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dc.contributor.authorXu, Maojia
dc.contributor.authorStattin, Eva-Lena
dc.contributor.authorShaw, Georgina
dc.contributor.authorHeinegård, Dick
dc.contributor.authorSullivan, Gareth
dc.contributor.authorWilmut, Ian
dc.contributor.authorColman, Alan
dc.contributor.authorÖnnerfjord, Patrik
dc.contributor.authorKhabut, Areej
dc.contributor.authorAspberg, Anders
dc.contributor.authorDockery, Peter
dc.contributor.authorHardingham, Timothy
dc.contributor.authorMurphy, Mary
dc.contributor.authorBarry, Frank
dc.identifier.citationXu, Maojia; Stattin, Eva-Lena; Shaw, Georgina; Heinegård, Dick; Sullivan, Gareth; Wilmut, Ian; Colman, Alan; Önnerfjord, Patrik; Khabut, Areej; Aspberg, Anders; Dockery, Peter; Hardingham, Timothy; Murphy, Mary; Barry, Frank (2016). Chondrocytes derived from mesenchymal stromal cells and induced pluripotent cells of patients with familial osteochondritis dissecans exhibit an endoplasmic reticulum stress response and defective matrix assembly. STEM CELLS Translational Medicine 5 (9), 1171-1181, doi: 10.5966/sctm.2015-0384en_IE
dc.description.abstractFamilial osteochondritis dissecans (FOCD) is an inherited skeletal defect characterized by the development of large cartilage lesions in multiple joints, short stature, and early onset of severe osteoarthritis. It is associated with a heterozygous mutation in the ACAN gene, resulting in a Val-Met replacement in the C-type lectin domain of aggrecan. To understand the cellular pathogenesis of this condition, we studied the chondrogenic differentiation of patient bone marrow mesenchymal stromal cells (BM-MSCs). We also looked at cartilage derived from induced pluripotent stem cells (iPSCs) generated from patient fibroblasts. Our results revealed several characteristics of the differentiated chondrocytes that help to explain the disease phenotype and susceptibility to cartilage injury. First, patient chondrogenic pellets had poor structural integrity but were rich in glycosaminoglycan. Second, it was evident that large amounts of aggrecan accumulated within the endoplasmic reticulum of chondrocytes differentiated from both BM-MSCs and iPSCs. In turn, there was a marked absence of aggrecan in the extracellular matrix. Third, it was evident that matrix synthesis and assembly were globally dysregulated. These results highlight some of the abnormal aspects of chondrogenesis in these patient cells and help to explain the underlying cellular pathology. The results suggest that FOCD is a chondrocyte aggrecanosis with associated matrix dysregulation. The work provides a new in vitro model of osteoarthritis and cartilage degeneration based on the use of iPSCs and highlights how insights into disease phenotype and pathogenesis can be uncovered by studying differentiation of patient stem cells.en_IE
dc.description.sponsorshipWe sincerely thank the family members who participated in the study and Dr. Yelverton Tegner, Luleå Technical University, Luleå, Sweden, for providing skin samples. We acknowledge the facilities and technical assistance of the Flow Cytometry Facility at the National University of Ireland Galway, a facility that is funded by National University of Ireland Galway and the Irish Government's Programme for Research in Third Level Institutions, Cycle5, National Development Plan 2007–2013. We thank Pierce Lalor, Dr. Kerry Thompson, and the Centre for Microscopy and Imaging ( for assistance with TEM and confocal imaging, and Jingqiu Zhang (A*STAR Institute of Medical Biology, Singapore) for assistance with the iPSC reprogramming technique. We also thank Maggie Hall for helpful editing of the manuscript. This study was funded by Science Foundation Ireland Grant SFI 09/SRC.B1794 and Irish Research Council Grant GOIPG/2014/96. This project has also received funding from the European Union's Seventh Framework Programme for Research, Technological Development and Demonstration under grant agreement no. 223298.en_IE
dc.relation.ispartofStem Cells Translational Medicineen
dc.subjectFamilial osteochondritis dissecansen_IE
dc.subjectMesenchymal stromal cellsen_IE
dc.subjectInduced pluripotent stem cellsen_IE
dc.subjectStem cell disease modelsen_IE
dc.subjectCellular pathologyen_IE
dc.subjectAggrecan mutationen_IE
dc.subjectEndoplasmic reticulum stressen_IE
dc.subjectG3 DOMAINen_IE
dc.titleChondrocytes derived from mesenchymal stromal cells and induced pluripotent cells of patients with familial osteochondritis dissecans exhibit an endoplasmic reticulum stress response and defective matrix assemblyen_IE
dc.contributor.funderScience Foundation Irelanden_IE
dc.contributor.funderIrish Research Councilen_IE
dc.contributor.funderSeventh Framework Programmeen_IE
dc.local.contactMary Murphy, Dept. Of Medicine & Remedi, Bms 1024, Biomedical Sciences Building,, North Campus. 5206 Email:
dcterms.projectinfo:eu-repo/grantAgreement/EC/FP7::SP1::HEALTH/223298/EU/Utilisation of the mesenchymal stem cell receptome for rational development of uniform, serum-free culture conditions and tools for cell characterization/PURSTEMen_IE

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