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Therapeutic Effects of FGF23 c-tail Fc in a Murine Preclinical Model of X-Linked Hypophosphatemia Via the Selective Modulation of Phosphate Reabsorption.

ABSTRACT: Fibroblast growth factor 23 (FGF23) is the causative factor of X-linked hypophosphatemia (XLH), a genetic disorder effecting 1:20,000 that is characterized by excessive phosphate excretion, elevated FGF23 levels and a rickets/osteomalacia phenotype. FGF23 inhibits phosphate reabsorption and suppresses 1?,25-dihydroxyvitamin D (1,25D) biosynthesis, analytes that differentially contribute to bone integrity and deleterious soft-tissue mineralization. As inhibition of ligand broadly modulates downstream targets, balancing efficacy and unwanted toxicity is difficult when targeting the FGF23 pathway. We demonstrate that a FGF23 c-tail-Fc fusion molecule selectively modulates the phosphate pathway in vivo by competitive antagonism of FGF23 binding to the FGFR/? klotho receptor complex. Repeated injection of FGF23 c-tail Fc in Hyp mice, a preclinical model of XLH, increases cell surface abundance of kidney NaPi transporters, normalizes phosphate excretion, and significantly improves bone architecture in the absence of soft-tissue mineralization. Repeated injection does not modulate either 1,25D or calcium in a physiologically relevant manner in either a wild-type or disease setting. These data suggest that bone integrity can be improved in models of XLH via the exclusive modulation of phosphate. We posit that the selective modulation of the phosphate pathway will increase the window between efficacy and safety risks, allowing increased efficacy to be achieved in the treatment of this chronic disease. © 2017 American Society for Bone and Mineral Research.

SUBMITTER: Johnson K

PROVIDER: S-EPMC5816679 | biostudies-literature | 2017 Oct

REPOSITORIES: biostudies-literature

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Therapeutic Effects of FGF23 c-tail Fc in a Murine Preclinical Model of X-Linked Hypophosphatemia Via the Selective Modulation of Phosphate Reabsorption.

Johnson Kristen K Levine Kymberly K Sergi Joseph J Chamoun Jean J Roach Rachel R Vekich Jacqueline J Favis Mike M Horn Mark M Cao Xianjun X Miller Brian B Snyder William W Aivazian Dikran D Reagan William W Berryman Edwin E Colangelo Jennifer J Markiewicz Victoria V Bagi Cedo M CM Brown Thomas P TP Coyle Anthony A Mohammadi Moosa M Magram Jeanne J

Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 20170825 10

Fibroblast growth factor 23 (FGF23) is the causative factor of X-linked hypophosphatemia (XLH), a genetic disorder effecting 1:20,000 that is characterized by excessive phosphate excretion, elevated FGF23 levels and a rickets/osteomalacia phenotype. FGF23 inhibits phosphate reabsorption and suppresses 1α,25-dihydroxyvitamin D (1,25D) biosynthesis, analytes that differentially contribute to bone integrity and deleterious soft-tissue mineralization. As inhibition of ligand broadly modulates downst ...[more]

PMID: 28600887

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Project description:The transgenic and knockout (KO) animals involving Fgf23 have been highly informative in defining novel aspects of mineral metabolism, but are limited by shortened lifespan, inability of spatial/temporal FGF23 control, and infertility of the global KO. To more finely test the role of systemic and genetic influences in FGF23 production, a mouse was developed that carried a floxed ("f")-Fgf23 allele (exon 2 floxed) which demonstrated in vivo recombination when bred to global-Cre transgenic mice (eIIa-cre). Mice homozygous for the recombined allele ("?") had undetectable serum intact FGF23, elevated serum phosphate (p?<?0.05), and increased kidney Cyp27b1 mRNA (p?<?0.05), similar to global Fgf23-KO mice. To isolate cellular FGF23 responses during phosphate challenge, Fgf23(?/f) mice were mated with early osteoblast type I?1 collagen 2.3-kb promoter-cre mice (Col2.3-cre) and the late osteoblast/early osteocyte Dentin matrix protein-1-cre (Dmp1-cre). Fgf23(?/f) /Col2.3-cre(+) and Fgf23(?/f) /Dmp1-cre(+) exhibited reduced baseline serum intact FGF23 versus controls. After challenge with high-phosphate diet Cre(-) mice had 2.1-fold to 2.5-fold increased serum FGF23 (p?<?0.01), but Col2.3-cre(+) mice had no significant increase, and Dmp1-cre(+) mice had only a 37% increase (p?<?0.01) despite prevailing hyperphosphatemia in both models. The Fgf23(?/f) /Col2.3-cre was bred onto the Hyp (murine X-linked hypophosphatemia [XLH] model) genetic background to test the contribution of osteoblasts and osteocytes to elevated FGF23 and Hyp disease phenotypes. Whereas Hyp mice maintained inappropriately elevated FGF23 considering their marked hypophosphatemia, Hyp/Fgf23(?/f) /Col2.3-cre(+) mice had serum FGF23 <4% of Hyp (p?<?0.01), and this targeted restriction normalized serum phosphorus and ricketic bone disease. In summary, deleting FGF23 within early osteoblasts and osteocytes demonstrated that both cell types contribute to baseline circulating FGF23 concentrations, and that targeting osteoblasts/osteocytes for FGF23 production can modify systemic responses to changes in serum phosphate concentrations and rescue the Hyp genetic syndrome. © 2016 American Society for Bone and Mineral Research.

Dataset Information

Therapeutic Effects of FGF23 c-tail Fc in a Murine Preclinical Model of X-Linked Hypophosphatemia Via the Selective Modulation of Phosphate Reabsorption.

Publications

Therapeutic Effects of FGF23 c-tail Fc in a Murine Preclinical Model of X-Linked Hypophosphatemia Via the Selective Modulation of Phosphate Reabsorption.

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