Abstract

Pharmacologic agents to enhance liver regeneration after injury would have wide therapeutic application. Based on previous work suggesting inhibition of Bone Morphogenetic Protein (BMP) signaling stimulates liver regeneration, we tested known and novel BMP-inhibitors for their ability to accelerate regeneration in a partial hepatectomy (PH) model. Compounds produced based on the 3,6-disubstituted pyrazolo[1,5-a] pyrimidine core of the BMP antagonist dorsomorphin (DM) were evaluated for their ability to inhibit BMP signaling and enhance liver regeneration. Antagonists of the BMP receptor activin receptor-like kinase 3 (Alk3), including LDN-193189 (LDN), DMH2 (VU0364849), and the novel compound VU0465350 (VU5350), blocked SMAD phosphorylation in vitro and in vivo and enhanced liver regeneration after PH. In contrast, an antagonist of the BMP receptor Alk2, VU0469381 (1LWY or ML347), did not affect liver regeneration. LDN did not affect liver synthetic or metabolic function. Mechanistically, LDN increased serum IL-6 levels and STAT3 phosphorylation in the liver, and modulated other factors known to be important for liver regeneration, including Socs3, and p53. These findings suggest that inhibition of Alk3 may be part of a therapeutic strategy for treating human liver disease.