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Pulmonary fibrosis (PF) associated with systemic sclerosis (SSc) results in significant morbidity and mortality. We previously reported that insulin-like growth factor-II (IGF-II) is overexpressed in lung tissues and fibroblasts from SSc patients, and IGF-II fosters fibrosis by upregulating collagen type I, fibronectin, and TGFβ. We now show that IGF-II augments mRNA levels of profibrotic signaling molecules <i>TGFβ2</i> (<i>p</i> ≤ 0.01) and <i>TGFβ3</i> (<i>p</i> ≤ 0.05), collagen type III (<i>p</i> ≤ 0.01), and the collagen posttranslational modification enzymes <i>P4HA2</i> (<i>p</i> ≤ 0.05), <i>P3H2</i> (<i>p</i> ≤ 0.05), <i>LOX</i> (<i>p =</i> 0.065), <i>LOXL2</i> (<i>p</i> ≤ 0.05), <i>LOXL4</i> (<i>p</i> ≤ 0.05) in primary human lung fibroblasts. IGF-II increases protein levels of TGFβ2 (<i>p</i> ≤ 0.01), as well as COL3A1, P4HA2, P4Hβ, and LOXL4 (<i>p ≤</i> 0.05). In contrast, IGF-II decreases mRNA levels of the collagen degradation enzymes cathepsin (CTS) K, <i>CTSB</i>, and <i>CTSL</i> and protein levels of CTSK (<i>p</i> ≤ 0.05). The SRY-box transcription factor 9 (SOX9) is overexpressed in SSc lung tissues at the mRNA (<i>p</i> ≤ 0.05) and protein (<i>p</i> ≤ 0.01) levels compared to healthy controls. IGF-II induces SOX9 in lung fibroblasts (<i>p ≤</i> 0.05) via the IGF1R/IR hybrid receptor, and SOX9 regulates TGFβ2 (<i>p</i> ≤ 0.05), TGFβ3 (<i>p</i> ≤ 0.05), COL3A1 (<i>p</i> ≤ 0.01), and P4HA2 (<i>p</i> ≤ 0.001) downstream of IGF-II. Our results identify a novel IGF-II signaling axis and downstream targets that are regulated in a SOX9-dependent and -independent manner. Our findings provide novel insights on the role of IGF-II in promoting pulmonary fibrosis.