Show simple item record

dc.contributor.authorKiper, Pelin O. Simsek
dc.contributor.authorSaito, Hiroaki
dc.contributor.authorGori, Francesca
dc.contributor.authorUnger, Sheila
dc.contributor.authorHesse, Eric
dc.contributor.authorYamana, Kei
dc.contributor.authorKiviranta, Riku
dc.contributor.authorSolban, Nicolas
dc.contributor.authorLiu, Jeff
dc.contributor.authorBrommage, Robert
dc.contributor.authorBoduroglu, Koray
dc.contributor.authorBonafe, Luisa
dc.contributor.authorCampos-Xavier, Belinda
dc.contributor.authorDikoglu, Esra
dc.contributor.authorEastell, Richard
dc.contributor.authorGossiel, Fatma
dc.contributor.authorHarshman, Keith
dc.contributor.authorNishimura, Gen
dc.contributor.authorGirisha, Katta M.
dc.contributor.authorStevenson, Brian J.
dc.contributor.authorTakita, Hiroyuki
dc.contributor.authorRivolta, Carlo
dc.contributor.authorSuperti-Furga, Andrea
dc.contributor.authorBaron, Roland
dc.date.accessioned2019-12-10T10:35:33Z
dc.date.available2019-12-10T10:35:33Z
dc.date.issued2016
dc.identifier.issn0028-4793
dc.identifier.urihttps://doi.org/10.1056/NEJMoa1509342
dc.identifier.urihttp://hdl.handle.net/11655/13883
dc.description.abstractBACKGROUND Cortical-bone fragility is a common feature in osteoporosis that is linked to non-vertebral fractures. Regulation of cortical-bone homeostasis has proved elusive. The study of genetic disorders of the skeleton can yield insights that fuel experimental therapeutic approaches to the treatment of rare disorders and common skeletal ailments. METHODS We evaluated four patients with Pyle's disease, a genetic disorder that is characterized by cortical-bone thinning, limb deformity, and fractures; two patients were examined by means of exome sequencing, and two were examined by means of Sanger sequencing. After a candidate gene was identified, we generated a knockout mouse model that manifested the phenotype and studied the mechanisms responsible for altered bone architecture. RESULTS In all affected patients, we found biallelic truncating mutations in SFRP4, the gene encoding secreted frizzled-related protein 4, a soluble Wnt inhibitor. Mice deficient in Sfrp4, like persons with Pyle's disease, have increased amounts of trabecular bone and unusually thin cortical bone, as a result of differential regulation of Wnt and bone morphogenetic protein (BMP) signaling in these two bone compartments. Treatment of Sfrp4-deficient mice with a soluble Bmp2 receptor (RAP-661) or with antibodies to sclerostin corrected the cortical-bone defect. CONCLUSIONS Our study showed that Pyle's disease was caused by a deficiency of sFRP4, that cortical-bone and trabecular-bone homeostasis were governed by different mechanisms, and that sFRP4-mediated cross-regulation between Wnt and BMP signaling was critical for achieving proper cortical-bone thickness and stability.
dc.language.isoen
dc.publisherMassachusetts Medical Soc
dc.relation.isversionof10.1056/NEJMoa1509342
dc.rightsinfo:eu-repo/semantics/openAccess
dc.subjectGeneral & Internal Medicine
dc.titleCortical-Bone Fragility - Insights From Sfrp4 Deficiency In Pyle'S Disease
dc.typeinfo:eu-repo/semantics/article
dc.typeinfo:eu-repo/semantics/publishedVersion
dc.relation.journalNew England Journal Of Medicine
dc.contributor.departmentÇocuk Sağlığı ve Hastalıkları
dc.identifier.volume374
dc.identifier.issue26
dc.identifier.startpage2553
dc.identifier.endpage2562
dc.description.indexWoS


Files in this item

This item appears in the following Collection(s)

Show simple item record