Gain-of-Function of FGFR3 Accelerates Bone Repair Following Ischemic Osteonecrosis in Juvenile Mice.
Daisaku KatoMasaki MatsushitaYasuhiko TakegamiKenichi MishimaNobuhiro KamiyaYusuke OsawaShiro ImagamaHiroshi KitohPublished in: Calcified tissue international (2022)
Bone collapse, bone deformity, and a long treatment period are major clinical problems associated with juvenile ischemic osteonecrosis (JIO). Accelerating the process of bone repair in JIO is expected to shorten the treatment duration and better maintain morphology. We previously indicated that both bone formation and resorption were accelerated following distraction osteogenesis-mediated limb lengthening in genetically engineered mutant mice with a gain-of-function mutation in fibroblast growth factor receptor 3 (FGFR3) gene (i.e., Fgfr3 mice). The purpose of this study was to investigate the role of FGFR3 in the bone repair process following surgically induced ischemic osteonecrosis in the mutant mice. Epiphyseal deformity was less in the Fgfr3 mice compared to the wild-type mice at 6 weeks following ischemic osteonecrosis in skeletally immature age. Assessment of the morphology by micro-computed tomography (CT) revealed that the trabecular bone volume was increased in the Fgfr3 mice. Dynamic bone histomorphometry revealed increased rates of bone formation and mineral apposition in the Fgfr3 mice at 4 weeks post-surgery. The number of tartrate-resistant acid phosphatase (TRAP)-positive cells rapidly increased, and the numbers of TdT-mediated dUTP nick-end labeling (TUNEL)-positive cells rapidly decreased in the Fgfr3 mice. Vascular endothelial growth factor (VEGF) expression was increased at the earlier phase post-surgery in the Fgfr3 mice. The activation of FGFR3 signaling shortens the time needed for bone repair after ischemic osteonecrosis by accelerating revascularization, bone resorption, and new bone formation. Our findings are clinically relevant as a new potential strategy for the treatment of JIO.
Keyphrases
- wild type
- bone mineral density
- high fat diet induced
- computed tomography
- vascular endothelial growth factor
- bone loss
- soft tissue
- minimally invasive
- bone regeneration
- type diabetes
- endothelial cells
- metabolic syndrome
- induced apoptosis
- dna methylation
- climate change
- cell cycle arrest
- coronary artery disease
- atrial fibrillation
- gene expression
- oxidative stress
- magnetic resonance
- single cell
- drug induced
- endoplasmic reticulum stress
- copy number
- positron emission tomography
- dual energy