title: MicroRNA-15b Modulates Molecular Mediators of Blood Induced Arthropathy in Hemophilia Mice.
abstract: The development of arthropathy is a major co-morbidity in patients with hemophilia. The present study was designed to study the role of a microRNA biomarker (miR-15b) in the development of joint disease. To investigate the expression profile of miR-15b during the development of arthropathy, we first isolated and studied small RNA from the acute and chronic hemarthrosis model of hemophilia A mice. We observed that miR-15b was consistently repressed (~1- to 4-fold) from the onset of joint bleeding (1, 3, 7 and 24 h) until six bleeding episodes (up to 90 days). To test if reconstitution of miR-15b modulates biomarkers of joint damage in a chronic hemarthrosis model, we administered an adeno-associated virus (AAV) 5-miR-15b vector intra-articularly alone or in combination with systemic administration of AAV2-factor VIII. miR-15b overexpression downregulated markers of angiogenesis and hypoxia (vascular epithelial growth factor α (VEGF-α) and hypoxia inducing factor 2α (HIF-2α), ~70% and ~34%, respectively) in the affected joints. In addition, the co-administration of miR-15b and factor VIII vectors reduced the levels of the chondrodegenerative matrix-metalloproteinases (MMPs) 1, 3, 9 and 14 (~14% to 60%) in the injured joints. These data demonstrate for the first time the role of a miR-15b in the development of hemophilic arthropathy and has implications in development of miR based therapies for joint disease.
authors.affiliation: Department of Hematology, Christian Medical College, 632004 Vellore, India. dsen@cmcvellore.ac.in.
authors.forename: Dwaipayan
authors.initials: D
authors.lastname: Sen
authors.affiliation: Department of Hematology, Christian Medical College, 632004 Vellore, India. jayrao@iitk.ac.in.|Department of Biological Sciences and Bioengineering, Indian Institute of Technology, 208016 Kanpur, India. jayrao@iitk.ac.in.
authors.forename: Giridhara R
authors.initials: GR
authors.lastname: Jayandharan
mesh_terms: D000818:Animals; D005786:Gene Expression Regulation; D006467:Hemophilia A / Q000150:complications* / Q000235:genetics*; D007592:Joint Diseases / Q000209:etiology* / Q000235:genetics*; D007596:Joints / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000235:genetics*; D019076:Transgenes
chemical_list: D035683:MicroRNAs; C570833:Mirn15 microRNA, mouse
keywords: factor VIII; hemophilia A; microRNA; murine model