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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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Cites
Analysis of Relative Gene Expression Data Using Real-Time Quantitative PCR and the 2−ΔΔCT Method
Livak, K. J., & Schmittgen, T. D. (2001) · Methods · doi:10.1006/meth.2001.1262 · Cited by 180,860 · cited 1×
“In Panels E, F, and G, fold differences in mRNA expression relative to that in wild-type cells were calculated as described by Livak and Schmittgen.(18) Panel H shows the effects of Sfrp4 deletion on Smad1, Smad5,”
MethodMutation of the mouse klotho gene leads to a syndrome resembling ageing
Kuro-o, M., Matsumura, Y., Aizawa, H., Kawaguchi, H., Suga, T., Utsugi, T., Ohyama, Y., Kurabayashi, M., Kaname, T., Kume, E., et al. (1997) · Nature · doi:10.1038/36285 · Cited by 3,837
WNT signaling in bone homeostasis and disease: From human mutations to treatments
Baron, R., & Kneissel, M. (2013) · Nature Medicine · doi:10.1038/nm.3074 · Cited by 2,093
Self-citationBlack, D. M., & Rosen, C. J. (2016) · New England Journal of Medicine · doi:10.1056/nejmcp1513724 · Cited by 1,790
Secreted antagonists of the Wnt signalling pathway
Kawano, Y., & Kypta, R. (2003) · Journal of Cell Science · doi:10.1242/jcs.00623 · Cited by 1,584
Canonical wnt signaling in differentiated osteoblasts controls osteoclast differentiation.
Glass, D. A., Bialek, P., Ahn, J. D., Starbuck, M., Patel, M. S., Clevers, H., Taketo, M. M., Long, F., McMahon, A. P., Lang, R. A., et al. (2005) · Developmental Cell · doi:10.1016/j.devcel.2005.02.017 · Cited by 1,558
Increased bone density in sclerosteosis is due to the deficiency of a novel secreted protein (SOST)
Balemans, W. (2001) · Human Molecular Genetics · doi:10.1093/hmg/10.5.537 · Cited by 1,147
Cho, Y. S., Go, M. J., Kim, Y. J., Heo, J. Y., Oh, J. H., Ban, H., Yoon, D., Lee, M. H., Kim, D. J., Park, M., et al. (2009) · Nature Genetics · doi:10.1038/ng.357 · Cited by 1,017
Sclerostin is a delayed secreted product of osteocytes that inhibits bone formation
Poole, K. E. S., Van Bezooijen, R. L., Loveridge, N., Hamersma, H., Papapoulos, S. E., Löwik, C. W., & Reeve, J. (2005) · The FASEB Journal · doi:10.1096/fj.05-4221fje · Cited by 965
van Bezooijen, R. L., Roelen, B. A. J., Visser, A., van der Wee-Pals, L. J. A., de Wilt, E., Karperien, M., Hamersma, H. A., Papapoulos, S. E., ten Dijke, P., & Löwik, C. W. G. M. (2004) · The Journal of Experimental Medicine · doi:10.1084/jem.20031454 · Cited by 893
Research works printed but not linked: 2
- Cohn M, 1933, Fortschr Röntgenstr, 47, 293
- Pyle E, 1931, J Bone Joint Surg Am, 13, 874
Cited by
Sorted by citations
Wnt/β-catenin signalling: function, biological mechanisms, and therapeutic opportunities
Liu, J., Xiao, Q., Xiao, J., Niu, C., Li, Y., Zhang, X., Zhou, Z., Shu, G., & Yin, G. (2022) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-021-00762-6 · Cited by 2,519
“Cortical bone determines bone strength; thus, cortical bone fragility is also a susceptibility factor for fractures.(140,141) Inflammation plays an important role in tissue regeneration and bone loss.”
BackgroundSelf-citationThe Regulation of Bone Metabolism and Disorders by Wnt Signaling
Maeda, K., Kobayashi, Y., Koide, M., Uehara, S., Okamoto, M., Ishihara, A., Kayama, T., Saito, M., & Marumo, K. (2019) · International Journal of Molecular Sciences · doi:10.3390/ijms20225525 · Cited by 360
“1) Loss-of-function (AR) Pyle disease metaphyseal dysplasia 265900 wide trabecular metaphyses, thin cortical bone, bone fragility [33]”
BackgroundMolecular genetics and targeted therapy of WNT-related human diseases (Review)
Katoh, M., & Katoh, M. (2017) · International Journal of Molecular Medicine · doi:10.3892/ijmm.2017.3071 · Cited by 216
“Heterozygous loss-of-function mutation in the LRP6 gene (R611C) was found in patients with familial osteoporosis and early-onset coronary artery disease (75).”
BackgroundVlashi, R., Zhang, X., Wu, M., & Chen, G. (2023) · Genes & Diseases · doi:10.1016/j.gendis.2022.07.011 · Cited by 165
“Gene alterations in SFRP4 are known to cause bone disorders such as metaphyseal chondrodysplasia (also known as the Pyle’s disease), characterized flaring of the ends of long bones amongst other abnormalities.(188) Upraised SFRP4 levels are linked to osteomalacia, characterized by a soft andmore flexible bone.”
BackgroundJansson, P., Curiac, D., Ahrén, I. L., Hansson, F., Niskanen, T. M., Sjögren, K., & Ohlsson, C. (2019) · The Lancet Rheumatology · doi:10.1016/s2665-9913(19)30068-2 · Cited by 168
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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