Although humans with X-linked hypophosphatemia (XLH) and the Hyp mouse, a murine homolog of XLH, are known to develop degenerative joint disease, the exact mechanism that drives the osteoarthritis (OA) phenotype remains unclear. Mice that overexpress high-molecular-weight fibroblast growth factor (FGF) 2 isoforms (HMWTg mice) phenocopy both XLH and Hyp, including OA with increased FGF23 production in bone and serum. Because HMWTg cartilage also has increased FGF23 and there is cross-talk between FGF23-Wnt/β-catenin signaling, the purpose of this study was to determine if OA observed in HMWTg mice is due to FGF23-mediated canonical Wnt signaling in chondrocytes, given that both pathways are implicated in OA pathogenesis. HMWTg OA joints had decreased Dkk1, Sost, and Lrp6 expression with increased Wnt5a, Wnt7b, Lrp5, Axin2, phospho-GSK3β, Lef1, and nuclear β-catenin, as indicated by immunohistochemistry or quantitative PCR analysis. Chondrocytes from HMWTg mice had enhanced alcian blue and alkaline phosphatase staining as well as increased FGF23, Adamts5, Il-1β, Wnt7b, Wnt16, and Wisp1 gene expression and phospho-GSK3β protein expression as indicated by Western blot, compared with chondrocytes of vector control and chondrocytes from mice overexpressing the low-molecular-weight isoform, which were protected from OA. Canonical Wnt inhibitor treatment rescued some of those parameters in HMWTg chondrocytes, seemingly delaying the initially accelerated chondrogenic differentiation. FGF23 neutralizing antibody treatment was able to partly ameliorate OA abnormalities in subchondral bone and reduce degradative/hypertrophic chondrogenic marker expression in HMWTg joints in vivo. These results demonstrate that osteoarthropathy of HMWTg is at least partially due to FGF23-modulated Wnt/β-catenin signaling in chondrocytes.
Pubmed ID: 29718273 RIS Download
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This unknown targets Non-phospho (Active) β-Catenin (Ser33/37/Thr41) (D13A1) Rabbit mAb
View all literature mentionsThis polyclonal secondary targets IgG
View all literature mentionsThis monoclonal targets β-Actin
View all literature mentionsThis polyclonal targets CTNNB1
View all literature mentionsThis polyclonal targets AXIN2 antibody produced in rabbit
View all literature mentionsThis monoclonal targets GSK-3beta (27C10) Rabbit mAb
View all literature mentionsThis polyclonal targets Phospho-GSK-3 (Ser9)
View all literature mentionsThis polyclonal targets Human MMP13 - Hinge region
View all literature mentionsThis unknown targets Human LEF1
View all literature mentionsThis polyclonal targets GSK3 beta (phospho Y216)
View all literature mentionsThis polyclonal targets Wnt7b antibody
View all literature mentionsThis unknown targets ND
View all literature mentionsThis polyclonal targets LRP5 (phospho T1492)
View all literature mentionsThis polyclonal targets Rabbit Phospho-LRP6 (Ser1490)
View all literature mentionsThis polyclonal targets Mouse SOST
View all literature mentionsThis unknown targets Non-phospho (Active) β-Catenin (Ser33/37/Thr41) (D13A1) Rabbit mAb
View all literature mentions