{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T23:42:37Z","timestamp":1791330157559,"version":"4.3.1"},"reference-count":38,"publisher":"Oxford University Press (OUP)","issue":"8","license":[{"start":{"date-parts":[[2016,3,1]],"date-time":"2016-03-01T00:00:00Z","timestamp":1456790400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"funder":[{"name":"Intramural Research Program of NICHD"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2016,8,1]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n               <jats:sec>\n                  <jats:title>\u2003<\/jats:title>\n                  <jats:p>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 \u03b12(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-\u03baB signaling expected in the ER overload. Altered expression of ER chaperones \u03b1B crystalline and HSP47, phosphorylation of EIF2\u03b1, 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. \u00a9 2016 American Society for Bone and Mineral Research.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1002\/jbmr.2824","type":"journal-article","created":{"date-parts":[[2016,3,1]],"date-time":"2016-03-01T12:51:09Z","timestamp":1456836669000},"page":"1608-1616","source":"Crossref","is-referenced-by-count":90,"title":["Osteoblast Malfunction Caused by Cell Stress Response to Procollagen Misfolding in \u03b12(I)-G610C Mouse Model of Osteogenesis Imperfecta"],"prefix":"10.1093","volume":"31","author":[{"given":"Lynn S","family":"Mirigian","sequence":"first","affiliation":[{"name":"Department of Cell BiologyUniversity of Texas Medical BranchGalvestonTXUSA"},{"name":"Section on Physical Biochemistry, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)National Institutes of HealthBethesdaMDUSA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elena","family":"Makareeva","sequence":"additional","affiliation":[{"name":"Section on Physical Biochemistry, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)National Institutes of HealthBethesdaMDUSA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Edward L","family":"Mertz","sequence":"additional","affiliation":[{"name":"Section on Physical Biochemistry, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)National Institutes of HealthBethesdaMDUSA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shakib","family":"Omari","sequence":"additional","affiliation":[{"name":"Section on Physical Biochemistry, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)National Institutes of HealthBethesdaMDUSA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna M","family":"Roberts-Pilgrim","sequence":"additional","affiliation":[{"name":"Section on Physical Biochemistry, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)National Institutes of HealthBethesdaMDUSA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arin K","family":"Oestreich","sequence":"additional","affiliation":[{"name":"Division of Biological SciencesUniversity of MissouriColumbiaMOUSA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Charlotte L","family":"Phillips","sequence":"additional","affiliation":[{"name":"Department of BiochemistryUniversity of MissouriColumbiaMOUSA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sergey","family":"Leikin","sequence":"additional","affiliation":[{"name":"Section on Physical Biochemistry, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)National Institutes of HealthBethesdaMDUSA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2016,3,1]]},"reference":[{"key":"2024021014184119500_jbmr2824-bib-0001","first-page":"1078","author":"Rosen","year":"2013"},{"issue":"3","key":"2024021014184119500_jbmr2824-bib-0002","doi-asserted-by":"crossref","first-page":"168","DOI":"10.1016\/j.tcb.2010.11.007","article-title":"Chaperoning osteogenesis: new protein-folding disease paradigms","volume":"21","author":"Makareeva","year":"2011","journal-title":"Trends Cell Biol"},{"key":"2024021014184119500_jbmr2824-bib-0003","first-page":"71\u2013","author":"Makareeva","year":"2014"},{"issue":"11","key":"2024021014184119500_jbmr2824-bib-0004","doi-asserted-by":"crossref","first-page":"2479","DOI":"10.1016\/j.bbamcr.2013.04.008","article-title":"A molecular ensemble in the rER for procollagen maturation","volume":"1833","author":"Ishikawa","year":"2013","journal-title":"Biochim Biophys Acta"},{"key":"2024021014184119500_jbmr2824-bib-0005","first-page":"555","author":"Shapiro","year":"2014"},{"issue":"7","key":"2024021014184119500_jbmr2824-bib-0006","doi-asserted-by":"crossref","first-page":"1519","DOI":"10.1002\/jbmr.1982","article-title":"Osteogenesis imperfecta, an ever-expanding conundrum","volume":"28","author":"Glorieux","year":"2013","journal-title":"J Bone Miner Res"},{"issue":"9","key":"2024021014184119500_jbmr2824-bib-0007","doi-asserted-by":"crossref","first-page":"540","DOI":"10.1038\/nrendo.2011.81","article-title":"New perspectives on osteogenesis imperfecta","volume":"7","author":"Forlino","year":"2011","journal-title":"Nat Rev Endocrinol"},{"issue":"3","key":"2024021014184119500_jbmr2824-bib-0008","doi-asserted-by":"crossref","first-page":"209","DOI":"10.1002\/humu.20429","article-title":"Consortium for osteogenesis imperfecta mutations in the helical domain of type I collagen: regions rich in lethal mutations align with collagen binding sites for integrins and proteoglycans","volume":"28","author":"Marini","year":"2007","journal-title":"Hum Mutat"},{"issue":"2","key":"2024021014184119500_jbmr2824-bib-0009","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1038\/nrm3270","article-title":"The unfolded protein response: controlling cell fate decisions under ER stress and beyond","volume":"13","author":"Hetz","year":"2012","journal-title":"Nat Rev Mol Cell Biol"},{"issue":"24","key":"2024021014184119500_jbmr2824-bib-0010","doi-asserted-by":"crossref","first-page":"18226","DOI":"10.1016\/S0021-9258(17)46834-7","article-title":"BiP binds type I procollagen pro alpha chains with mutations in the carboxyl-terminal propeptide synthesized by cells from patients with osteogenesis imperfecta","volume":"268","author":"Chessler","year":"1993","journal-title":"J Biol Chem"},{"issue":"2","key":"2024021014184119500_jbmr2824-bib-0011","doi-asserted-by":"crossref","first-page":"247","DOI":"10.1359\/jbmr.090720","article-title":"Variable bone fragility associated with an Amish COL1A2 variant and a knock-in mouse model","volume":"25","author":"Daley","year":"2010","journal-title":"J Bone Miner Res"},{"issue":"10","key":"2024021014184119500_jbmr2824-bib-0012","doi-asserted-by":"crossref","first-page":"2297","DOI":"10.1002\/jbmr.2198","article-title":"Targeting the LRP5 pathway improves bone properties in a mouse model of osteogenesis imperfecta","volume":"29","author":"Jacobsen","year":"2014","journal-title":"J Bone Miner Res"},{"issue":"6","key":"2024021014184119500_jbmr2824-bib-0013","doi-asserted-by":"crossref","first-page":"670","DOI":"10.1038\/nm.3544","article-title":"Excessive transforming growth factor-beta signaling is a common mechanism in osteogenesis imperfecta","volume":"20","author":"Grafe","year":"2014","journal-title":"Nat Med"},{"key":"2024021014184119500_jbmr2824-bib-0014","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1007\/978-1-61779-415-5_2","article-title":"Osteoblast isolation from murine calvaria and long bones","volume":"816","author":"Bakker","year":"2012","journal-title":"Methods Mol Biol"},{"issue":"11","key":"2024021014184119500_jbmr2824-bib-0015","doi-asserted-by":"crossref","first-page":"e86","DOI":"10.1182\/blood-2011-08-372334","article-title":"Isolation of the stromal-vascular fraction of mouse bone marrow markedly enhances the yield of clonogenic stromal progenitors","volume":"119","author":"Suire","year":"2012","journal-title":"Blood"},{"key":"2024021014184119500_jbmr2824-bib-0016","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1007\/978-1-59745-019-5_2","article-title":"Derivation of primary mouse embryonic fibroblast (PMEF) cultures","volume":"633","author":"Garfield","year":"2010","journal-title":"Methods Mol Biol"},{"issue":"5\u20136","key":"2024021014184119500_jbmr2824-bib-0017","doi-asserted-by":"crossref","first-page":"403","DOI":"10.3109\/03008207.2014.959120","article-title":"Pulse-chase analysis of procollagen biosynthesis by azidohomoalanine labeling","volume":"55","author":"Mirigian","year":"2014","journal-title":"Connect Tissue Res"},{"issue":"11","key":"2024021014184119500_jbmr2824-bib-0018","doi-asserted-by":"crossref","first-page":"4366","DOI":"10.1158\/0008-5472.CAN-09-4057","article-title":"Carcinomas contain a matrix metalloproteinase-resistant isoform of type I collagen exerting selective support to invasion","volume":"70","author":"Makareeva","year":"2010","journal-title":"Cancer Res"},{"issue":"6","key":"2024021014184119500_jbmr2824-bib-0019","doi-asserted-by":"crossref","first-page":"1697","DOI":"10.1002\/bp060274b","article-title":"Examination of mineralized nodule formation in living osteoblastic cultures using fluorescent dyes","volume":"22","author":"Wang","year":"2006","journal-title":"Biotechnol Prog"},{"issue":"8","key":"2024021014184119500_jbmr2824-bib-0020","doi-asserted-by":"crossref","first-page":"4787","DOI":"10.1074\/jbc.M705773200","article-title":"Structural heterogeneity of type I collagen triple helix and its role in osteogenesis imperfecta","volume":"283","author":"Makareeva","year":"2008","journal-title":"J Biol Chem"},{"issue":"11","key":"2024021014184119500_jbmr2824-bib-0021","doi-asserted-by":"crossref","first-page":"1589","DOI":"10.1002\/humu.22139","article-title":"Absence of FKBP10 in recessive type XI osteogenesis imperfecta leads to diminished collagen cross-linking and reduced collagen deposition in extracellular matrix","volume":"33","author":"Barnes","year":"2012","journal-title":"Hum Mutat"},{"issue":"7","key":"2024021014184119500_jbmr2824-bib-0022","doi-asserted-by":"crossref","first-page":"897","DOI":"10.1038\/nn.2580","article-title":"In situ visualization and dynamics of newly synthesized proteins in rat hippocampal neurons","volume":"13","author":"Dieterich","year":"2010","journal-title":"Nat Neurosci"},{"issue":"3","key":"2024021014184119500_jbmr2824-bib-0023","doi-asserted-by":"crossref","first-page":"562","DOI":"10.1096\/fj.05-4870fje","article-title":"Proteasome blockade exerts an antifibrotic activity by coordinately down-regulating type I collagen and tissue inhibitor of metalloproteinase-1 and up-regulating metalloproteinase-1 production in human dermal fibroblasts","volume":"20","author":"Fineschi","year":"2006","journal-title":"FASEB J"},{"issue":"3","key":"2024021014184119500_jbmr2824-bib-0024","doi-asserted-by":"crossref","first-page":"902","DOI":"10.1016\/0006-291X(82)91055-5","article-title":"Lysosomotropic agents ammonium chloride and chloroquine inhibit both the synthesis and secretion of procollagen by freshly isolated embryonic chick tendon cells","volume":"105","author":"Neblock","year":"1982","journal-title":"Biochem Biophys Res Commun"},{"issue":"2","key":"2024021014184119500_jbmr2824-bib-0025","doi-asserted-by":"crossref","first-page":"151","DOI":"10.4161\/auto.5338","article-title":"Guidelines for the use and interpretation of assays for monitoring autophagy in higher eukaryotes","volume":"4","author":"Klionsky","year":"2008","journal-title":"Autophagy"},{"issue":"2","key":"2024021014184119500_jbmr2824-bib-0026","doi-asserted-by":"crossref","first-page":"280","DOI":"10.1016\/j.molcel.2010.09.023","article-title":"Autophagy and the integrated stress response","volume":"40","author":"Kroemer","year":"2010","journal-title":"Mol Cell"},{"issue":"12","key":"2024021014184119500_jbmr2824-bib-0027","doi-asserted-by":"crossref","first-page":"837","DOI":"10.1042\/CS20080484","article-title":"Alpha1-antitrypsin deficiency, chronic obstructive pulmonary disease and the serpinopathies","volume":"116","author":"Ekeowa","year":"2009","journal-title":"Clin Sci (Lond)"},{"issue":"10","key":"2024021014184119500_jbmr2824-bib-0028","doi-asserted-by":"crossref","first-page":"1822","DOI":"10.1359\/jbmr.2002.17.10.1822","article-title":"Dentin matrix protein 1, a target molecule for Cbfa1 in bone, is a unique bone marker gene","volume":"17","author":"Fen","year":"2002","journal-title":"J Bone Miner Res"},{"issue":"11","key":"2024021014184119500_jbmr2824-bib-0029","doi-asserted-by":"crossref","first-page":"2744","DOI":"10.1091\/mbc.e08-11-1092","article-title":"Autophagic elimination of misfolded procollagen aggregates in the endoplasmic reticulum as a means of cell protection","volume":"20","author":"Ishida","year":"2009","journal-title":"Mol Biol Cell"},{"key":"2024021014184119500_jbmr2824-bib-0030","doi-asserted-by":"crossref","first-page":"e00895","DOI":"10.7554\/eLife.00895","article-title":"Less translational control, more memory","volume":"2","author":"Pavitt","year":"2013","journal-title":"Elife"},{"issue":"6","key":"2024021014184119500_jbmr2824-bib-0031","doi-asserted-by":"crossref","first-page":"682","DOI":"10.1038\/nm.1954","article-title":"Inhibition of osteoblastic bone formation by nuclear factor-kappaB","volume":"15","author":"Chang","year":"2009","journal-title":"Nat Med"},{"issue":"8","key":"2024021014184119500_jbmr2824-bib-0032","doi-asserted-by":"crossref","first-page":"921","DOI":"10.1002\/jbmr.5650070809","article-title":"Extracellular matrix formation by osteoblasts from patients with osteogenesis imperfecta","volume":"7","author":"Fedarko","year":"1992","journal-title":"J Bone Miner Res"},{"issue":"7","key":"2024021014184119500_jbmr2824-bib-0033","doi-asserted-by":"crossref","first-page":"1122","DOI":"10.1002\/jbmr.5650100718","article-title":"Extracellular matrix stoichiometry in osteoblasts from patients with osteogenesis imperfecta","volume":"10","author":"Fedarko","year":"1995","journal-title":"J Bone Miner Res"},{"issue":"7","key":"2024021014184119500_jbmr2824-bib-0034","doi-asserted-by":"crossref","first-page":"1465","DOI":"10.1002\/stem.1107","article-title":"Impaired osteoblastogenesis in a murine model of dominant osteogenesis imperfecta: a new target for osteogenesis imperfecta pharmacological therapy","volume":"30","author":"Gioia","year":"2012","journal-title":"Stem Cells"},{"issue":"4","key":"2024021014184119500_jbmr2824-bib-0035","doi-asserted-by":"crossref","first-page":"564","DOI":"10.1002\/jor.1100110411","article-title":"Effects of transforming growth factor beta on cells derived from bone and callus of patients with osteogenesis imperfecta","volume":"11","author":"Morike","year":"1993","journal-title":"J Orthop Res"},{"issue":"10","key":"2024021014184119500_jbmr2824-bib-0036","doi-asserted-by":"crossref","first-page":"1211","DOI":"10.1101\/gad.13.10.1211","article-title":"Stress signaling from the lumen of the endoplasmic reticulum: coordination of gene transcriptional and translational controls","volume":"13","author":"Kaufman","year":"1999","journal-title":"Genes Dev"},{"issue":"2","key":"2024021014184119500_jbmr2824-bib-0037","doi-asserted-by":"crossref","first-page":"348","DOI":"10.1002\/jcb.21180","article-title":"TGF-beta1 calcium signaling in osteoblasts","volume":"101","author":"Nesti","year":"2007","journal-title":"J Cell Biochem"},{"issue":"10","key":"2024021014184119500_jbmr2824-bib-0038","doi-asserted-by":"crossref","first-page":"6463\u2013","DOI":"10.1074\/jbc.M511830200","article-title":"Molecular mechanism of alpha 1(I)-osteogenesis imperfecta\/Ehlers-Danlos syndrome\u2014unfolding of an N-anchor domain at the N-terminal end of the type I collagen triple helix","volume":"281","author":"Makareeva","year":"2006","journal-title":"J Biol Chem"}],"container-title":["Journal of Bone and Mineral Research"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1002%2Fjbmr.2824","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1002%2Fjbmr.2824","content-type":"unspecified","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/academic.oup.com\/jbmr\/article-pdf\/31\/8\/1608\/56651437\/jbmr2824.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/jbmr\/article-pdf\/31\/8\/1608\/56651437\/jbmr2824.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,3,13]],"date-time":"2024-03-13T14:56:03Z","timestamp":1710341763000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/jbmr\/article\/31\/8\/1608-1616\/7605455"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2016,3,1]]},"references-count":38,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2016,3,1]]},"published-print":{"date-parts":[[2016,8,1]]}},"URL":"https:\/\/doi.org\/10.1002\/jbmr.2824","relation":{},"ISSN":["0884-0431","1523-4681"],"issn-type":[{"value":"0884-0431","type":"print"},{"value":"1523-4681","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2016,8,1]]},"published":{"date-parts":[[2016,3,1]]}}}