BMP4 is a novel paracrine inhibitor of liver regeneration

Abstract

Transforming growth factor (TGF)-β family members exert strong effects on restoration of liver mass after injury. Bone morphogenetic proteins (BMPs) are members of the TGF-β family and are found in the liver, suggesting that these proteins may play a role in liver regeneration. We examined BMP signaling in the liver during hepatectomy. We found that BMP4 is constitutively expressed in the peribiliary stroma and endothelial cells of the liver and that expression is decreased after hepatectomy. Mice driven to maintain BMP4 expression in the liver display inhibited hepatocyte proliferation and restoration of liver mass after hepatectomy, suggesting that reduced BMP4 is necessary for normal regeneration. Consistent with this finding, hepatocyte-specific deletion of the BMP receptor activin receptor-like kinase 3 (Alk3) enhances regeneration and reduces phosphorylation of SMAD1/5/8, a transducer of BMP signaling. In contrast to experiments in wild-type mice, maintaining BMP4 levels has no effect on liver regeneration in hepatocyte-specific Alk3 null mice, providing evidence that BMP4 signals through Alk3 to inhibit liver regeneration. Consistent with these findings, the BMP4 antagonist Noggin enhances regeneration. Furthermore, high-dose BMP4 inhibits proliferation of primary hepatocytes and HepG2 cells in culture. These findings elucidate a new, potentially clinically relevant paradigm in which a constitutively expressed paracrine inhibitory factor plays a critical role in liver regeneration.

Transforming growth factor‐β in liver cancer stem cells and regeneration

“…Bone morphogenetic proteins (BMPs) are members of the TGF‐β family and act as constitutively expressed repressors of regeneration. Consistent with this hypothesis, BMPs are expressed in the initial phase within 2 hours and then down‐regulated as TGF‐β spikes 116, 120. In the normal liver, strong BMP2 expression is observed around the central and portal veins.…”

“…The observed down‐regulation of BMP2 in rat liver following partial hepatectomy suggests that such down‐regulation may be necessary for hepatocyte proliferation 121. Mice driven to maintain BMP4 expression in the liver, display inhibited hepatocyte proliferation and restoration of liver mass after hepatectomy, suggesting that reduced BMP4 is necessary for normal regeneration 120. Consistent with this finding, the BMP receptors also follow an inverse pattern of up‐regulation compared with TGF‐β activation and are mostly up‐regulated in the anti‐proliferative/termination phase 116…”

“…Hepatocyte‐specific deletion of the BMP receptor Activin receptor‐like kinase 3 enhances regeneration 120. The BMP4 antagonist Noggin has also been reported to enhance regeneration.…”

Specific Activin Receptor–Like Kinase 3 Inhibitors Enhance Liver Regeneration

“…Our previous results using conditional inactivation of ALK3 in hepatocytes suggested that inhibiting ALK3 signaling could be a therapeutic strategy to enhance liver regeneration (Do et al, 2012). We therefore investigated selective inhibitors of ALK3, and compared them to selective inhibitors of ALK2 for similar effects.…”

“…Our recent findings that bone morphogenetic protein (BMP) signaling constitutively inhibits liver regeneration suggested that pharmacologic agents that inhibit BMPs might have therapeutic utility (Do et al, 2012). BMP signaling is a subset of transforming growth factor b (TGF-b) signaling and involves multiple ligands, antagonists, and receptors.…”