FGF23 Regulates Wnt/ß-Catenin Signaling-Mediated Osteoarthritis in Mice Overexpressing High-Molecular-Weight FGF2.

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/ß-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-GSK3ß, Lef1, and nuclear ß-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-1ß, Wnt7b, Wnt16, and Wisp1 gene expression and phospho-GSK3ß 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/ß-catenin signaling in chondrocytes.

FGF2 High Molecular Weight Isoforms Contribute to Osteoarthropathy in Male Mice.

Humans with X-linked hypophosphatemia (XLH) and Hyp mice, the murine homolog of the disease, develop severe osteoarthropathy and the precise factors that contribute to this joint degeneration remain largely unknown. Fibroblast growth factor 2 (FGF2) is a key regulatory growth factor in osteoarthritis. Although there are multiple FGF2 isoforms the potential involvement of specific FGF2 isoforms in joint degradation has not been investigated. Mice that overexpress the high molecular weight FGF2 isoforms in bone (HMWTg mice) phenocopy Hyp mice and XLH subjects and Hyp mice overexpress the HMWFGF2 isoforms in osteoblasts and osteocytes. Given that Hyp mice and XLH subjects develop osteoarthropathies we examined whether HMWTg mice also develop knee joint degeneration at 2, 8, and 18 mo compared with VectorTg (control) mice. HMWTg mice developed spontaneous osteoarthropathy as early as age 2 mo with thinning of subchondral bone, osteophyte formation, decreased articular cartilage thickness, abnormal mineralization within the joint, increased cartilage degradative enzymes, hypertrophic markers, and angiogenesis. FGF receptors 1 and 3 and fibroblast growth factor 23 were significantly altered compared with VectorTg mice. In addition, gene expression of growth factors and cytokines including bone morphogenetic proteins, Insulin like growth factor 1, Interleukin 1 beta, as well as transcription factors Sex determining region Y box 9, hypoxia inducible factor 1, and nuclear factor kappa B subunit 1 were differentially modulated in HMWTg compared with VectorTg. This study demonstrates that overexpression of the HMW isoforms of FGF2 in bone results in catabolic activity in joint cartilage and bone that leads to osteoarthropathy.