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Patient-Specific iPSC-Derived Models Link Aberrant Endoplasmic Reticulum Stress Sensing and Response to Juvenile Osteochondritis Dissecans Etiology

Juvenile osteochondritis dissecans (JOCD) is a pediatric disease, which begins with an osteonecrotic lesion in the secondary ossification center which, over time, results in the separation of the necrotic fragment from the parent bone. JOCD predisposes to early-onset osteoarthritis. However, the kno...

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Autores principales: Salazar-Noratto, Giuliana E, Nations, Catriana C, Stevens, Hazel Y, Xu, Maojia, Gaynard, Sean, Dooley, Claire, de Nijs, Nica, McDonagh, Katya, Shen, Sanbing, Willimon, S Clifton, Barry, Frank, Guldberg, Robert E
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10184700/
https://www.ncbi.nlm.nih.gov/pubmed/37184892
http://dx.doi.org/10.1093/stcltm/szad018
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author Salazar-Noratto, Giuliana E
Nations, Catriana C
Stevens, Hazel Y
Xu, Maojia
Gaynard, Sean
Dooley, Claire
de Nijs, Nica
McDonagh, Katya
Shen, Sanbing
Willimon, S Clifton
Barry, Frank
Guldberg, Robert E
author_facet Salazar-Noratto, Giuliana E
Nations, Catriana C
Stevens, Hazel Y
Xu, Maojia
Gaynard, Sean
Dooley, Claire
de Nijs, Nica
McDonagh, Katya
Shen, Sanbing
Willimon, S Clifton
Barry, Frank
Guldberg, Robert E
author_sort Salazar-Noratto, Giuliana E
collection PubMed
description Juvenile osteochondritis dissecans (JOCD) is a pediatric disease, which begins with an osteonecrotic lesion in the secondary ossification center which, over time, results in the separation of the necrotic fragment from the parent bone. JOCD predisposes to early-onset osteoarthritis. However, the knowledge gap in JOCD pathomechanisms severely limits current therapeutic strategies. To elucidate its etiology, we conducted a study with induced pluripotent stem cells (iPSCs) from JOCD and control patients. iPSCs from skin biopsies were differentiated to iMSCs (iPSC-derived mesenchymal stromal cells) and subjected to chondrogenic and endochondral ossification, and endoplasmic reticulum (ER)-stress induction assays. Our study, using 3 JOCD donors, showed that JOCD cells have lower chondrogenic capability and their endochondral ossification process differs from control cells; yet, JOCD- and control-cells accomplish osteogenesis of similar quality. Our findings show that endoplasmic reticulum stress sensing and response mechanisms in JOCD cells, which partially regulate chondrocyte and osteoblast differentiation, are related to these differences. We suggest that JOCD cells are more sensitive to ER stress than control cells, and in pathological microenvironments, such as microtrauma and micro-ischemia, JOCD pathogenesis pathways may be initiated. This study is the first, to the best of our knowledge, to realize the important role that resident cells and their differentiating counterparts play in JOCD and to put forth a novel etiological hypothesis that seeks to consolidate and explain previously postulated hypotheses. Furthermore, our results establish well-characterized JOCD-specific iPSC-derived in vitro models and identified potential targets which could be used to improve diagnostic tools and therapeutic strategies in JOCD.
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spelling pubmed-101847002023-05-16 Patient-Specific iPSC-Derived Models Link Aberrant Endoplasmic Reticulum Stress Sensing and Response to Juvenile Osteochondritis Dissecans Etiology Salazar-Noratto, Giuliana E Nations, Catriana C Stevens, Hazel Y Xu, Maojia Gaynard, Sean Dooley, Claire de Nijs, Nica McDonagh, Katya Shen, Sanbing Willimon, S Clifton Barry, Frank Guldberg, Robert E Stem Cells Transl Med Pluripotent Stem Cells Juvenile osteochondritis dissecans (JOCD) is a pediatric disease, which begins with an osteonecrotic lesion in the secondary ossification center which, over time, results in the separation of the necrotic fragment from the parent bone. JOCD predisposes to early-onset osteoarthritis. However, the knowledge gap in JOCD pathomechanisms severely limits current therapeutic strategies. To elucidate its etiology, we conducted a study with induced pluripotent stem cells (iPSCs) from JOCD and control patients. iPSCs from skin biopsies were differentiated to iMSCs (iPSC-derived mesenchymal stromal cells) and subjected to chondrogenic and endochondral ossification, and endoplasmic reticulum (ER)-stress induction assays. Our study, using 3 JOCD donors, showed that JOCD cells have lower chondrogenic capability and their endochondral ossification process differs from control cells; yet, JOCD- and control-cells accomplish osteogenesis of similar quality. Our findings show that endoplasmic reticulum stress sensing and response mechanisms in JOCD cells, which partially regulate chondrocyte and osteoblast differentiation, are related to these differences. We suggest that JOCD cells are more sensitive to ER stress than control cells, and in pathological microenvironments, such as microtrauma and micro-ischemia, JOCD pathogenesis pathways may be initiated. This study is the first, to the best of our knowledge, to realize the important role that resident cells and their differentiating counterparts play in JOCD and to put forth a novel etiological hypothesis that seeks to consolidate and explain previously postulated hypotheses. Furthermore, our results establish well-characterized JOCD-specific iPSC-derived in vitro models and identified potential targets which could be used to improve diagnostic tools and therapeutic strategies in JOCD. Oxford University Press 2023-04-17 /pmc/articles/PMC10184700/ /pubmed/37184892 http://dx.doi.org/10.1093/stcltm/szad018 Text en © The Author(s) 2023. Published by Oxford University Press. https://creativecommons.org/licenses/by-nc/4.0/This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial License (https://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com.
spellingShingle Pluripotent Stem Cells
Salazar-Noratto, Giuliana E
Nations, Catriana C
Stevens, Hazel Y
Xu, Maojia
Gaynard, Sean
Dooley, Claire
de Nijs, Nica
McDonagh, Katya
Shen, Sanbing
Willimon, S Clifton
Barry, Frank
Guldberg, Robert E
Patient-Specific iPSC-Derived Models Link Aberrant Endoplasmic Reticulum Stress Sensing and Response to Juvenile Osteochondritis Dissecans Etiology
title Patient-Specific iPSC-Derived Models Link Aberrant Endoplasmic Reticulum Stress Sensing and Response to Juvenile Osteochondritis Dissecans Etiology
title_full Patient-Specific iPSC-Derived Models Link Aberrant Endoplasmic Reticulum Stress Sensing and Response to Juvenile Osteochondritis Dissecans Etiology
title_fullStr Patient-Specific iPSC-Derived Models Link Aberrant Endoplasmic Reticulum Stress Sensing and Response to Juvenile Osteochondritis Dissecans Etiology
title_full_unstemmed Patient-Specific iPSC-Derived Models Link Aberrant Endoplasmic Reticulum Stress Sensing and Response to Juvenile Osteochondritis Dissecans Etiology
title_short Patient-Specific iPSC-Derived Models Link Aberrant Endoplasmic Reticulum Stress Sensing and Response to Juvenile Osteochondritis Dissecans Etiology
title_sort patient-specific ipsc-derived models link aberrant endoplasmic reticulum stress sensing and response to juvenile osteochondritis dissecans etiology
topic Pluripotent Stem Cells
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10184700/
https://www.ncbi.nlm.nih.gov/pubmed/37184892
http://dx.doi.org/10.1093/stcltm/szad018
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