Fibrosis is a debilitating condition that can lead to impairment of the affected organ's function. Excessive deposition of extracellular matrix (ECM) molecules is characteristic of most fibrotic tissues. Fibroblasts activated by cytokines or growth factors differentiate into myofibroblasts that drive fibrosis by depositing ECM molecules, such as collagen, fibronectin, and connective tissue growth factor. Transforming growth factor-β (TGF-β) is one of the major profibrotic cytokines which promotes fibrosis by signaling abnormal ECM regulation. Hyaluronan (HA) is a major ECM glycosaminoglycan that is regulated by TGF-β and whose role in fibrosis is emerging. Aside from its role as a hydrating, space filling polymer, HA regulates different cellular functions and is known to have a role in wound healing and inflammation. Importantly, HA deposition is increased in multiple fibrotic diseases. In this review we highlight studies that link HA to fibrosis and discuss what is known about the role of HA, its receptors, and its anabolic and catabolic enzymes in different fibrotic diseases.

Background & Aims Crohn’s Disease (CD) is a chronic inflammatory disease of the gastrointestinal tract. Fibrosis, a serious complication of CD, occurs when activated intestinal fibroblasts deposit excessive amounts of extracellular matrix (ECM) in affected areas. A major component of the ECM is high molecular weight hyaluronan (HA) which, when depolymerized to low molecular weight fragments, becomes pro-inflammatory and pro-fibrotic. Mechanisms for HA degradation are incompletely understood, but the novel protein KIAA1199 was recently discovered to degrade HA. We hypothesize that KIAA1199 protein is increased in CD colon fibroblasts and generates HA fragments that foster inflammation and fibrosis. Methods Fibroblasts were isolated from explants of surgically resected colon tissue from CD and non-IBD control (ND) patients. Protein levels and tissue distribution of KIAA1199 were assessed by immunoblot and immunostaining, and functional HA degradation was measured biochemically. Results Elevated levels of KIAA1199 protein were produced and deposited in the ECM by cultured CD fibroblasts compared to controls. Treatment of fibroblasts with the pro- inflammatory cytokine interleukin-6 (IL-6) increased deposition of KIAA1199 in the ECM. CD fibroblasts also produce significantly higher levels of IL-6 compared to controls, and antibody blockade of IL-6 receptors in CD colon fibroblasts decreased the level of KIAA1199 protein in the ECM. Colon fibroblasts degrade HA, however siRNA silencing of KIAA1199 abrogated that ability. Conclusions CD fibroblasts produce elevated levels of KIAA1199 primarily through an IL-6 driven autocrine mechanism. This leads to excessive degradation of HA and the generation of pro-inflammatory HA fragments that contributes to maintenance of gut inflammation and fibrosis.

No abstract

Inflammatory bowel diseases (IBD) are chronic inflammatory gastrointestinal diseases, primarily consisting of ulcerative colitis and Crohn's disease. The complex nature of the disease, as well as the limited therapeutic options characterized by low efficiency and major side effects, highlights the importance of developing novel strategies of therapeutic intervention in IBD. Susceptibility loci related to IBD are present only in a small percentage of IBD patients, implying that epigenetic modifications could influence the pathogenesis of the disease. MicroRNAs (miRNAs) are small noncoding RNAs that regulate multiple molecular pathways involved in IBD pathobiology. MiRNA inhibitors targeting the IBD-activated miRNAs could have therapeutic value for IBD patients. This review provides an overview of the recent advances in miRNA biology related to IBD pathogenesis and the pharmacological development of miRNA-based therapeutics.

No abstract