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

Maojia Xu, Eva Lena Stattin, Georgina Shaw, Dick Heinegård, Gareth Sullivan, Ian Wilmut, Alan Colman, Patrik Önnerfjord, Areej Khabut, Anders Aspberg, Peter Dockery, Timothy Hardingham, Mary Murphy, Frank Barry

Forskningsoutput: TidskriftsbidragArtikel i vetenskaplig tidskriftPeer review

21 Citeringar (SciVal)

Sammanfattning

Familial 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.

Originalspråkengelska
Sidor (från-till)1171-1181
Antal sidor11
TidskriftStem cells translational medicine
Volym5
Utgåva9
DOI
StatusPublished - 2016

Ämnesklassifikation (UKÄ)

  • Cell- och molekylärbiologi

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