Saudi Cultural Missions Theses & Dissertations
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Item Restricted OSTERIX - POSITIVE CELL-INTRINSIC IRE1α /XBP1 SIGNALING REGULATES THE POSTNATAL BONE DEVELOPMENT AND BONE MARROW HOMEOSTASIS(Saudi Digital Library, 2022) Alshalawy, Faisal; Ouyang, HongjiaoX-box binding protein-1 (XBP1) is a transcription factor that plays a critical role in managing cellular responses to endoplasmic reticulum (ER) stress. Under stress conditions, the transcriptionally active form of XBP1 is generated from unspliced Xbp1 by the inositol-requiring enzyme-1 (IRE1), an endoplasmic reticulum (ER) stress sensor and an ER-membrane residing endoribonuclease and kinase. The IRE1/XBP1s signaling is implicated in the development and homeostasis of many professional secretory cells and organs. Herein, In the second chapter of the dissertation, we demonstrate that deficiency of IRE1α, an IRE1 isoform that is expressed by osteoblast-lineage cells (Osterix-expressing cells), e.g., osteoblasts and skeletal progenitor cells, leads to osteoporosis/osteopenia with reduced bone formation/osteoblastogenesis and bone resorption/osteoclastogenesis, as well as enhanced bone marrow adipogenesis, in vivo. IRE1 deficiency results in compromised XBP1s signaling in osteolineage cells. In order to determine whether XBP1 is an important biological mediator of IRE1α in regulating postnatal bone development and bone hemostasis. In the third chapter of the dissertation, we showed that functional deficiency of XBP1 in Osterix-expressing cells, e.g., osteoblasts and skeletal progenitor cells, leads to osteoporosis/osteopenia with a significant compromised osteoblastogenesis and osteoclastogenesis, and increased bone marrow adipogenesis, in vivo. XBP1 deficiency results in both direct reduction in mRNA levels of XBP1 spliced and XBP1 total. Our study provides mouse genetic evidence demonstrating that Osx+ cell-intrinsic IRE1α/XBP1 is a physiological regulator for the postnatal bone development and bone marrow homeostasis.28 0