Pemigatinib suppresses liver fibrosis and subsequent osteodystrophy in mice.

Background: Liver fibrosis could lead to serious secondary diseases, including osteodystrophy. The interaction between liver and bone has not been fully elucidated, thus existing therapies for osteodystrophy secondary to liver fibrosis are often ineffective. FGF23 was initially found as an endocrine regulator of phosphate homeostasis, but recently, its involvement in fibrosis has been suggested. In this study, we hypothesized that the FGF23 level increases with liver injury, which in turn induces liver fibrosis and osteodystrophy.

Methods: Liver fibrosis model mice were generated via carbon tetrachloride administration and bile duct ligation. Fibrosis was assessed using Masson trichrome staining and hydroxyproline assay. The bone structure was evaluated using dual-energy x-ray absorptiometry and microcomputed tomography. Human HSC lines LX-2 and primary rat HSCs were used for in vitro analyses.

Results: Carbon tetrachloride-induced and bile duct ligation-induced liver injury increased the serum FGF23 level compared with that in control mice. RNA sequencing analysis of FGF23-treated LX-2 showed that FGF23 promotes the production of matrisome, which helps in forming the extracellular matrix. The FGF receptor antagonist pemigatinib alleviated carbon tetrachloride-induced and bile duct ligation-induced liver fibrosis and the deleterious alterations in bone density and microstructure in mice.

Conclusions: The serum FGF23 level increased with liver injury, and FGF23 promoted liver fibrosis. Moreover, pemigatinib alleviated liver fibrosis and hepatic osteodystrophy. These findings suggest that FGF23 mediates the communication between the liver and bone and that FGF23 may be a new therapeutic target for liver fibrosis and subsequent osteodystrophy.