CEMIP (KIAA1199) induces a fibrosis-like process in osteoarthritic chondrocytes

被引:72
作者
Deroyer, Celine [1 ]
Charlier, Edith [1 ]
Neuville, Sophie [1 ]
Malaise, Olivier [1 ]
Gillet, Philippe [2 ]
Kurth, William [2 ]
Chariot, Alain [3 ,4 ]
Malaise, Michel [1 ]
de Seny, Dominique [1 ]
机构
[1] Univ Liege, CHU Liege, Lab Rheumatol, GIGA I3, Liege, Belgium
[2] CHU Liege, Orthoped Surg Unit, Liege, Belgium
[3] Univ Liege, Med Chem Lab, GIGA Mol Biol Dis, Liege, Belgium
[4] Walloon Excellence Life Sci & Biotechnol WELBIO, Liege, Belgium
关键词
KNEE-JOINT CARTILAGE; MESSENGER-RNAS; X COLLAGEN; TGF-BETA; EXPRESSION; PROTEIN; PROMOTES; GENE; LOCALIZATION; HYPERTROPHY;
D O I
10.1038/s41419-019-1377-8
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
CEMIP (for "Cell migration-inducing protein" also called KIAA1199 and Hybid for "Hyaluronan-binding protein") expression is increased in cancers and described as a regulator of cell survival, growth and invasion. In rheumatoid arthritis, CEMIP is referred to as an angiogenic marker and participates in hyaluronic acid degradation. In this study, CEMIP expression is investigated in healthy and osteoarthritis (OA) cartilage from human and mouse. Its role in OA physiopathology is deciphered, specifically in chondrocytes proliferation and dedifferentiation and in the extracellular matrix remodeling. To this end, CEMIP, alpha SMA and types I and III collagen expressions were assessed in human OA and non-OA cartilage. CEMIP expression was also investigated in a mouse OA model. CEMIP expression was studied in vitro using a chondrocyte dedifferentiation model. High-throughput RNA sequencing was performed on chondrocytes after CEMIP silencing. Results showed that CEMIP was overexpressed in human and murine OA cartilage and along chondrocytes dedifferentiation. Most of genes deregulated in CEMIP-depleted cells were involved in cartilage turnover (e.g., collagens), mesenchymal transition and fibrosis. CEMIP regulated beta-catenin protein level. Moreover, CEMIP was essential for chondrocytes proliferation and promoted aSMA expression, a fibrosis marker, and TGF beta signaling towards the p-Smad2/3 (Alk5/PAI-1) pathway. Interestingly, CEMIP was induced by the pSmad1/5 (Alk1) pathway. aSMA and type III collagen expressions were overexpressed in human OA cartilage and along chondrocytes dedifferentiation. Finally, CEMIP was co-expressed in situ with aSMA in all OA cartilage layers. In conclusion, CEMIP was sharply overexpressed in human and mouse OA cartilage and along chondrocytes dedifferentiation. CEMIP-regulated transdifferentiation of chondrocytes into "chondro-myo-fibroblasts" expressing alpha-SMA and type III collagen, two fibrosis markers. Moreover, these "chondro-myo-fibroblasts" were found in OA cartilage but not in healthy cartilage.
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页数:17
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共 54 条
[31]   Dkk-1 expression in chondrocytes inhibits experimental osteoarthritic cartilage destruction in mice [J].
Oh, Hwanhee ;
Chun, Churl-Hong ;
Chun, Jang-Soo .
ARTHRITIS AND RHEUMATISM, 2012, 64 (08) :2568-2578
[32]   Bone morphogenetic protein-2-induced Wnt/β-catenin signaling pathway activation through enhanced low-density-lipoprotein receptor-related protein 5 catabolic activity contributes to hypertrophy in osteoarthritic chondrocytes [J].
Papathanasiou, Ioanna ;
Malizos, Konstantinos N. ;
Tsezou, Aspasia .
ARTHRITIS RESEARCH & THERAPY, 2012, 14 (02)
[33]   Osteoarthritis cartilage histopathology: grading and staging [J].
Pritzker, KPH ;
Gay, S ;
Jimenez, SA ;
Ostergaard, K ;
Pelletier, JP ;
Revell, PA ;
Salter, D ;
van den Berg, WB .
OSTEOARTHRITIS AND CARTILAGE, 2006, 14 (01) :13-29
[34]   INSITU HYBRIDIZATION STUDIES ON THE EXPRESSION OF TYPE-X COLLAGEN IN FETAL HUMAN CARTILAGE [J].
REICHENBERGER, E ;
AIGNER, T ;
VONDERMARK, K ;
STOSS, H ;
BERTLING, W .
DEVELOPMENTAL BIOLOGY, 1991, 148 (02) :562-572
[35]   Genistein induces adipogenesis but inhibits leptin induction in human synovial fibroblasts [J].
Relic, Biserka ;
Zeddou, Mustapha ;
Desoroux, Aline ;
Beguin, Yves ;
de Seny, Dominique ;
Malaise, Michel G. .
LABORATORY INVESTIGATION, 2009, 89 (07) :811-822
[36]   Unravelling osteoarthritis-related synovial fibrosis: a step closer to solving joint stiffness [J].
Remst, Dennis F. G. ;
Davidson, Esmeralda N. Blaney ;
van der Kraan, Peter M. .
RHEUMATOLOGY, 2015, 54 (11) :1954-1963
[37]   Transcriptome profile of human colorectal adenomas [J].
Sabates-Beliver, Jacob ;
Van der Flier, Laurens G. ;
de Palo, Mariagrazia ;
Cattaneo, Elisa ;
Maake, Caroline ;
Rehrauer, Hubert ;
Laczko, Endre ;
Kurowski, Michal A. ;
Bujnicki, Janusz M. ;
Menigatti, Mirco ;
Luz, Judith ;
Ranalli, Teresa V. ;
Gornes, Vito ;
Pastorelli, Alfredo ;
Faggiani, Roberto ;
Anti, Marcello ;
Jiricny, Josef ;
Clevers, Hans ;
Marra, Giancarlo .
MOLECULAR CANCER RESEARCH, 2007, 5 (12) :1263-1275
[38]   LOCALIZATION OF TYPE-I, TYPE-II, AND TYPE-III COLLAGEN MESSENGER-RNAS IN DEVELOPING HUMAN SKELETAL TISSUES BY INSITU HYBRIDIZATION [J].
SANDBERG, M ;
VUORIO, E .
JOURNAL OF CELL BIOLOGY, 1987, 104 (04) :1077-1084
[39]   ALTERNATIVELY SPLICED TYPE-II PROCOLLAGEN MESSENGER-RNAS DEFINE DISTINCT POPULATIONS OF CELLS DURING VERTEBRAL DEVELOPMENT - DIFFERENTIAL EXPRESSION OF THE AMINO-PROPEPTIDE [J].
SANDELL, LJ ;
MORRIS, N ;
ROBBINS, JR ;
GOLDRING, MB .
JOURNAL OF CELL BIOLOGY, 1991, 114 (06) :1307-1319
[40]   Articular cartilage and changes in arthritis - An introduction: Cell biology of osteoarthritis [J].
Sandell, LJ ;
Aigner, T .
ARTHRITIS RESEARCH, 2001, 3 (02) :107-113