1,25-Dihydroxyvitamin D Alone Improves Skeletal Growth, Microarchitecture, and Strength in a Murine Model of XLH, Despite Enhanced FGF23 Expression

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dc.contributor Sistema FMUSP-HC: Faculdade de Medicina da Universidade de São Paulo (FMUSP) e Hospital das Clínicas da FMUSP
dc.contributor.author LIU, Eva S.
MARTINS, Janaina S.
RAIMANN, Adalbert
CHAE, Byongsoo Timothy
BROOKS, Daniel J.
JORGETTI, Vanda FMUSP-HC
BOUXSEIN, Mary L.
DEMAY, Marie B.
dc.date.issued 2016
dc.identifier.citation JOURNAL OF BONE AND MINERAL RESEARCH, v.31, n.5, p.929-939, 2016
dc.identifier.issn 0884-0431
dc.identifier.uri http://observatorio.fm.usp.br/handle/OPI/14502
dc.description.abstract X-linked hypophosphatemia (XLH) is characterized by impaired renal tubular reabsorption of phosphate owing to increased circulating FGF23 levels, resulting in rickets in growing children and impaired bone mineralization. Increased FGF23 decreases renal brush border membrane sodium-dependent phosphate transporter IIa (Npt2a) causing renal phosphate wasting, impairs 1-alpha hydroxylation of 25-hydroxyvitamin D, and induces the vitamin D 24-hydroxylase, leading to inappropriately low circulating levels of 1,25-dihydroxyvitamin D (1,25D). The goal of therapy is prevention of rickets and improvement of growth in children by phosphate and 1,25D supplementation. However, this therapy is often complicated by hypercalcemia and nephrocalcinosis and does not always prevent hyperparathyroidism. To determine if 1,25D or blocking FGF23 action can improve the skeletal phenotype without phosphate supplementation, mice with XLH (Hyp) were treated with daily 1,25D repletion, FGF23 antibodies (FGF23Ab), or biweekly high-dose 1,25D from d2 to d75 without supplemental phosphate. All treatments maintained normocalcemia, increased serum phosphate, and normalized parathyroid hormone levels. They also prevented the loss of Npt2a, alpha-Klotho, and pERK1/2 immunoreactivity observed in the kidneys of untreated Hyp mice. Daily treatment with 1,25D decreased urine phosphate losses despite a marked increase in bone FGF23 mRNA and in circulating FGF23 levels. Daily 1,25D was more effective than other treatments in normalizing the growth plate and metaphyseal organization. In addition to being the only therapy that normalized lumbar vertebral height and body weight, daily 1,25D therapy normalized bone geometry and was more effective than FGF23Ab in improving trabecular bone structure. Daily 1,25D and FGF23Ab improved cortical microarchitecture and whole-bone biomechanical properties more so than biweekly 1,25D. Thus, monotherapy with 1,25D improves growth, skeletal microarchitecture, and bone strength in the absence of phosphate supplementation despite enhancing FGF23 expression, demonstrating that 1,25D has direct beneficial effects on the skeleton in XLH, independent of its role in phosphate homeostasis. (C) 2016 American Society for Bone and Mineral Research.
dc.description.sponsorship · National Institutes of Health [P30 AR061313, R01 AR061376, T32 DK007529, F32 AR065386, K08 AR067854]
· European Society for Paediatric Endocrinology
dc.language.iso eng
dc.publisher WILEY-BLACKWELL
dc.relation.ispartof Journal of Bone and Mineral Research
dc.rights restrictedAccess
dc.subject GENETIC MOUSE MODELS; PTH/VIT D/FGF23; GROWTH PLATE; BONE QCT/mu CT; BIOMECHANICS
dc.subject.other linked hypophosphatemic rickets; hyp mice; male-mouse; hypertrophic chondrocytes; parathyroid-hormone; mineral metabolism; bone-formation; knockout mice; phosphate; osteomalacia
dc.title 1,25-Dihydroxyvitamin D Alone Improves Skeletal Growth, Microarchitecture, and Strength in a Murine Model of XLH, Despite Enhanced FGF23 Expression
dc.type article
dc.rights.holder Copyright WILEY-BLACKWELL
dc.description.group LIM/16
dc.identifier.doi 10.1002/jbmr.2783
dc.identifier.pmid 26751835
dc.type.category original article
dc.type.version publishedVersion
hcfmusp.author JORGETTI, Vanda:HC:ICHC
hcfmusp.author.external · LIU, Eva S.:Brigham & Womens Hosp, Div Endocrinol Diabet & Hypertens, 75 Francis St, Boston, MA 02115 USA; Massachusetts Gen Hosp, Endocrine Unit, 50 Blossom St,Thier 11, Boston, MA 02114 USA; Harvard Univ, Sch Med, Boston, MA USA
· MARTINS, Janaina S.:Massachusetts Gen Hosp, Endocrine Unit, 50 Blossom St,Thier 11, Boston, MA 02114 USA; Harvard Univ, Sch Med, Boston, MA USA; Univ Sao Paulo, Div Nephrol, Sao Paulo, Brazil
· RAIMANN, Adalbert:Massachusetts Gen Hosp, Endocrine Unit, 50 Blossom St,Thier 11, Boston, MA 02114 USA; Harvard Univ, Sch Med, Boston, MA USA; Med Univ Vienna, Dept Pediat & Adolescent Med, Vienna, Austria
· CHAE, Byongsoo Timothy:Massachusetts Gen Hosp, Endocrine Unit, 50 Blossom St,Thier 11, Boston, MA 02114 USA
· BROOKS, Daniel J.:Massachusetts Gen Hosp, Endocrine Unit, 50 Blossom St,Thier 11, Boston, MA 02114 USA; Beth Israel Deaconess Med Ctr, Dept Orthoped, Boston, MA 02215 USA
· BOUXSEIN, Mary L.:Massachusetts Gen Hosp, Endocrine Unit, 50 Blossom St,Thier 11, Boston, MA 02114 USA; Harvard Univ, Sch Med, Boston, MA USA; Beth Israel Deaconess Med Ctr, Dept Orthoped, Boston, MA 02215 USA
· DEMAY, Marie B.:Massachusetts Gen Hosp, Endocrine Unit, 50 Blossom St,Thier 11, Boston, MA 02114 USA; Harvard Univ, Sch Med, Boston, MA USA
hcfmusp.origem.id 2-s2.0-84968880437
hcfmusp.origem.id WOS:000377270400003
hcfmusp.publisher.city HOBOKEN
hcfmusp.publisher.country USA
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dc.description.index MEDLINE
dc.identifier.eissn 1523-4681
hcfmusp.citation.scopus 19
hcfmusp.citation.wos 16
hcfmusp.affiliation.country Brasil
hcfmusp.affiliation.country Estados Unidos
hcfmusp.affiliation.country Áustria


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