FGF23

Blocking FGF23 signaling improves the growth plate of mice with X-linked hypophosphatemia

AUTHORS

Rocío Fuente, Eva-Maria Pastor-Arroyo, Nicole Gehring, Patricia Oro Carbajosa, Laura Alonso-Durán, Ivan Zderic, James Tapia-Dean, Ahmad Kamal Hamid, Carla Bettoni, Fernando Santos, Carsten A. Wagner, and Isabel Rubio-Aliaga

ABTRACT

Fibroblast growth factor 23 (FGF23) is a phosphaturic hormone. X-linked hypophosphatemia (XLH) is the most prevalent inherited phosphate wasting disorder due to mutations in the PHEX gene, which cause elevated circulating FGF23 levels. Clinically, it is characterized by growth impairment and defective mineralization of bones and teeth. Treatment of XLH is challenging. Since 2018 neutralizing antibodies against FGF23 have dramatically improved therapy of XLH patients, although not all patients fully respond to the treatment, and it is very costly. C-terminal fragments of FGF23 have recently emerged as blockers of intact FGF23 signaling. Here, we analyzed the effect on growth and bone of a short 26 residues long C-terminal FGF23 (cFGF23) fragment and two N-acetylated and C-amidated cFGF23 peptides using young XLH mice (PhexC733RMhda mice). Although no major changes in blood parameters were observed after 7 days treatment with these peptides, bone length and growth plate structure improved. The modified peptides accelerated growth rate probably by improving growth plate structure and dynamics. The processes of chondrocyte proliferation, death, hypertrophy, and the cartilaginous composition in the growth plate were partially improved in young treated XLH mice. In conclusion, these findings contribute to understand the role of FGF23 signaling in growth plate metabolism and show that this may occur despite continuous hypophosphatemia.

Targeted Disruption of NF1 in Osteocytes Increases FGF23 and Osteoid With Osteomalacia-like Bone Phenotype

Neurofibromatosis type 1 (NF1, OMIM 162200), caused by NF1 gene mutations, exhibits multi-system abnormalities, including skeletal deformities in humans. Osteocytes play critical roles in controlling bone modeling and remodeling. However, the role of neurofibromin, the protein product of the NF1 gene, in osteocytes is largely unknown. This study investigated the role of neurofibromin in osteocytes by disrupting Nf1 under the Dmp1-promoter.