Atypical cell death and insufficient matrix organization in long-bone growth plates from Tric-b-knockout mice
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- Ichimura, Atsuhiko
- Graduate School of Pharmaceutical Sciences, Kyoto University
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- Miyazaki, Yuu
- Graduate School of Pharmaceutical Sciences, Kyoto University
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- Nagatomo, Hiroki
- Graduate School of Pharmaceutical Sciences, Kyoto University
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- Kawabe, Takaaki
- Graduate School of Pharmaceutical Sciences, Kyoto University
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- Nakajima, Nobuhisa
- Graduate School of Pharmaceutical Sciences, Kyoto University
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- Kim, Ga Eun
- Graduate School of Pharmaceutical Sciences, Kyoto University
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- Tomizawa, Masato
- Graduate School of Pharmaceutical Sciences, Kyoto University
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- Okamoto, Naoki
- Graduate School of Pharmaceutical Sciences, Kyoto University
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- Komazaki, Shinji
- Saitama Medical University
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- Kakizawa, Sho
- Graduate School of Pharmaceutical Sciences, Kyoto University
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- Nishi, Miyuki
- Graduate School of Pharmaceutical Sciences, Kyoto University
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- Takeshima, Hiroshi
- Graduate School of Pharmaceutical Sciences, Kyoto University
Abstract
TRIC-A and TRIC-B proteins form homotrimeric cation-permeable channels in the endoplasmic reticulum (ER) and nuclear membranes and are thought to contribute to counterionic flux coupled with store Ca²⁺ release in various cell types. Serious mutations in the TRIC-B (also referred to as TMEM38B) locus cause autosomal recessive osteogenesis imperfecta (OI), which is characterized by insufficient bone mineralization. We have reported that Tric-b-knockout mice can be used as an OI model; Tric-b deficiency deranges ER Ca²⁺ handling and thus reduces extracellular matrix (ECM) synthesis in osteoblasts, leading to poor mineralization. Here we report irregular cell death and insufficient ECM in long-bone growth plates from Tric-b-knockout embryos. In the knockout growth plate chondrocytes, excess pro-collagen fibers were occasionally accumulated in severely dilated ER elements. Of the major ER stress pathways, activated PERK/eIF2α (PKR-like ER kinase/ eukaryotic initiation factor 2α) signaling seemed to inordinately alter gene expression to induce apoptosis-related proteins including CHOP (CCAAT/enhancer binding protein homologous protein) and caspase 12 in the knockout chondrocytes. Ca²⁺ imaging detected aberrant Ca²⁺ handling in the knockout chondrocytes; ER Ca²⁺ release was impaired, while cytoplasmic Ca²⁺ level was elevated. Our observations suggest that Tric-b deficiency directs growth plate chondrocytes to pro-apoptotic states by compromising cellular Ca²⁺-handling and exacerbating ER stress response, leading to impaired ECM synthesis and accidental cell death.
Journal
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- Cell Death & Disease
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Cell Death & Disease 14 2023-12-20
Springer Nature
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Keywords
Details 詳細情報について
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- CRID
- 1050861538000628480
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- ISSN
- 20414889
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- HANDLE
- 2433/286465
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- Text Lang
- en
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- Article Type
- journal article
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- Data Source
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- IRDB