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

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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.

Original languageEnglish
Pages (from-to)2553-2562
Number of pages10
JournalNew England Journal of Medicine
Volume374
Issue number26
DOIs
Publication statusPublished - 30-06-2016

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Bone Morphogenetic Proteins
Inborn Genetic Diseases
Bone and Bones
Homeostasis
Exome
Pyle disease
Cortical Bone
Skeleton
Knockout Mice
Genes
Osteoporosis
Therapeutics
Extremities
Phenotype
Mutation
Antibodies
Cancellous Bone
rat Sfrp4 protein

All Science Journal Classification (ASJC) codes

  • Medicine(all)

Cite this

Kiper, P. O. S., Saito, H., Gori, F., Unger, S., Hesse, E., Yamana, K., ... Baron, R. (2016). Cortical-bone fragility - Insights from sFRP4 deficiency in Pyle's disease. New England Journal of Medicine, 374(26), 2553-2562. https://doi.org/10.1056/NEJMoa1509342
Kiper, Pelin O.Simsek ; Saito, Hiroaki ; Gori, Francesca ; Unger, Sheila ; Hesse, Eric ; Yamana, Kei ; Kiviranta, Riku ; Solban, Nicolas ; Liu, Jeff ; Brommage, Robert ; Boduroglu, Koray ; Bonafé, Luisa ; Campos-Xavier, Belinda ; Dikoglu, Esra ; Eastell, Richard ; Gossiel, Fatma ; Harshman, Keith ; Nishimura, Gen ; Girisha, Katta M. ; Stevenson, Brian J. ; Takita, Hiroyuki ; Rivolta, Carlo ; Superti-Furga, Andrea ; Baron, Roland. / Cortical-bone fragility - Insights from sFRP4 deficiency in Pyle's disease. In: New England Journal of Medicine. 2016 ; Vol. 374, No. 26. pp. 2553-2562.
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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.",
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Kiper, POS, Saito, H, Gori, F, Unger, S, Hesse, E, Yamana, K, Kiviranta, R, Solban, N, Liu, J, Brommage, R, Boduroglu, K, Bonafé, L, Campos-Xavier, B, Dikoglu, E, Eastell, R, Gossiel, F, Harshman, K, Nishimura, G, Girisha, KM, Stevenson, BJ, Takita, H, Rivolta, C, Superti-Furga, A & Baron, R 2016, 'Cortical-bone fragility - Insights from sFRP4 deficiency in Pyle's disease', New England Journal of Medicine, vol. 374, no. 26, pp. 2553-2562. https://doi.org/10.1056/NEJMoa1509342

Cortical-bone fragility - Insights from sFRP4 deficiency in Pyle's disease. / Kiper, Pelin O.Simsek; Saito, Hiroaki; Gori, Francesca; Unger, Sheila; Hesse, Eric; Yamana, Kei; Kiviranta, Riku; Solban, Nicolas; Liu, Jeff; Brommage, Robert; Boduroglu, Koray; Bonafé, Luisa; Campos-Xavier, Belinda; Dikoglu, Esra; Eastell, Richard; Gossiel, Fatma; Harshman, Keith; Nishimura, Gen; Girisha, Katta M.; Stevenson, Brian J.; Takita, Hiroyuki; Rivolta, Carlo; Superti-Furga, Andrea; Baron, Roland.

In: New England Journal of Medicine, Vol. 374, No. 26, 30.06.2016, p. 2553-2562.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Cortical-bone fragility - Insights from sFRP4 deficiency in Pyle's disease

AU - Kiper, Pelin O.Simsek

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.

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.

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Kiper POS, Saito H, Gori F, Unger S, Hesse E, Yamana K et al. Cortical-bone fragility - Insights from sFRP4 deficiency in Pyle's disease. New England Journal of Medicine. 2016 Jun 30;374(26):2553-2562. https://doi.org/10.1056/NEJMoa1509342