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Cortical-Bone Fragility — Insights from sFRP4 Deficiency in Pyle’s Disease
Open accessAbstract
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.).
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“sFRP4 is known to be a Wnt regulator, and mutations in SFRP4 in humans have been shown to cause Pyle disease, which is characterized by cortical bone fragility and fractures (45).”
From Targeting myostatin/activin A protects against skeletal muscle and bone loss during spaceflight (2020) · cites this paper as [45]
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Metadata
- Authors
- Simsek Kiper, P. O., 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, K. M., Stevenson, B. J., Takita, H., Rivolta, C., Superti-Furga, A., & Baron, R.
- ORCID
- Venue
- New England Journal of Medicine
- Publisher
- Massachusetts Medical Society
- Published
- 2016-06-30
- Volume
- 374
- Issue
- 26
- Pages
- 2553-2562
- ISSN
- 0028-4793 (ISSN-L)
- 1533-4406
- PMC
- PMC5070790
- OpenAlex
- W2475138245
- Cited by
- 151
- References
- 37
- Citations by year
- 2026: 12 · 2025: 9 · 2024: 10 · 2023: 11 · 2022: 13 · 2021: 18 · 2020: 18 · 2019: 22 · 2018: 21 · 2017: 16 · 2016: 1
- FWCI
- 24.37
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- New England Journal of Medicine (publishedVersion)
- PubMed (publishedVersion)
- edoc (University of Basel) (acceptedVersion)
- White Rose Research Online (University of Leeds, The University of Sheffield, University of York) (acceptedVersion)
- PubMed Central (acceptedVersion)
- IRIS (submittedVersion)
- Hacettepe University Institutional Repository (hacettepe.edu.tr) (submittedVersion, other-oa)
- SERVAL (Université de Lausanne) (submittedVersion)
- edoc (University of Basel)
- Funders
- Amgen
- National Institute for Health and Care Research (NF-SI-0513-10073)
- Türkiye Bilimsel ve Teknolojik Araştırma Kurumu
- Fondation Leenaards
- National Institutes of Health
- Medical Research Council (MR/K006312/1)
- Japan Society for the Promotion of Science
- National Institute of Arthritis and Musculoskeletal and Skin Diseases (R01AR064724)
- Topics
- Health Sciences › Medicine › Orthopedics and Sports Medicine › Bone health and osteoporosis research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Bone Metabolism and Diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Wnt/β-catenin signaling in development and cancer
- Keywords
- SFRP4, cortical bone thinning, trabecular bone, Wnt signaling, BMP signaling, sclerostin, bone homeostasis, hereditary bone disease, knockout mouse models, non-vertebral fractures
- MeSH terms
- Secreted Frizzled-Related Proteins, Adolescent, Animals, Bone and Bones, Child, Preschool, Disease Models, Animal, Female, Homeostasis, Humans, Male, Middle Aged, Osteochondrodysplasias, Proto-Oncogene Proteins, Signal Transduction, Biomarkers, Bone Density, Bone Remodeling, Gene Deletion, Sequence Analysis, DNA, Mice, Knockout, Bone Morphogenetic Proteins, Wnt Proteins, Mice
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