Deletion of Gremlin1 increases cell proliferation and migration responses in mouse embryonic fibroblasts

Gremlin1 (Grem1) is an antagonist of bone morphogenetic proteins (BMPs) that plays a critical role in embryonic and postnatal development. Grem1 has been implicated as both a promoter and an inhibitor of cell proliferation driven by BMP-4 and other mitogens in a diverse range of cell types. Recent data showed that Grem1 can trigger angiogenesis via vascular endothelial growth factor receptor (VEGFR2) binding, highlighting that the precise modalities of Grem1 signalling require further elucidation. In an attempt to enhance our understanding of the role of Grem1 in cell proliferation, mouse embryonic fibroblasts lacking grem1 (grem1-/-) were generated. Grem1-/- cells showed elevated levels of proliferation in vitro compared to wild-type and grem1+/-, with accelerated scratch wound repair but no obvious changes in cell cycle profile. Modest increases in BMP-4-stimulated Smad1/5/8 phosphorylation were detected in grem1-/- cells, with concomitant modest changes in Smad-dependent gene expression. Surprisingly, levels of ERK phosphorylation were reduced in grem1-/- cells compared to wild-type. These data suggest Grem1 is an inhibitor of embryonic fibroblast proliferation in vitro. Furthermore, the signalling pathways causing increased cell proliferation in the absence of Grem1 may involve other pathways distinct from canonical Smad and non-canonical ERK signalling. (C) 2012 Elsevier Inc. All rights reserved.