ResearchIn-Press PreviewBone biologyMetabolism
Open Access | 10.1172/jci.insight.156850
1Division of Nephrology and Hypertension, Northwestern University, Chicago, United States of America
2Department of Biomedical Sciences, Texas A&M College of Dentistry, Dallas, United States of America
3Department of Medicine, University of California, San Francisco, San Francisco, United States of America
4Shanxi Medical University School and Hospital of Stomatology, Clinical Medical Research Center of Oral Diseases of Shanxi Province, Taiyuan, China
5Northwestern University, Chicago, United States of America
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Courbon, G.
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1Division of Nephrology and Hypertension, Northwestern University, Chicago, United States of America
2Department of Biomedical Sciences, Texas A&M College of Dentistry, Dallas, United States of America
3Department of Medicine, University of California, San Francisco, San Francisco, United States of America
4Shanxi Medical University School and Hospital of Stomatology, Clinical Medical Research Center of Oral Diseases of Shanxi Province, Taiyuan, China
5Northwestern University, Chicago, United States of America
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1Division of Nephrology and Hypertension, Northwestern University, Chicago, United States of America
2Department of Biomedical Sciences, Texas A&M College of Dentistry, Dallas, United States of America
3Department of Medicine, University of California, San Francisco, San Francisco, United States of America
4Shanxi Medical University School and Hospital of Stomatology, Clinical Medical Research Center of Oral Diseases of Shanxi Province, Taiyuan, China
5Northwestern University, Chicago, United States of America
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1Division of Nephrology and Hypertension, Northwestern University, Chicago, United States of America
2Department of Biomedical Sciences, Texas A&M College of Dentistry, Dallas, United States of America
3Department of Medicine, University of California, San Francisco, San Francisco, United States of America
4Shanxi Medical University School and Hospital of Stomatology, Clinical Medical Research Center of Oral Diseases of Shanxi Province, Taiyuan, China
5Northwestern University, Chicago, United States of America
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1Division of Nephrology and Hypertension, Northwestern University, Chicago, United States of America
2Department of Biomedical Sciences, Texas A&M College of Dentistry, Dallas, United States of America
3Department of Medicine, University of California, San Francisco, San Francisco, United States of America
4Shanxi Medical University School and Hospital of Stomatology, Clinical Medical Research Center of Oral Diseases of Shanxi Province, Taiyuan, China
5Northwestern University, Chicago, United States of America
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1Division of Nephrology and Hypertension, Northwestern University, Chicago, United States of America
2Department of Biomedical Sciences, Texas A&M College of Dentistry, Dallas, United States of America
3Department of Medicine, University of California, San Francisco, San Francisco, United States of America
4Shanxi Medical University School and Hospital of Stomatology, Clinical Medical Research Center of Oral Diseases of Shanxi Province, Taiyuan, China
5Northwestern University, Chicago, United States of America
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Spindler, J.
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1Division of Nephrology and Hypertension, Northwestern University, Chicago, United States of America
2Department of Biomedical Sciences, Texas A&M College of Dentistry, Dallas, United States of America
3Department of Medicine, University of California, San Francisco, San Francisco, United States of America
4Shanxi Medical University School and Hospital of Stomatology, Clinical Medical Research Center of Oral Diseases of Shanxi Province, Taiyuan, China
5Northwestern University, Chicago, United States of America
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Von Drasek, J.
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1Division of Nephrology and Hypertension, Northwestern University, Chicago, United States of America
2Department of Biomedical Sciences, Texas A&M College of Dentistry, Dallas, United States of America
3Department of Medicine, University of California, San Francisco, San Francisco, United States of America
4Shanxi Medical University School and Hospital of Stomatology, Clinical Medical Research Center of Oral Diseases of Shanxi Province, Taiyuan, China
5Northwestern University, Chicago, United States of America
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Ndjonko, L.
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1Division of Nephrology and Hypertension, Northwestern University, Chicago, United States of America
2Department of Biomedical Sciences, Texas A&M College of Dentistry, Dallas, United States of America
3Department of Medicine, University of California, San Francisco, San Francisco, United States of America
4Shanxi Medical University School and Hospital of Stomatology, Clinical Medical Research Center of Oral Diseases of Shanxi Province, Taiyuan, China
5Northwestern University, Chicago, United States of America
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1Division of Nephrology and Hypertension, Northwestern University, Chicago, United States of America
2Department of Biomedical Sciences, Texas A&M College of Dentistry, Dallas, United States of America
3Department of Medicine, University of California, San Francisco, San Francisco, United States of America
4Shanxi Medical University School and Hospital of Stomatology, Clinical Medical Research Center of Oral Diseases of Shanxi Province, Taiyuan, China
5Northwestern University, Chicago, United States of America
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Lynch, S.
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1Division of Nephrology and Hypertension, Northwestern University, Chicago, United States of America
2Department of Biomedical Sciences, Texas A&M College of Dentistry, Dallas, United States of America
3Department of Medicine, University of California, San Francisco, San Francisco, United States of America
4Shanxi Medical University School and Hospital of Stomatology, Clinical Medical Research Center of Oral Diseases of Shanxi Province, Taiyuan, China
5Northwestern University, Chicago, United States of America
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Hivert, L.
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1Division of Nephrology and Hypertension, Northwestern University, Chicago, United States of America
2Department of Biomedical Sciences, Texas A&M College of Dentistry, Dallas, United States of America
3Department of Medicine, University of California, San Francisco, San Francisco, United States of America
4Shanxi Medical University School and Hospital of Stomatology, Clinical Medical Research Center of Oral Diseases of Shanxi Province, Taiyuan, China
5Northwestern University, Chicago, United States of America
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1Division of Nephrology and Hypertension, Northwestern University, Chicago, United States of America
2Department of Biomedical Sciences, Texas A&M College of Dentistry, Dallas, United States of America
3Department of Medicine, University of California, San Francisco, San Francisco, United States of America
4Shanxi Medical University School and Hospital of Stomatology, Clinical Medical Research Center of Oral Diseases of Shanxi Province, Taiyuan, China
5Northwestern University, Chicago, United States of America
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Chang, W.
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1Division of Nephrology and Hypertension, Northwestern University, Chicago, United States of America
2Department of Biomedical Sciences, Texas A&M College of Dentistry, Dallas, United States of America
3Department of Medicine, University of California, San Francisco, San Francisco, United States of America
4Shanxi Medical University School and Hospital of Stomatology, Clinical Medical Research Center of Oral Diseases of Shanxi Province, Taiyuan, China
5Northwestern University, Chicago, United States of America
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1Division of Nephrology and Hypertension, Northwestern University, Chicago, United States of America
2Department of Biomedical Sciences, Texas A&M College of Dentistry, Dallas, United States of America
3Department of Medicine, University of California, San Francisco, San Francisco, United States of America
4Shanxi Medical University School and Hospital of Stomatology, Clinical Medical Research Center of Oral Diseases of Shanxi Province, Taiyuan, China
5Northwestern University, Chicago, United States of America
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David, V.
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1Division of Nephrology and Hypertension, Northwestern University, Chicago, United States of America
2Department of Biomedical Sciences, Texas A&M College of Dentistry, Dallas, United States of America
3Department of Medicine, University of California, San Francisco, San Francisco, United States of America
4Shanxi Medical University School and Hospital of Stomatology, Clinical Medical Research Center of Oral Diseases of Shanxi Province, Taiyuan, China
5Northwestern University, Chicago, United States of America
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Martin, A.
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Published November 9, 2023 - More info
Fibroblast growth factor 23 (FGF23) is a phosphate (Pi)-regulating hormone produced by bone. Hereditary hypophosphatemic disorders are associated with FGF23 excess, impaired skeletal growth and osteomalacia. Blocking FGF23 became an effective therapeutic strategy in X-linked hypophosphatemia, but testing remains limited in autosomal recessive hypophosphatemic rickets (ARHR). This study investigates the effects of Pi repletion and bone specific deletion of Fgf23 on bone and mineral metabolism in the Dmp1 knockout (Dmp1KO) mouse model of ARHR.At 12 weeks, Dmp1KO mice showed increased serum FGF23 and PTH levels, hypophosphatemia, impaired growth, rickets and osteomalacia. Six weeks of dietary Pi supplementation exacerbated FGF23 production, hyperparathyroidism, renal Pi excretion and osteomalacia. In contrast, osteocyte-specific deletion of Fgf23 resulted in a partial correction of FGF23 excess, which was sufficient to fully restore serum Pi levels, but only partially corrected the bone phenotype. In vitro, we show that FGF23 directly impairs osteoprogenitors differentiation and that DMP1 deficiency contributes to impaired mineralization independently of FGF23 or Pi levels.
In conclusion, FGF23-induced hypophosphatemia is only partially responsible for the bone defects observed in Dmp1KO mice. Our data suggest that combined DMP1 repletion and FGF23 blockade could effectively correct ARHR-associated mineral and bone disorders.