Cortical-Bone Fragility--Insights from sFRP4 Deficiency in Pyle's Disease

TY - JOUR

T1 - Cortical-Bone Fragility--Insights from sFRP4 Deficiency in Pyle's Disease

AU - Simsek Kiper, Pelin O

AU - Saito, Hiroaki

AU - Gori, Francesca

AU - Unger, Sheila

AU - Hesse, Eric

AU - Yamana, Kei

AU - Kiviranta, Riku

AU - Solban, Nicolas

AU - Liu, Jeff

AU - Brommage, Robert

AU - Boduroglu, Koray

AU - Bonafé, Luisa

AU - Campos-Xavier, Belinda

AU - Dikoglu, Esra

AU - Eastell, Richard

AU - Gossiel, Fatma

AU - Harshman, Keith

AU - Nishimura, Gen

AU - Girisha, Katta M

AU - Stevenson, Brian J

AU - Takita, Hiroyuki

AU - Rivolta, Carlo

AU - Superti-Furga, Andrea

AU - Baron, Roland

PY - 2016/6/30

Y1 - 2016/6/30

N2 - 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.).

AB - 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.).

KW - Adolescent

KW - Animals

KW - Biomarkers

KW - Bone Density

KW - Bone Morphogenetic Proteins

KW - Bone Remodeling

KW - Bone and Bones

KW - Child, Preschool

KW - Disease Models, Animal

KW - Female

KW - Gene Deletion

KW - Homeostasis

KW - Humans

KW - Male

KW - Mice

KW - Mice, Knockout

KW - Middle Aged

KW - Osteochondrodysplasias

KW - Proto-Oncogene Proteins

KW - Sequence Analysis, DNA

KW - Signal Transduction

KW - Wnt Proteins

KW - Case Reports

KW - Journal Article

KW - Research Support, N.I.H., Extramural

KW - Research Support, Non-U.S. Gov't

U2 - 10.1056/NEJMoa1509342

DO - 10.1056/NEJMoa1509342

M3 - SCORING: Journal article

C2 - 27355534

VL - 374

SP - 2553

EP - 2562

JO - NEW ENGL J MED

JF - NEW ENGL J MED

SN - 0028-4793

IS - 26

ER -