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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

Xu, Maojia; Stattin, Eva Lena; Shaw, Georgina; Heinegård, Dick LU ; Sullivan, Gareth; Wilmut, Ian; Colman, Alan; Önnerfjord, Patrik LU ; Khabut, Areej LU and Aspberg, Anders LU , et al. (2016) In Stem cells translational medicine 5(9). p.1171-1181
Abstract

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... (More)

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.

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published
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keywords
Aggrecan mutation, Cellular pathology, Endoplasmic reticulum stress, Familial osteochondritis dissecans, Induced pluripotent stem cells, Mesenchymal stromal cells, Osteoarthritis, Stem cell disease models
in
Stem cells translational medicine
volume
5
issue
9
pages
11 pages
publisher
AlphaMed Press
external identifiers
  • scopus:84983389929
  • wos:000382420500008
ISSN
2157-6564
DOI
10.5966/sctm.2015-0384
language
English
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yes
id
233f23a3-c209-4c45-bf8d-cee19e9f60e4
date added to LUP
2016-10-14 11:33:27
date last changed
2017-05-07 04:46:40
@article{233f23a3-c209-4c45-bf8d-cee19e9f60e4,
  abstract     = {<p>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.</p>},
  author       = {Xu, Maojia and Stattin, Eva Lena and Shaw, Georgina and Heinegård, Dick and Sullivan, Gareth and Wilmut, Ian and Colman, Alan and Önnerfjord, Patrik and Khabut, Areej and Aspberg, Anders and Dockery, Peter and Hardingham, Timothy and Murphy, Mary and Barry, Frank},
  issn         = {2157-6564},
  keyword      = {Aggrecan mutation,Cellular pathology,Endoplasmic reticulum stress,Familial osteochondritis dissecans,Induced pluripotent stem cells,Mesenchymal stromal cells,Osteoarthritis,Stem cell disease models},
  language     = {eng},
  number       = {9},
  pages        = {1171--1181},
  publisher    = {AlphaMed Press},
  series       = {Stem cells translational medicine},
  title        = {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},
  url          = {http://dx.doi.org/10.5966/sctm.2015-0384},
  volume       = {5},
  year         = {2016},
}