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Osteoblast Malfunction Caused by Cell Stress Response to Procollagen Misfolding in α2(I)-G610C Mouse Model of Osteogenesis Imperfecta.
- Source :
-
Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research [J Bone Miner Res] 2016 Aug; Vol. 31 (8), pp. 1608-1616. Date of Electronic Publication: 2016 Apr 13. - Publication Year :
- 2016
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Abstract
- Glycine (Gly) substitutions in collagen Gly-X-Y repeats disrupt folding of type I procollagen triple helix and cause severe bone fragility and malformations (osteogenesis imperfecta [OI]). However, these mutations do not elicit the expected endoplasmic reticulum (ER) stress response, in contrast to other protein-folding diseases. Thus, it has remained unclear whether cell stress and osteoblast malfunction contribute to the bone pathology caused by Gly substitutions. Here we used a mouse with a Gly610 to cysteine (Cys) substitution in the procollagen α2(I) chain to show that misfolded procollagen accumulation in the ER leads to an unusual form of cell stress, which is neither a conventional unfolded protein response (UPR) nor ER overload. Despite pronounced ER dilation, there is no upregulation of binding immunoglobulin protein (BIP) expected in the UPR and no activation of NF-κB signaling expected in the ER overload. Altered expression of ER chaperones αB crystalline and HSP47, phosphorylation of EIF2α, activation of autophagy, upregulation of general stress response protein CHOP, and osteoblast malfunction reveal some other adaptive response to the ER disruption. We show how this response alters differentiation and function of osteoblasts in culture and in vivo. We demonstrate that bone matrix deposition by cultured osteoblasts is rescued by activation of misfolded procollagen autophagy, suggesting a new therapeutic strategy for OI. © 2016 American Society for Bone and Mineral Research.<br /> (© 2016 American Society for Bone and Mineral Research.)
- Subjects :
- Animals
Animals, Newborn
Biomarkers metabolism
Cells, Cultured
Disease Models, Animal
Embryo, Mammalian pathology
Endoplasmic Reticulum metabolism
Endoplasmic Reticulum ultrastructure
Extracellular Matrix metabolism
Mice, Inbred C57BL
Osteoblasts pathology
Osteoblasts ultrastructure
Osteogenesis Imperfecta metabolism
Protein Processing, Post-Translational
Proteolysis
Collagen Type I genetics
Mutation genetics
Osteoblasts metabolism
Osteogenesis Imperfecta pathology
Procollagen chemistry
Procollagen metabolism
Protein Folding
Stress, Physiological
Subjects
Details
- Language :
- English
- ISSN :
- 1523-4681
- Volume :
- 31
- Issue :
- 8
- Database :
- MEDLINE
- Journal :
- Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research
- Publication Type :
- Academic Journal
- Accession number :
- 26925839
- Full Text :
- https://doi.org/10.1002/jbmr.2824