Inhibition of FGFR signaling with infigratinib improves linear bone growth in the female <i>Aga2/+</i> mouse model of osteogenesis imperfecta

Osteogenesis imperfecta, a genetically heterogeneous disorder, is characterized by brittle bones with recurrent fractures as well as short stature. A recent study investigating cellular signaling in growth plate chondrocytes identified an increased expression of FGF receptors and elevated FGF signaling. We inhibited FGF receptor activation with the small molecule infigratinib in growing <i>Aga2/+</i> mice and then characterized linear growth, cartilage growth plate histology, and bone morphometrics. Infigratinib treatment resulted in increased female femur length, increased growth plate lengths in both sexes, specifically in the proliferative zone, and reduced phospho-ERK1/2 as well as SOX9 expression in lower hypertrophic chondrocytes. Infigratinib had no impact on cortical bone but reduced male trabecular bone parameters in <i>Aga2/+</i> mice. Three point bending biomechanical tests showed that <i>Aga2/+</i>-treated males had increased bone strength for some parameters, but reduced bone strength in treated WT males, correlating with the negative impact on trabecular bone parameters. WT and Aga2-treated male mice also showed increased serum testosterone levels. Together, these data establish FGFR as a therapeutic target for short stature in osteogenesis imperfecta and identify potential negative effects of pan-FGFR inhibition, particularly in the male skeleton.