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Patient-Specific iPSC-Derived Models Link Aberrant Endoplasmic Reticulum Stress Sensing and Response to Juvenile
Giuliana E Salazar-Noratto1,2, Catriana C Nations1, Hazel Y Stevens2,3
1Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, GA, USA.
Insights
Juvenile osteochondritis dissecans (JOCD) involves bone lesions and predisposes to early arthritis. JOCD cells show reduced chondrogenic capacity and altered ossification due to heightened endoplasmic reticulum stress sensitivity, offering new etiological insights.
Area of Science:
- Pediatric Orthopedics
- Stem Cell Biology
- Molecular Biology
Background:
- Juvenile osteochondritis dissecans (JOCD) is a pediatric condition affecting secondary ossification centers, leading to bone fragment separation and early-onset osteoarthritis.
- Current understanding of JOCD pathomechanisms is limited, hindering effective therapeutic strategies.
Purpose of the Study:
- To investigate the etiology of JOCD by examining the behavior of patient-derived induced pluripotent stem cells (iPSCs).
- To establish in vitro models for JOCD research using iPSC-derived mesenchymal stromal cells (iMSCs).
Main Methods:
- Skin biopsies from JOCD patients and controls were used to generate iPSCs.
- iPSCs were differentiated into iMSCs and subjected to chondrogenesis, endochondral ossification, and endoplasmic reticulum (ER) stress assays.
- Comparative analysis of cellular behavior and differentiation potential between JOCD and control cells.
Main Results:
- JOCD-derived iMSCs exhibited lower chondrogenic capability and distinct endochondral ossification compared to controls.
- Osteogenesis quality was similar between JOCD and control cells.
- JOCD cells demonstrated increased sensitivity to ER stress, which influences chondrocyte and osteoblast differentiation.
Conclusions:
- Endoplasmic reticulum stress plays a significant role in JOCD pathogenesis, potentially initiated by microtrauma or micro-ischemia in susceptible individuals.
- This study introduces a novel etiological hypothesis for JOCD, highlighting the role of resident and differentiating cells.
- Established JOCD-specific iPSC-derived models provide valuable tools for improving diagnostic and therapeutic strategies for JOCD.
Abstract:
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.
