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4PBA reduces growth deficiency in osteogenesis imperfecta by enhancing transition of hypertrophic chondrocytes to osteoblasts

Short stature is a major skeletal phenotype in osteogenesis imperfecta (OI), a genetic disorder mainly caused by mutations in genes encoding type I collagen. However, the underlying mechanism is poorly understood, and no effective treatment is available. In OI mice that carry a G610C mutation in COL...

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Autores principales: Scheiber, Amanda L., Wilkinson, Kevin J., Suzuki, Akiko, Enomoto-Iwamoto, Motomi, Kaito, Takashi, Cheah, Kathryn S.E., Iwamoto, Masahiro, Leikin, Sergey, Otsuru, Satoru
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Society for Clinical Investigation 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8855815/
https://www.ncbi.nlm.nih.gov/pubmed/34990412
http://dx.doi.org/10.1172/jci.insight.149636
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author Scheiber, Amanda L.
Wilkinson, Kevin J.
Suzuki, Akiko
Enomoto-Iwamoto, Motomi
Kaito, Takashi
Cheah, Kathryn S.E.
Iwamoto, Masahiro
Leikin, Sergey
Otsuru, Satoru
author_facet Scheiber, Amanda L.
Wilkinson, Kevin J.
Suzuki, Akiko
Enomoto-Iwamoto, Motomi
Kaito, Takashi
Cheah, Kathryn S.E.
Iwamoto, Masahiro
Leikin, Sergey
Otsuru, Satoru
author_sort Scheiber, Amanda L.
collection PubMed
description Short stature is a major skeletal phenotype in osteogenesis imperfecta (OI), a genetic disorder mainly caused by mutations in genes encoding type I collagen. However, the underlying mechanism is poorly understood, and no effective treatment is available. In OI mice that carry a G610C mutation in COL1A2, we previously found that mature hypertrophic chondrocytes (HCs) are exposed to cell stress due to accumulation of misfolded mutant type I procollagen in the endoplasmic reticulum (ER). By fate mapping analysis of HCs in G610C OI mice, we found that HCs stagnate in the growth plate, inhibiting translocation of HC descendants to the trabecular area and their differentiation to osteoblasts. Treatment with 4-phenylbutyric acid (4PBA), a chemical chaperone, restored HC ER structure and rescued this inhibition, resulting in enhanced longitudinal bone growth in G610C OI mice. Interestingly, the effects of 4PBA on ER dilation were limited in osteoblasts, and the bone fragility was not ameliorated. These results highlight the importance of targeting HCs to treat growth deficiency in OI. Our findings demonstrate that HC dysfunction induced by ER disruption plays a critical role in the pathogenesis of OI growth deficiency, which lays the foundation for developing new therapies for OI.
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spelling pubmed-88558152022-02-22 4PBA reduces growth deficiency in osteogenesis imperfecta by enhancing transition of hypertrophic chondrocytes to osteoblasts Scheiber, Amanda L. Wilkinson, Kevin J. Suzuki, Akiko Enomoto-Iwamoto, Motomi Kaito, Takashi Cheah, Kathryn S.E. Iwamoto, Masahiro Leikin, Sergey Otsuru, Satoru JCI Insight Research Article Short stature is a major skeletal phenotype in osteogenesis imperfecta (OI), a genetic disorder mainly caused by mutations in genes encoding type I collagen. However, the underlying mechanism is poorly understood, and no effective treatment is available. In OI mice that carry a G610C mutation in COL1A2, we previously found that mature hypertrophic chondrocytes (HCs) are exposed to cell stress due to accumulation of misfolded mutant type I procollagen in the endoplasmic reticulum (ER). By fate mapping analysis of HCs in G610C OI mice, we found that HCs stagnate in the growth plate, inhibiting translocation of HC descendants to the trabecular area and their differentiation to osteoblasts. Treatment with 4-phenylbutyric acid (4PBA), a chemical chaperone, restored HC ER structure and rescued this inhibition, resulting in enhanced longitudinal bone growth in G610C OI mice. Interestingly, the effects of 4PBA on ER dilation were limited in osteoblasts, and the bone fragility was not ameliorated. These results highlight the importance of targeting HCs to treat growth deficiency in OI. Our findings demonstrate that HC dysfunction induced by ER disruption plays a critical role in the pathogenesis of OI growth deficiency, which lays the foundation for developing new therapies for OI. American Society for Clinical Investigation 2022-02-08 /pmc/articles/PMC8855815/ /pubmed/34990412 http://dx.doi.org/10.1172/jci.insight.149636 Text en © 2022 Scheiber et al. https://creativecommons.org/licenses/by/4.0/This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Research Article
Scheiber, Amanda L.
Wilkinson, Kevin J.
Suzuki, Akiko
Enomoto-Iwamoto, Motomi
Kaito, Takashi
Cheah, Kathryn S.E.
Iwamoto, Masahiro
Leikin, Sergey
Otsuru, Satoru
4PBA reduces growth deficiency in osteogenesis imperfecta by enhancing transition of hypertrophic chondrocytes to osteoblasts
title 4PBA reduces growth deficiency in osteogenesis imperfecta by enhancing transition of hypertrophic chondrocytes to osteoblasts
title_full 4PBA reduces growth deficiency in osteogenesis imperfecta by enhancing transition of hypertrophic chondrocytes to osteoblasts
title_fullStr 4PBA reduces growth deficiency in osteogenesis imperfecta by enhancing transition of hypertrophic chondrocytes to osteoblasts
title_full_unstemmed 4PBA reduces growth deficiency in osteogenesis imperfecta by enhancing transition of hypertrophic chondrocytes to osteoblasts
title_short 4PBA reduces growth deficiency in osteogenesis imperfecta by enhancing transition of hypertrophic chondrocytes to osteoblasts
title_sort 4pba reduces growth deficiency in osteogenesis imperfecta by enhancing transition of hypertrophic chondrocytes to osteoblasts
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8855815/
https://www.ncbi.nlm.nih.gov/pubmed/34990412
http://dx.doi.org/10.1172/jci.insight.149636
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