Heparanase may contribute to idiopathic pulmonary fibrosis via nuclear translocation of cleaved heparan sulfate proteoglycans

Heparanase (HPSE) is an endo‐β‐glucuronidase capable of cleaving heparan sulfate (HS) side chains of heparin sulfate proteoglycans (HSPGs), important components of the extracellular matrix (ECM). HPSE has important roles in a variety of biological processes, including angiogenesis, inflammation, wound healing and metastasis. Little is known about HPSE and human idiopathic pulmonary fibrosis (IPF). Using immunohistochemistry, we noted that 6/6 human IPF lung biopsies expressed HPSE in vascular smooth muscle (VSM), endothelial cells and macrophages. In VSM and endothelium, heparanase was localized in both of the cytoplasm and nucleus. To determine if expressed HPSE was enzymatically active, we, immunostained with anti‐HS mAb 3G10 (which detects remnant HS fragment cleaved by HPSE). An abundance of 3G10 immunostaining were found in the nucleus of the most type of the cells. We hypothesized that prolonged HPSE activity cleaves HS in the ECM/cell surface, inducing an internalization and nuclear translocation of HSPGs. These findings were confirmed using mouse lung fibroblasts treated with heparinase‐III, a HPSE analog, which demonstrated nuclear translocation of 3G10 positive (HS‐fragmented) proteoglycans. Our findings suggest that nuclear HS/HSPGs may be directly involved in regulating biological processes including transcription and cell cycle progression, leading to the abnormal cell proliferation and wound repair characteristic of IPF. Support or Funding Information K08 HL105538