title: Heparanase and autoimmune diabetes.
abstract: Heparanase (Hpse) is the only known mammalian endo-β-d-glucuronidase that degrades the glycosaminoglycan heparan sulfate (HS), found attached to the core proteins of heparan sulfate proteoglycans (HSPGs). Hpse plays a homeostatic role in regulating the turnover of cell-associated HS and also degrades extracellular HS in basement membranes (BMs) and the extracellular matrix (ECM), where HSPGs function as a barrier to cell migration. Secreted Hpse is harnessed by leukocytes to facilitate their migration from the blood to sites of inflammation. In the non-obese diabetic (NOD) model of autoimmune Type 1 diabetes (T1D), Hpse is also used by insulitis leukocytes to solubilize the islet BM to enable intra-islet entry of leukocytes and to degrade intracellular HS, an essential component for the survival of insulin-producing islet beta cells. Treatment of pre-diabetic adult NOD mice with the Hpse inhibitor PI-88 significantly reduced the incidence of T1D by ~50% and preserved islet HS. Hpse therefore acts as a novel immune effector mechanism in T1D. Our studies have identified T1D as a Hpse-dependent disease and Hpse inhibitors as novel therapeutics for preventing T1D progression and possibly the development of T1D vascular complications.
authors.affiliation: Diabetes/Transplantation Immunobiology Laboratory, The John Curtin School of Medical Research, The Australian National University , Canberra, ACT , Australia ; Cancer and Vascular Biology Group, Department of Immunology, The John Curtin School of Medical Research, The Australian National University , Canberra, ACT , Australia.
authors.forename: Charmaine J
authors.initials: CJ
authors.lastname: Simeonovic
authors.affiliation: Diabetes/Transplantation Immunobiology Laboratory, The John Curtin School of Medical Research, The Australian National University , Canberra, ACT , Australia ; Cancer and Vascular Biology Group, Department of Immunology, The John Curtin School of Medical Research, The Australian National University , Canberra, ACT , Australia.
authors.forename: Andrew F
authors.initials: AF
authors.lastname: Ziolkowski
authors.affiliation: Diabetes/Transplantation Immunobiology Laboratory, The John Curtin School of Medical Research, The Australian National University , Canberra, ACT , Australia ; Cancer and Vascular Biology Group, Department of Immunology, The John Curtin School of Medical Research, The Australian National University , Canberra, ACT , Australia.
authors.forename: Zuopeng
authors.initials: Z
authors.lastname: Wu
authors.affiliation: Diabetes/Transplantation Immunobiology Laboratory, The John Curtin School of Medical Research, The Australian National University , Canberra, ACT , Australia ; Cancer and Vascular Biology Group, Department of Immunology, The John Curtin School of Medical Research, The Australian National University , Canberra, ACT , Australia.
authors.forename: Fui Jiun
authors.initials: FJ
authors.lastname: Choong
authors.affiliation: Cancer and Vascular Biology Group, Department of Immunology, The John Curtin School of Medical Research, The Australian National University , Canberra, ACT , Australia.
authors.forename: Craig
authors.initials: C
authors.lastname: Freeman
authors.affiliation: Cancer and Vascular Biology Group, Department of Immunology, The John Curtin School of Medical Research, The Australian National University , Canberra, ACT , Australia.
authors.forename: Christopher R
authors.initials: CR
authors.lastname: Parish
keywords: diabetes; heparan sulfate; heparanase; inflammation; islet; vascular complications