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

Kiper, Pelin O. Simsek and Saito, Hiroaki and Gori, Francesca and Unger, Sheila and Hesse, Eric and Yamana, Kei and Kiviranta, Riku and Solban, Nicolas and Liu, Jeff and Brommage, Robert and Boduroglu, Koray and Bonafé, Luisa and Campos-Xavier, Belinda and Dikoglu, Esra and Eastell, Richard and Gossiel, Fatma and Harshman, Keith and Nishimura, Gen and Girisha, Katta M. and Stevenson, Brian J. and Takita, Hiroyuki and Rivolta, Carlo and Superti-Furga, Andrea and Baron, Roland. (2016) Cortical-Bone Fragility--Insights from sFRP4 Deficiency in Pyle's Disease. The New England Journal of Medicine, 374 (26). pp. 2553-2562.

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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.; 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.; 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.; 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.).
Faculties and Departments:03 Faculty of Medicine
09 Associated Institutions > Institute of Molecular and Clinical Ophthalmology Basel (IOB)
UniBasel Contributors:Rivolta, Carlo
Item Type:Article, refereed
Article Subtype:Research Article
Publisher:Massachusetts Medical Society
Note:Publication type according to Uni Basel Research Database: Journal article
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Last Modified:02 Mar 2021 15:01
Deposited On:02 Mar 2021 15:01

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