Document Detail


Mineralizing enthesopathy is a common feature of renal phosphate-wasting disorders attributed to FGF23 and is exacerbated by standard therapy in hyp mice.
MedLine Citation:
PMID:  23038738     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
We have previously confirmed a paradoxical mineralizing enthesopathy as a hallmark of X-linked hypophosphatemia. X-linked hypophosphatemia is the most common of the phosphate-wasting disorders mediated by elevated fibroblast growth factor 23 (FGF23) and occurs as a consequence of inactivating mutations of the PHEX gene product. Despite childhood management of the disease, these complications of tendon and ligament insertion sites account for a great deal of the disease's morbidity into adulthood. It is unclear whether the enthesopathy occurs in other forms of renal phosphate-wasting disorders attributable to high FGF23 levels. Here we describe two patients with autosomal recessive hypophosphatemic rickets due to the Met1Val mutation in dentin matrix acidic phosphoprotein 1 (DMP1). In addition to the biochemical and skeletal features of long-standing rickets with elevated FGF23 levels, these individuals exhibited severe, debilitating, generalized mineralized enthesopathy. These data suggest that enthesophytes are a feature common to FGF23-mediated phosphate-wasting disorders. To address this possibility, we examined a murine model of FGF23 overexpression using a transgene encoding the secreted form of human FGF23 (R176Q) cDNA (FGF23-TG mice). We report that FGF23-TG mice display a similar mineralizing enthesopathy of the Achilles and plantar facial insertions. In addition, we examined the impact of standard therapy for phosphate-wasting disorders on enthesophyte progression. We report that fibrochondrocyte hyperplasia persisted in Hyp mice treated with oral phosphate and calcitriol. In addition, treatment had the untoward effect of further exacerbating the mineralization of fibrochondrocytes that define the bone spur of the Achilles insertion. These studies support the need for newer interventions targeted at limiting the actions of FGF23 and minimizing both the toxicities and potential morbidities associated with standard therapy.
Authors:
Andrew C Karaplis; Xiuying Bai; Jean-Pierre Falet; Carolyn M Macica
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural     Date:  2012-10-04
Journal Detail:
Title:  Endocrinology     Volume:  153     ISSN:  1945-7170     ISO Abbreviation:  Endocrinology     Publication Date:  2012 Dec 
Date Detail:
Created Date:  2012-11-29     Completed Date:  2013-01-31     Revised Date:  2013-12-04    
Medline Journal Info:
Nlm Unique ID:  0375040     Medline TA:  Endocrinology     Country:  United States    
Other Details:
Languages:  eng     Pagination:  5906-17     Citation Subset:  AIM; IM    
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MeSH Terms
Descriptor/Qualifier:
Animals
Extracellular Matrix Proteins / genetics
Familial Hypophosphatemic Rickets / metabolism*
Female
Fibroblast Growth Factors / genetics,  metabolism*
Genetic Diseases, X-Linked*
Immunohistochemistry / methods
Kidney / metabolism*
Male
Mice
Mice, Inbred C57BL
Mice, Transgenic
Models, Genetic
Mutation
Pedigree
Phosphates / metabolism
Phosphoproteins / genetics
Rheumatic Diseases / diagnosis*,  physiopathology
Transgenes
Up-Regulation
Grant Support
ID/Acronym/Agency:
P30 AR46032/AR/NIAMS NIH HHS; P50 AR054086/AR/NIAMS NIH HHS; R01 DK-49230/DK/NIDDK NIH HHS; R01 DK62515/DK/NIDDK NIH HHS; UL1 RR024139/RR/NCRR NIH HHS; UL1 TR000142/TR/NCATS NIH HHS
Chemical
Reg. No./Substance:
0/DMP1 protein, human; 0/Extracellular Matrix Proteins; 0/Phosphates; 0/Phosphoproteins; 0/fibroblast growth factor 23; 62031-54-3/Fibroblast Growth Factors
Comments/Corrections

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