title: Cortical-Bone Fragility--Insights from sFRP4 Deficiency in Pyle's Disease.
abstract: BACKGROUND
  Cortical-bone fragility is a common feature in osteoporosis that is linked to nonvertebral 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. (Funded by the Swiss National Foundation and the National Institutes of Health.).
authors.forename: Pelin O Simsek
authors.initials: POS
authors.lastname: Kiper
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Saito
authors.forename: Francesca
authors.initials: F
authors.lastname: Gori
authors.forename: Sheila
authors.initials: S
authors.lastname: Unger
authors.forename: Eric
authors.initials: E
authors.lastname: Hesse
authors.forename: Kei
authors.initials: K
authors.lastname: Yamana
authors.forename: Riku
authors.initials: R
authors.lastname: Kiviranta
authors.forename: Nicolas
authors.initials: N
authors.lastname: Solban
authors.forename: Jeff
authors.initials: J
authors.lastname: Liu
authors.forename: Robert
authors.initials: R
authors.lastname: Brommage
authors.forename: Koray
authors.initials: K
authors.lastname: Boduroglu
authors.forename: Luisa
authors.initials: L
authors.lastname: Bonafé
authors.forename: Belinda
authors.initials: B
authors.lastname: Campos-Xavier
authors.forename: Esra
authors.initials: E
authors.lastname: Dikoglu
authors.forename: Richard
authors.initials: R
authors.lastname: Eastell
authors.forename: Fatma
authors.initials: F
authors.lastname: Gossiel
authors.forename: Keith
authors.initials: K
authors.lastname: Harshman
authors.forename: Gen
authors.initials: G
authors.lastname: Nishimura
authors.forename: Katta M
authors.initials: KM
authors.lastname: Girisha
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Stevenson
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Takita
authors.forename: Carlo
authors.initials: C
authors.lastname: Rivolta
authors.forename: Andrea
authors.initials: A
authors.lastname: Superti-Furga
authors.forename: Roland
authors.initials: R
authors.lastname: Baron
mesh_terms: D000293:Adolescent; D000818:Animals; D015415:Biomarkers / Q000097:blood; D015519:Bone Density / Q000235:genetics*; D019485:Bone Morphogenetic Proteins / Q000378:metabolism; D016723:Bone Remodeling / Q000235:genetics* / Q000502:physiology; D001842:Bone and Bones / Q000473:pathology / Q000502:physiology; D002675:Child, Preschool; D004195:Disease Models, Animal; D005260:Female; D017353:Gene Deletion; D006706:Homeostasis; D006801:Humans; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008875:Middle Aged; D010009:Osteochondrodysplasias / Q000235:genetics* / Q000503:physiopathology; D011518:Proto-Oncogene Proteins / Q000172:deficiency* / Q000235:genetics*; D017422:Sequence Analysis, DNA; D015398:Signal Transduction; D051153:Wnt Proteins / Q000378:metabolism; D000094742:Secreted Frizzled-Related Proteins
chemical_list: D015415:Biomarkers; D019485:Bone Morphogenetic Proteins; D011518:Proto-Oncogene Proteins; D051153:Wnt Proteins; C118723:SFRP4 protein, human; D000094742:Secreted Frizzled-Related Proteins; C498454:Sfrp4 protein, mouse