title: Osteoblast Malfunction Caused by Cell Stress Response to Procollagen Misfolding in α2(I)-G610C Mouse Model of Osteogenesis Imperfecta.
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.
authors.affiliation: Section on Physical Biochemistry, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health, Bethesda, MD 20892.|Department of Cell Biology, University of Texas Medical Branch, Galveston, TX 77555.
authors.forename: Lynn S
authors.initials: LS
authors.lastname: Mirigian
authors.affiliation: Section on Physical Biochemistry, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health, Bethesda, MD 20892.
authors.forename: Elena
authors.initials: E
authors.lastname: Makareeva
authors.affiliation: Section on Physical Biochemistry, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health, Bethesda, MD 20892.
authors.forename: Edward L
authors.initials: EL
authors.lastname: Mertz
authors.affiliation: Section on Physical Biochemistry, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health, Bethesda, MD 20892.
authors.forename: Shakib
authors.initials: S
authors.lastname: Omari
authors.affiliation: Section on Physical Biochemistry, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health, Bethesda, MD 20892.
authors.forename: Anna M
authors.initials: AM
authors.lastname: Roberts-Pilgrim
authors.affiliation: Division of Biological Sciences, University of Missouri, Columbia, MO 65211.
authors.forename: Arin K
authors.initials: AK
authors.lastname: Oestreich
authors.affiliation: Department of Biochemistry, University of Missouri, Columbia, MO 65211.
authors.forename: Charlotte L
authors.initials: CL
authors.lastname: Phillips
authors.affiliation: Section on Physical Biochemistry, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health, Bethesda, MD 20892.
authors.forename: Sergey
authors.initials: S
authors.lastname: Leikin
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D015415:Biomarkers / Q000378:metabolism; D002478:Cells, Cultured; D024042:Collagen Type I / Q000235:genetics*; D004195:Disease Models, Animal; D004622:Embryo, Mammalian / Q000473:pathology; D004721:Endoplasmic Reticulum / Q000378:metabolism / Q000648:ultrastructure; D005109:Extracellular Matrix / Q000378:metabolism; D008810:Mice, Inbred C57BL; D009154:Mutation / Q000235:genetics*; D010006:Osteoblasts / Q000378:metabolism* / Q000473:pathology / Q000648:ultrastructure; D010013:Osteogenesis Imperfecta / Q000378:metabolism / Q000473:pathology*; D011347:Procollagen / Q000737:chemistry* / Q000378:metabolism*; D017510:Protein Folding; D011499:Protein Processing, Post-Translational; D059748:Proteolysis; D013312:Stress, Physiological
chemical_list: D015415:Biomarkers; D024042:Collagen Type I; D011347:Procollagen
keywords: AUTOPHAGY; CELL STRESS; OSTEOBLAST; OSTEOGENESIS IMPERFECTA; PROCOLLAGEN