growth plate

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.

FGF signaling in the osteoprogenitor lineage non-autonomously regulates postnatal chondrocyte proliferation and skeletal growth

Fibroblast growth factor (FGF) signaling is important for skeletal development; however, cell-specific functions, redundancy and feedback mechanisms regulating bone growth are poorly understood. FGF receptors 1 and 2 (Fgfr1 and Fgfr2) are both expressed in the osteoprogenitor lineage.

Chondrocyte-Specific Modulation of Cyp27b1 Expression Supports a Role for Local Synthesis of 1,25-Dihydroxyvitamin D3 in Growth Plate Development

The Cyp27b1 enzyme (25-hydroxyvitamin D-1-hydroxylase) that converts 25-hydroxyvitamin D into the active metabolite, 1,25-dihydroxyvitamin D3 [1,25(OH)2D3], is expressed in kidney but also in other cell types such as chondrocytes. This suggests that local production of 1,25(OH)2D3 could play an important role in the differentiation of these cells.