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dc.contributor.authorChan, WCWen_US
dc.contributor.authorTsang, KYen_US
dc.contributor.authorCheng, YWen_US
dc.contributor.authorNg, VCWen_US
dc.contributor.authorChik, Hen_US
dc.contributor.authorTan, ZJen_US
dc.contributor.authorBoot-Handford, Ren_US
dc.contributor.authorBoyde, Aen_US
dc.contributor.authorCheung, KMCen_US
dc.contributor.authorCheah, KSEen_US
dc.contributor.authorChan, Den_US
dc.description.abstractBone remodeling is a balanced process between bone synthesis and degradation, maintaining homeostasis and a constant bone mass in adult life. Imbalance will lead to conditions such as osteoporosis or hyperostosis. Osteoblasts build bone, becoming embedded in bone matrix as mature osteocytes. Osteocytes have a role in sensing and translating mechanical loads into biochemical signals, regulating the differentiation and activity of osteoblasts residing at the bone surface through the secretion of Sclerostin (SOST), an inhibitor of WNT signaling. Excessive mechanical load can lead to activation of cellular stress responses altering cell behavior and differentiation. The unfolded protein response (UPR) is a shared pathway utilized by cells to cope with stress stimuli. We showed that in a transgenic mouse model, activation of the UPR in early differentiating osteocytes delays maturation, maintaining active bone synthesis. In addition, expression of SOST is delayed or suppressed; resulting in active WNT signaling and enhanced periosteal bone formation, and the combined outcome is generalized hyperostosis. A clear relationship between the activation of the unfolded protein response was established and the onset of hyperostosis that can be suppressed with a chemical chaperone, sodium 4-phenobutyrate (4-PBA). As the phenotype is highly consistent with craniodiaphyseal dysplasia (CDD; OMIM 122860), we propose activation of the UPR could be part of the disease mechanism for CDD patients as these patients are heterozygous for SOST mutations that impair protein folding and secretion. Thus, therapeutic agents ameliorating protein folding or the UPR can be considered as a potential therapeutic treatment.en_US
dc.description.sponsorshipUniversity Grants Committee of Hong Kong (GRF, grant number 7303/04M; Area of Excellence programme, grant number AoEM04/04; and Theme based research scheme programme, grant number T12-708/12N), and the Ministry of Science and Technology of the People’s Republic of China: National strategic basic research program (‘973’) grant number 2014CB942901.en_US
dc.format.extent4572 - 4587en_US
dc.relation.ispartofHum Mol Geneten_US
dc.subjectBone Morphogenetic Proteinsen_US
dc.subjectBone Remodelingen_US
dc.subjectBone and Bonesen_US
dc.subjectCollagen Type Xen_US
dc.subjectCraniofacial Abnormalitiesen_US
dc.subjectGenetic Markersen_US
dc.subjectMice, Transgenicen_US
dc.subjectStress, Mechanicalen_US
dc.subjectUnfolded Protein Responseen_US
dc.subjectWnt Signaling Pathwayen_US
dc.titleActivating the unfolded protein response in osteocytes causes hyperostosis consistent with craniodiaphyseal dysplasia.en_US
pubs.notesNot knownen_US

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