FGF-18, A NOVEL MEMBER OF THE FIBROBLAST-GROWTH-FACTOR FAMILY, STIMULATES HEPATIC AND INTESTINAL PROLIFERATION

The fibroblast growth factors (FGFs) play key roles in controlling tis sue growth, morphogenesis, and repair in animals. We have cloned a nov el member of the FGF family, designated FGF-18, that is expressed prim arily in the lungs and kidneys and at lower levels in the heart, teste s, spleen, skeletal muscle, and brain. Sequence comparison indicates t hat FGF-18 is highly conserved between humans and mice and is most hom ologous to FGF-8 among the FGF family members. FGF-18 has a typical si gnal sequence and was glycosylated and secreted when it was transfecte d into 293-EBNA cells. Recombinant murine FGF-18 protein (rMuFGF-18) s timulated proliferation in the fibroblast cell line NIH 3T3 in vitro i n a heparan sulfate-dependent manner. To examine its biological activi ty in vivo, rMuFGF-18 was injected into normal mice and ectopically ov erexpressed in transgenic mice by using a liver-specific promoter. Inj ection of rMuFGF-18 induced proliferation in a wide variety of tissues , including tissues of both epithelial and mesenchymal origin. The two tissues which appeared to be the primary targets of FGF-18 were the l iver and small intestine, both of which exhibited histologic evidence of proliferation and showed significant gains in organ weight followin g 7 (sometimes 3) days of FGF-18 treatment. Transgenic mice that overe xpressed FGF-18 in the liver also exhibited an increase in liver weigh t and hepatocellular proliferation. These results suggest that:FGF-18 is a pleiotropic growth factor that stimulates proliferation in a numb er of tissues, most notably the liver and small intestine.