Abstract
Disclosure: M.M. Hurley: None. L. Xiao: None. Human with X-linked hypophosphatemia (XLH) and its Hyp mice homolog develop several phenotypic abnormalities due to phosphate wasting mediated by abnormal Fibroblast Growth Factor Receptor-1 (FGFR1) and Fibroblast Growth Factor 23 (FGF23) signaling. XLH and Hyp mice also develop severe osteoarthropathy (OA) whose etiology is not fully defined. We previously reported that Fibroblast growth factor 2 (FGF2) regulates FGF23, specifically, mice overexpressing the high molecular weight FGF2 isoforms (HMWFGF2) in osteoprogenitors phenocopy Hyp mice including development of OA that worsens with age. Since we also reported that Hyp mice overexpress HMWFGF2 isoforms in osteoblasts and osteocytes, we examined whether the knee OA phenotype in Hyp mice was associated with aberrant FGFR1, FGF2, FGF23 signaling in knee joint articular cartilage and subchondral bone and whether in vivo FGFR tyrosine kinase inhibitor BGJ398 would modulate the OA phenotype in knee joints of Hyp mice. Ten weeks-old Control and Hyp mice were treated with Vehicle or BGJ398 for 12 weeks. Safranin-O staining of knee articular cartilage for proteoglycan revealed decreased staining in Hyp vehicle-treated mice that was partially restored to the cartilage thickness of Control mice in the Hyp-BGJ398-treated group. Significantly increased degradative enzyme matrix metalloproteinase-13 (MMP-13) in Hyp vehicle-treated knee articular cartilage was significantly reduced by BGJ398. Immunostaining revealed significantly increased phosphorylated FGFR1, FGF2 and FGF23 in both articular cartilage and subchondral bone. While BGJ398 significantly reduced immunostaining for phosphoFGFR1 and FGF2 in both articular cartilage and subchondral bone, it significantly reduced FGF23 in subchondral bone but not in articular cartilage. Significantly increased phospho-ERK1/2 labeling in Hyp-vehicle treated articular cartilage was partially rescued by BGJ398. This study demonstrates that increased FGFR1/FGF2 signaling contributes to OA in Hyp mice that can be partially rescued by FGF receptor inhibitor via reduction in MAPK signaling. Presentation: 6/1/2024