Bone proteins PHEX and DMP1 regulate fibroblastic growth factor Fgf23 expression in osteocytes through a common pathway involving FGF receptor (FGFR) signaling
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Fibroblastic growth factor 23 (FGF23) is a circulating phosphaturic hormone. Inactivating mutations of the endopeptidase PHEX or the SIBLING protein DMP1 result in equivalent intrinsic bone mineralization defects and increased Fgf23 expression in osteocytes. The mechanisms whereby PHEX and DMP1 regulate Fgf23 expression are unknown. We examined the possibility that PHEX and DMP1 regulate Fgf23 through a common pathway by analyzing the phenotype of compound Phex and Dmp1 mutant mice (Hyp/Dmp1 –/– ). Compared to single‐mutant littermates, compound‐mutant Hyp/Dmp1 –/– mice displayed nonadditive elevations of serum FGF23 (1912 ± 183, 1715 ± 178, and 1799 ± 181 pg/ml), hypophosphatemia (P i : 6.0 ± 0.3, 5.8 ± 0.2, and 5.4 ±0.1 mg/dl), and severity of rickets/osteomalacia (bone mineral density: –36, –36, and –30%). Microarray analysis of long bones identified gene expression profiles implicating common activation of the FGFR pathway in all the mutant groups. Furthermore, inhibiting FGFR signaling using SU5402 in Hyp‐ and Dmp1 –/– ‐derived bone marrow stromal cells prevented the increase in Fgf23 mRNA expression (129‐ and 124‐fold increase in Hyp and Dmp1 –/– vs. 1.3‐fold in Hyp+SU5402 and 2.5‐fold in Dmp1 –/– +SU5402, P <0.05). For all analyses, samples collected from nonmutant wild‐type littermates served as controls. These findings indicate that PHEX and DMP1 control a common pathway regulating bone mineralization and FGF23 production, the latter involving activation of the FGFR signaling in osteocytes.—Martin, A., Liu, S., David, V., Li, H., Karydis, A., Feng, J. Q., Quarles, L. D. Bone proteins PHEX and DMP1 regulate fibroblastic growth factor Fgf23 expression in osteocytes through a common pathway. FASEB J. 25, 2551–2562 (2011). www.fasebj.org
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Osteocytes regulate phosphate metabolism by producing FGF23, which acts on parathyroid gland and kidneys to reduce circulating phosphate levels.
“These cells are able to regulate phosphate metabolism by the production of FGF23, which acts on other organs including parathyroid gland and kidneys to reduce the circulating levels of phosphates [208, 209].”
From Biology of Bone Tissue: Structure, Function, and Factors That Influence Bone Cells (2015) · cites this paper as [209]
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- Authors
- Martin, A., Liu, S., David, V., Li, H., Karydis, A., Feng, J. Q., & Quarles, L. D.
- Affiliations
- University of Tennessee Health Science Center (US)
- Genzyme Framingham Massachusetts USA
- Department of Biomedical Sciences Baylor College of Dentistry Dallas Texas USA
- Corresponding author
- Quarles, L. Darryl
- ORCID
- Venue
- The FASEB Journal
- Publisher
- Wiley
- Published
- 2011-04-20
- Volume
- 25
- Issue
- 8
- Pages
- 2551-2562
- ISSN
- 0892-6638 (ISSN-L)
- 1530-6860
- PMC
- PMC3136343
- OpenAlex
- W2155036045
- Cited by
- 254
- References
- 62
- Citations by year
- 2026: 9 · 2025: 7 · 2024: 6 · 2023: 15 · 2022: 18 · 2021: 10 · 2020: 18 · 2019: 17 · 2018: 14 · 2017: 19 · 2016: 19 · 2015: 17 · 2014: 21 · 2013: 31 · 2012: 30
- FWCI
- 21.10
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- The FASEB Journal (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute of Arthritis and Musculoskeletal and Skin Diseases
- Topics
- Health Sciences › Medicine › Nephrology › Parathyroid Disorders and Treatments
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Alkaline Phosphatase Research Studies
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Bone Metabolism and Diseases
- Keywords
- PHEX, DMP1, SIBLING proteins, fibroblast growth factor 23, osteocytes, FGF receptor signaling, bone mineralization, hypophosphatemia, rickets, osteomalacia, compound mutant mice, mesenchymal stem cells, SU5402
- MeSH terms
- Fibroblast Growth Factor-23, Animals, Calcification, Physiologic, Female, Fibroblast Growth Factors, Gene Expression Regulation, Kidney, Male, Mice, Transgenic, Osteocytes, Phenotype, RNA, Messenger, Signal Transduction, Extracellular Matrix Proteins, Receptors, Fibroblast Growth Factor, Mice, Knockout, Mice, Familial Hypophosphatemic Rickets, PHEX Phosphate Regulating Neutral Endopeptidase
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