The Heparanase Regulatory Network in Health and Disease

Abstract

The extracellular matrix (ECM) is a structural framework that has many important physiological functions which include maintaining tissue structure and integrity, serving as a barrier to invading pathogens, and acting as a reservoir for bioactive molecules. This cellular scaffold is made up of various types of macromolecules including heparan sulfate proteoglycans (HSPGs). HSPGs comprise a protein core linked to the complex glycosaminoglycan heparan sulfate (HS), the remodeling of which is important for many physiological processes such as wound healing as well as pathological processes including cancer metastasis. Turnover of HS is tightly regulated by a single enzyme capable of cleaving HS side chains: heparanase. Heparanase upregulation has been identified in many inflammatory diseases including atherosclerosis, fibrosis, and cancer, where it has been shown to play multiple roles in processes such as epithelial-mesenchymal transition, angiogenesis, and cancer metastasis. Heparanase expression and activity are tightly regulated. Understanding the regulation of heparanase and its downstream targets is attractive for the development of treatments for these diseases. This review provides a comprehensive overview of the regulators of heparanase as well as the enzyme’s downstream gene and protein targets, and implications for the development of new therapeutic strategies.

TNF-α Inhibitors in Combination with MTX Reduce Circulating Levels of Heparan Sulfate/Heparin and Endothelial Dysfunction Biomarkers (sVCAM-1, MCP-1, MMP-9 and ADMA) in Women with Rheumatoid Arthritis

“…High activity of heparanase was also found in synovial fluid and the synovium of RA patients [ 42 ]. Not surprisingly, the major proinflammatory cytokines involved in RA pathogenesis, TNF-α and IL-1, have been shown to upregulate heparanase expression in endothelial cells [ 43 , 44 ], which may be a potential cause of an increased risk of atherosclerosis associated with this arthropathy. HPSE degrades HS in regions of high sulfation, resulting in the release of 5–7 kDa soluble HS fragments, which induce inflammatory signaling and cytokine upregulation through a direct interaction with TLR4 and possibly TLR2, and tyrosine kinase receptor EphA3 [ 39 , 41 , 45 ].…”

Variability in proteoglycan biosynthetic genes reveals new facets of heparan sulfates diversity. A systematic review and analysis

“…3). To avoid loss of clustering, HSPG biosynthetic genes involved in tumor development and growth was not considered, as most HSPG are altered in cancer 16,20,21 .…”

“…Sulfation of IdoA is assured by 2-Osulfotransferase (HS2ST1), whereas sulfation of GlcNAc is assured by N-deacetyl-Nsulfotransferases (coded by NDST1, NDST2, NDST3, or NDST4), 6-O-sulfotransferases (coded by HS6ST1, HS6ST2, or HS6ST3), and 3-O-sulfotransferases (coded by HS3ST1, HS3ST2, HS3ST3A1, HS3ST3B1, HS3ST4, HS3ST5, or HS3ST6) 3,12 . During biosynthesis, the HS chain elongation can be stopped by the unproductive glycosyltransferases EXTL1 or EXTL2 (coded by EXTL2 or EXTL1) 13 , whereas after secretion of the HSPG at the extracellular space 6-O-sulfatases SULF1 and SULF2 (coded by SULF1 and SULF2) and heparanase (coded by HPSE) can modify the HS chain structures [14][15][16] . Globally, this process leads to formation of different HS structural domains 3,17 .…”

The Key Role of Lysosomal Protease Cathepsins in Viral Infections

“…Interestingly, cathepsins play a key role in promoting virus release and spread by upregulating and processing the host enzyme Heparanase (HPSE), an endoglycosidase that degrades the glycosaminoglycan heparan sulfate (HS) [ 89 , 90 , 91 , 92 , 93 , 94 ]. Human HPSE mRNA encodes for a 61.2-kDa protein containing 543 amino acids.…”