Cortical-bone fragility - Insights from sFRP4 deficiency in Pyle's disease

Pelin O.Simsek Kiper, Hiroaki Saito, Francesca Gori, Sheila Unger, Eric Hesse, Kei Yamana, Riku Kiviranta, Nicolas Solban, Jeff Liu, Robert Brommage, Koray Boduroglu, Luisa Bonafé, Belinda Campos-Xavier, Esra Dikoglu, Richard Eastell, Fatma Gossiel, Keith Harshman, Gen Nishimura, Katta M. Girisha, Brian J. StevensonHiroyuki Takita, Carlo Rivolta, Andrea Superti-Furga, Roland Baron

Research output: Contribution to journalArticlepeer-review

104 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)2553-2562
Number of pages10
JournalNew England Journal of Medicine
Issue number26
Publication statusPublished - 30-06-2016

All Science Journal Classification (ASJC) codes

  • General Medicine


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