell. Physiol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"756","DOI":"10.1016\/j.jcyt.2017.03.072","article-title":"Cox-2 inhibition potentiates mouse bone marrow stem cell engraftment and differentiation-mediated wound repair","volume":"19","author":"Geesala","year":"2017","journal-title":"Cytotherapy"},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Waterman, R.S., Tomchuck, S.L., Henkle, S.L., and Betancourt, A.M. (2010). A new mesenchymal stem cell (MSC) paradigm: Polarization into a pro-inflammatory MSC1 or an immunosuppressive MSC2 phenotype. PLoS ONE, 5.","DOI":"10.1371\/journal.pone.0010088"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1089\/ten.tea.2011.0083","article-title":"Catabolic factors and osteoarthritis-conditioned medium inhibit chondrogenesis of human mesenchymal stem cells","volume":"18","author":"Heldens","year":"2012","journal-title":"Tissue Eng. Part A"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"255","DOI":"10.3389\/fphar.2017.00255","article-title":"Rescued chondrogenesis of mesenchymal stem cells under interleukin 1 challenge by foamyviral interleukin 1 receptor antagonist gene transfer","volume":"8","author":"Armbruster","year":"2017","journal-title":"Front. Pharmacol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.biocel.2014.07.022","article-title":"MSCs and hyaluronan: Sticking together for new therapeutic potential?","volume":"55","author":"Kota","year":"2014","journal-title":"Int. J. Biochem. Cell Biol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1225","DOI":"10.1002\/stem.2328","article-title":"Hyaluronan is crucial for stem cell differentiation into smooth muscle lineage","volume":"34","author":"Simpson","year":"2016","journal-title":"Stem Cells"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"23465","DOI":"10.1074\/jbc.M114.557447","article-title":"Umbilical cord mesenchymal stem cells suppress host rejection: The role of the glycocalyx","volume":"289","author":"Gesteira","year":"2014","journal-title":"J. Biol. Chem."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1","DOI":"10.3389\/fimmu.2015.00261","article-title":"The content and size of hyaluronan in biological fluids and tissues","volume":"6","author":"Cowman","year":"2015","journal-title":"Front. Immunol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"43094","DOI":"10.1074\/jbc.M112.349209","article-title":"The high and low molecular weight forms of hyaluronan have distinct effects on CD44 clustering","volume":"287","author":"Yang","year":"2012","journal-title":"J. Biol. Chem."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/bs.accb.2017.10.001","article-title":"Hyaluronan and hyaluronan fragments","volume":"74","author":"Cowman","year":"2017","journal-title":"Adv. Carbohydr. Chem. Biochem."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1272","DOI":"10.4049\/jimmunol.177.2.1272","article-title":"Hyaluronan fragments act as an endogenous danger signal by engaging TLR2","volume":"177","author":"Scheibner","year":"2006","journal-title":"J. Immunol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"221","DOI":"10.1152\/physrev.00052.2009","article-title":"Hyaluronan as an immune regulator in human diseases","volume":"91","author":"Jiang","year":"2011","journal-title":"Physiol. Rev."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"101","DOI":"10.3389\/fimmu.2014.00101","article-title":"Hyaluronan, a crucial regulator of inflammation","volume":"5","author":"Petrey","year":"2014","journal-title":"Front. Immunol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"563818","DOI":"10.1155\/2015\/563818","article-title":"Size matters: Molecular weight specificity of hyaluronan effects in cell biology","volume":"2015","author":"Cyphert","year":"2015","journal-title":"Int. J. Cell Biol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"631","DOI":"10.1016\/j.biomaterials.2009.09.089","article-title":"Enhancement of chondrogenesis of human adipose derived stem cells in a hyaluronan-enriched microenvironment","volume":"31","author":"Wu","year":"2010","journal-title":"Biomaterials"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1610","DOI":"10.1152\/japplphysiol.01132.2012","article-title":"Hyaluronan initiates chondrogenesis mainly via CD44 in human adipose-derived stem cells","volume":"114","author":"Wu","year":"2013","journal-title":"J. Appl. Physiol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"224","DOI":"10.1016\/j.actbio.2017.11.025","article-title":"Hyaluronan size alters chondrogenesis of adipose-derived stem cells via the CD44\/ERK\/SOX-9 pathway","volume":"66","author":"Wu","year":"2018","journal-title":"Acta Biomater."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"928","DOI":"10.1634\/stemcells.2005-0186","article-title":"The role of the hyaluronan receptor CD44 in mesenchymal stem cell migration in the extracellular matrix","volume":"24","author":"Zhu","year":"2006","journal-title":"Stem Cells"},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Reiprich, S., Hofbauer, E., Kiderlen, S., Clausen-Schaumann, H., Bocker, W., Aszodi, A., and Schonitzer, V. (2020). Adhesive Properties of the Hyaluronan Pericellular coat in hyaluronan synthases overexpressing mesenchymal stem cells. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21113827"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"G462","DOI":"10.1152\/ajpgi.00494.2004","article-title":"Regulation of hyaluronan synthase-2 expression in human intestinal mesenchymal cells: Mechanisms of interleukin-1beta-mediated induction","volume":"289","author":"Ducale","year":"2005","journal-title":"Am. J. Physiol. Gastrointest. Liver Physiol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"4565","DOI":"10.1038\/srep04565","article-title":"Differential MSC activation leads to distinct mononuclear leukocyte binding mechanisms","volume":"4","author":"Kota","year":"2014","journal-title":"Sci. Rep."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"411","DOI":"10.1016\/j.ydbio.2007.02.023","article-title":"Hyaluronan in limb morphogenesis","volume":"305","author":"Li","year":"2007","journal-title":"Dev. Biol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"174","DOI":"10.1002\/bdrc.10013","article-title":"Hyaluronan and CD44: Strategic players for cell-matrix interactions during chondrogenesis and matrix assembly","volume":"69","author":"Knudson","year":"2003","journal-title":"Birth Defects Res. Part C Embryo Today Rev."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"32","DOI":"10.1016\/j.matbio.2018.02.005","article-title":"The pericellular hyaluronan of articular chondrocytes","volume":"78\u201379","author":"Knudson","year":"2019","journal-title":"Matrix Biol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"261","DOI":"10.2741\/3687","article-title":"Hyaluronan and mesenchymal stem cells: From germ layer to cartilage and bone","volume":"16","author":"Astachov","year":"2011","journal-title":"Front. Biosci."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1343","DOI":"10.1083\/jcb.117.6.1343","article-title":"Molecular cloning of a novel hyaluronan receptor that mediates tumor cell motility","volume":"117","author":"Hardwick","year":"1992","journal-title":"J. Cell. Biol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1017","DOI":"10.1083\/jcb.200511027","article-title":"Rhamm\u2212\/\u2212 fibroblasts are defective in CD44-mediated ERK1,2 motogenic signaling, leading to defective skin wound repair","volume":"175","author":"Tolg","year":"2006","journal-title":"J. Cell. Biol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"255","DOI":"10.1016\/j.matbio.2018.08.002","article-title":"The Receptor for Hyaluronan-Mediated Motility (CD168) promotes inflammation and fibrosis after acute lung injury","volume":"78\u201379","author":"Cui","year":"2019","journal-title":"Matrix Biol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1482","DOI":"10.1016\/j.jid.2019.11.032","article-title":"Function-blocking RHAMM peptides attenuate fibrosis and promote anti-fibrotic adipokines in a bleomycin-induced murine model of systemic sclerosis","volume":"141","author":"Wu","year":"2021","journal-title":"J. Investig. Dermatol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"236","DOI":"10.1016\/j.matbio.2018.08.008","article-title":"Hyaluronic acid, CD44 and RHAMM regulate myoblast behavior during embryogenesis","volume":"78\u201379","author":"Leng","year":"2019","journal-title":"Matrix Biol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1250","DOI":"10.1016\/j.ajpath.2012.06.036","article-title":"A RHAMM mimetic peptide blocks hyaluronan signaling and reduces inflammation and fibrogenesis in excisional skin wounds","volume":"181","author":"Tolg","year":"2012","journal-title":"Am. J. Pathol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"223","DOI":"10.1039\/C7IB00002B","article-title":"Receptor for hyaluronan mediated motility (RHAMM\/HMMR) is a novel target for promoting subcutaneous adipogenesis","volume":"9","author":"Bahrami","year":"2017","journal-title":"Integr. Biol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"5194","DOI":"10.1016\/j.bmc.2018.09.018","article-title":"A truncated RHAMM protein for discovering novel therapeutic peptides","volume":"26","author":"Tolg","year":"2018","journal-title":"Bioorg. Med. Chem."},{"key":"ref_40","first-page":"346","article-title":"Design of peptide mimetics to block pro-inflammatory functions of HA fragments","volume":"78\u201379","author":"Luyt","year":"2019","journal-title":"Matrix Biol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"8617","DOI":"10.1016\/S0021-9258(18)52919-7","article-title":"Identification of two hyaluronan-binding domains in the hyaluronan receptor RHAMM","volume":"268","author":"Yang","year":"1993","journal-title":"J. Biol. Chem."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"286","DOI":"10.1002\/j.1460-2075.1994.tb06261.x","article-title":"Identification of a common hyaluronan binding motif in the hyaluronan binding proteins RHAMM, CD44 and link protein","volume":"13","author":"Yang","year":"1994","journal-title":"EMBO J."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1441","DOI":"10.1038\/s41598-020-57586-7","article-title":"A Hyaluronan-binding Peptide (P15-1) reduces inflammatory and catabolic events in IL-1beta-treated human articular chondrocytes","volume":"10","author":"Shortt","year":"2020","journal-title":"Sci. Rep."},{"key":"ref_44","unstructured":"Cowman, M.K., Kirsch, T., Strauss, E.J., Turley, E.A., Toelg, C., and Luyt, L.G. (2017). Compositions and Methods for Cartilage Defect Repair Using a RHAMM-Mimetic Peptide. (No. US20170239318A1), U.S. Patent."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"29642","DOI":"10.1074\/jbc.M113.477422","article-title":"Inter-alpha-inhibitor impairs TSG-6-induced hyaluronan cross-linking","volume":"288","author":"Baranova","year":"2013","journal-title":"J. Biol. Chem."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"42","DOI":"10.1053\/joca.2000.0348","article-title":"Up-regulation and differential expression of the hyaluronan-binding protein TSG-6 in cartilage and synovium in rheumatoid arthritis and osteoarthritis","volume":"9","author":"Bayliss","year":"2001","journal-title":"Osteoarthr. Cartil."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"245","DOI":"10.1016\/j.joca.2017.10.019","article-title":"TSG-6\u2014A double-edged sword for osteoarthritis (OA)","volume":"26","author":"Chou","year":"2018","journal-title":"Osteoarthr. Cartil."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1016\/S1359-6101(97)00008-7","article-title":"TSG-6: An IL-1\/TNF-inducible protein with anti-inflammatory activity","volume":"8","author":"Wisniewski","year":"1997","journal-title":"Cytokine Growth Factor Rev."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"56","DOI":"10.1007\/s00223-008-9189-3","article-title":"Comparison of multipotent differentiation potentials of murine primary bone marrow stromal cells and mesenchymal stem cell line C3H10T1\/2","volume":"84","author":"Zhao","year":"2009","journal-title":"Calcif. Tissue Int."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"128","DOI":"10.1002\/art.20776","article-title":"Role of interleukin-1 and tumor necrosis factor alpha in matrix degradation of human osteoarthritic cartilage","volume":"52","author":"Kobayashi","year":"2005","journal-title":"Arthritis Rheum."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"1808","DOI":"10.1007\/s10753-019-01043-9","article-title":"Role of hyaluronan in inflammatory effects on human articular chondrocytes","volume":"42","author":"Cowman","year":"2019","journal-title":"Inflammation"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"60","DOI":"10.1016\/j.matbio.2018.01.011","article-title":"TSG-6: A multifunctional protein with anti-inflammatory and tissue-protective properties","volume":"78\u201379","author":"Day","year":"2019","journal-title":"Matrix Biol."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"54","DOI":"10.1016\/j.stem.2009.05.003","article-title":"Intravenous hMSCs improve myocardial infarction in mice because cells embolized in lung are activated to secrete the anti-inflammatory protein TSG-6","volume":"5","author":"Lee","year":"2009","journal-title":"Cell Stem Cell"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"22771","DOI":"10.1074\/jbc.M114.629774","article-title":"Acute and temporal expression of tumor necrosis factor (TNF)-alpha-stimulated gene 6 product, TSG6, in mesenchymal stem cells creates microenvironments required for their successful transplantation into muscle tissue","volume":"290","author":"Torihashi","year":"2015","journal-title":"J. Biol. Chem."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1186\/s13287-017-0531-4","article-title":"Interleukin-1 primes human mesenchymal stem cells towards an anti-inflammatory and pro-trophic phenotype in vitro","volume":"8","author":"Cunningham","year":"2017","journal-title":"Stem Cell Res. Ther."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1046\/j.1432-0436.1999.6420077.x","article-title":"Chondrogenic differentiation of murine C3H10T1\/2 multipotential mesenchymal cells: II. Stimulation by bone morphogenetic protein-2 requires modulation of N-cadherin expression and function","volume":"64","author":"Haas","year":"1999","journal-title":"Differentiation"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/13\/7058\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T06:23:59Z","timestamp":1760163839000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/13\/7058"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,6,30]]},"references-count":56,"journal-issue":{"issue":"13","published-online":{"date-parts":[[2021,7]]}},"alternative-id":["ijms22137058"],"URL":"https:\/\/doi.org\/10.3390\/ijms22137058","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,6,30]]}}}