FGF23 Neutralizing Antibody Partially Improves Bone Mineralization Defect of HMWFGF2 Isoforms in Transgenic Female Mice

• Published in: Journal of bone and mineral research Vol. 33; no. 7; pp. 1347 - 1361
• Main Authors: Xiao, Liping, Homer‐Bouthiette, Collin, Hurley, Marja M
• Format: Journal Article
• Language: English
• Published: England Wiley Subscription Services, Inc 01.07.2018
• Subjects: Alkaline Phosphatase - blood; Animal models; Animals; Antibodies, Neutralizing - administration & dosage; Antibodies, Neutralizing - pharmacology; Apposition; Biomarkers - metabolism; Body Weight - drug effects; Bone and Bones - diagnostic imaging; Bone and Bones - drug effects; Bone growth; Bone histomorphometry; Bone mineral density; Calcification, Physiologic - drug effects; Computed tomography; Female; Femur; FGF23; FGF23 NEUTRALIZING ANTIBODY; Fibroblast growth factor 2; Fibroblast Growth Factor 2 - genetics; Fibroblast Growth Factor-23; Fibroblast Growth Factors - immunology; Gene expression; Gene Expression Regulation - drug effects; HMW FGF2 ISOFORM MICE; Humans; Hydroxylase; Hypophosphatemia; HYPOPHOSPHATEMIC OSTEOMALACIA; Immunoglobulin G; Isoforms; Kidneys; Mice, Transgenic; Mineralization; Molecular Weight; Osteoblasts - drug effects; Osteoblasts - metabolism; Osteocytes - drug effects; Osteocytes - metabolism; Osteogenesis; Osteoid; PHOSPHATE HOMEOSTASIS; Protein Isoforms; Rickets; Spine; Transgenic mice; Vitamin D; Vitamin D-24-hydroxylase; HYPOPHOSPHATEMIC OSTEOMALACIA; FGF23 NEUTRALIZING ANTIBODY; PHOSPHATE HOMEOSTASIS; FGF23; HMW FGF2 ISOFORM MICE
• ISSN: 0884-0431; 1523-4681
• DOI: 10.1002/jbmr.3417

ABSTRACT Mice overexpressing high molecular weight FGF2 isoforms (HMWTg) in osteoblast lineage phenocopy human X‐linked hypophosphatemic rickets (XLH) and a Hyp murine model of XLH demonstrating increased FGF23/FGF receptor signaling and hypophosphatemic rickets/osteomalacia. Because HMWFGF2 was upregulated in bones of Hyp mice and abnormal FGF23 signaling is important in XLH, HMWTg mice were used to examine the effect of the FGF23 neutralizing antibody (FGF23Ab). Eight‐week‐old female Vector control mice and HMWTg mice were treated with FGF23Ab or control IgG. A single injection of FGF23Ab rescued abnormal hypophosphatemia in HMWTg. The decreased type II sodium‐dependent phosphate co‐transporter (Npt2a) was rescued by FGF23Ab treatment. Inappropriately low serum 1,25(OH)2D in HMWTg mice was normalized by FGF23Ab treatment, which is accompanied by increased anabolic vitamin D hydroxylase Cyp27b1 and decreased catabolic vitamin D hydroxylase Cyp24 mRNA in kidney. Long‐term treatment with FGF23Ab normalized femur length and significantly increased vertebrae BMD and BMC, and femur BMC in HMWTg mice compared to IgG‐treated HMWTg mice. Micro–computed tomography (μCT) revealed increased cortical porosity and decreased cortical apparent density in the HMWTg‐IgG group compared with the Vector‐IgG group; however, FGF23Ab treatment rescued defective cortical mineralization, decreased porosity, and increased apparent density in HMWTg mice. Bone histomorphometry analysis showed FGF23Ab treatment decreased osteoid volume, increased intra‐label thickness, mineralization apposition rate, and bone formation rate in HMWTg mice. FGF23Ab improved disorganized double labeling in femurs from HMWTg mice. Quantitative real‐time PCR analysis of tibia shafts showed FGF23Ab treatment normalized the osteocalcin (Ocn) mRNA expression in HMWTg mice, but further increased expression of SIBLING protein–related and pyrophosphate‐related genes that are important in matrix mineralization, suggesting that HMWFGF2 modulates these genes independent of FGF23. We conclude that FGF23Ab partially rescued hypophosphatemic osteomalacia in HMWTg. However, long‐term treatment with FGF23Ab further increased SIBLING protein–related genes and pyrophosphate‐related genes in bone that could contribute to incomplete rescue of the mineralization defect. © 2018 American Society for Bone and Mineral Research.