ABSTRACT Organ fibrosis is an irreversible endpoint of several diseases, leading to organ failure. Systemic sclerosis (SSc) is a prototypic multisystem fibrotic disease with fibrosis affecting multiple organs including the lung. SSc has the highest case fatality among rheumatic diseases and lung involvement is currently the leading cause of death of patients with this disease. The only available therapeutic option for patients with fibrosis is organ transplantation, which is clinically impossible on the scale necessary. The hallmark of fibrosis in multiple organs is the disruption of extracellular matrix (ECM) homeostasis, resulting in accumulation of ECM components and subsequent organ failure. We identified IGF-II as a gene overexpressed in SSc lung tissues, whereas in the adult IGF-II is only expressed in the liver. The role of IGF-II in pulmonary fibrosis and in SSc remains unexplored. We show that IGF-II promotes fibrosis in vitro in primary pulmonary fibroblasts, in vivo in mouse lungs, and ex vivo in human tissue in organ culture. We also show that IGF-II promotes its effects via increasing expression of ECM components, tipping the MMP:TIMP balance in favor of a fibrotic milieu, and inducing expression of TGFb isoforms, thus recapitulating the fibrotic phenotype. We hypothesize that IGF-II promotes fibrosis via engagement of hybrid IGF-IR/IR receptors, activation of the transcription factors Egr-1 and Sox9 and subsequent phosphorylation of the scaffold protein NEDD9. We also propose that increased expression of IGF-II in SSc lung is due to epigenetic regulation. We propose to test our hypothesis with the following specific aims: 1) Define the factors that promote the IGF-II-mediated fibrotic phenotype. Specifically we will determine the role of the transcription factors Sox-9 and Egr-1 in orchestrating the effects of IGF-II and the role of the scaffold protein NEDD9 in mediating the response to IGF-II; 2) Identify the receptors mediating the effects of IGF-II on fibroblasts by blocking IGF-IR, IR, and IGF-IIR and inhibiting receptor tyrosine kinase activity; and 3) Examine the regulation of IGF-II gene expression in SSc by examining if IGF-II mRNA in SSc lung fibroblasts shows biallelic expression and assessing the methylation status of the IGF-II—H19 locus. Our findings will provide new insights into the pathogenesis of fibrosis in SSc and other fibrotic disorders and will result in the identification of new targets for the development of therapies. Our approach will result in findings that are of direct relevance to the human disease, will advance mechanistic knowledge of the response to IGF-II, and a rationale for targeting IGF-II and/or its receptor(s) as a therapeutic strategy in SSc.