| First Author | Ichimura A | Year | 2023 |
| Journal | Cell Death Dis | Volume | 14 |
| Issue | 12 | Pages | 848 |
| PubMed ID | 38123563 | Mgi Jnum | J:343609 |
| Mgi Id | MGI:7568088 | Doi | 10.1038/s41419-023-06285-y |
| Citation | Ichimura A, et al. (2023) Atypical cell death and insufficient matrix organization in long-bone growth plates from Tric-b-knockout mice. Cell Death Dis 14(12):848 |
| abstractText | 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 Ca(2+) 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 Ca(2+) 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/eIF2alpha (PKR-like ER kinase/ eukaryotic initiation factor 2alpha) 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. Ca(2+) imaging detected aberrant Ca(2+) handling in the knockout chondrocytes; ER Ca(2+) release was impaired, while cytoplasmic Ca(2+) level was elevated. Our observations suggest that Tric-b deficiency directs growth plate chondrocytes to pro-apoptotic states by compromising cellular Ca(2+)-handling and exacerbating ER stress response, leading to impaired ECM synthesis and accidental cell death. |
