Elevated suppressor of cytokine signaling-1 (SOCS-1): a mechanism for dysregulated osteoclastogenesis in HIV transgenic rats

• Type of Material: Article
• Authors: Mark K. Lafferty, University of Maryland; Lori Fantry, University of Maryland; Joseph Bryant, University of Maryland; Odell Jones, University of Maryland; Dima Hammoud, National Institutes of Health; M. Neale Weitzmann, Emory University; George K. Lewis, University of Maryland; Alfredo Garzino-Demo, University of Maryland; William Reid, University of Maryland
• Language: English
• Date: 2014-06-01
• Publisher: Oxford University Press (OUP): Policy B - Oxford Open Option D
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2013 Federation of European Microbiological Societies. Published by John Wiley & Sons Ltd. All rights reserved.
• Final Published Version (URL): https://doi.org/10.1111/2049-632X.12117
• Title of Journal or Parent Work: Pathogens and Disease
• ISSN: 2049-632X
• Volume: 71
• Issue: 1
• Start Page: 81
• End Page: 89
• Grant/Funding Information: This work was supported by National Institute of Allergy and Infectious Diseases, NIH grants R01A1063171 and R01AI087181; and National Institute of Neurological Disorders And Stroke, NIH grant R01NS066842.
• Keywords: BONE-MINERAL DENSITY; osteoporosis; OSTEOPROTEGERIN LIGAND; Immunology; SOCS-1; Infectious Diseases; Microbiology; Life Sciences & Biomedicine; B LIGAND RANKL; IFN-GAMMA; T-CELLS; Science & Technology; HIV-1; ANTIRETROVIRAL THERAPY; CROSS-TALK; VIRUS-INFECTED WOMEN; RECEPTOR ACTIVATOR; INHIBITORY FACTOR; osteoclast
• Research Categories: Biology, Cell; Biology, Virology; Health Sciences, Medicine and Surgery

Abstract

Accelerated bone loss leading to osteopenia, osteoporosis, and bone fracture is a major health problem that is increasingly common in human immunodeficiency virus (HIV)-infected patients. The underlying pathogenesis is unclear but occurs in both treatment naïve and individuals receiving antiretroviral therapies. We developed an HIV-1 transgenic rat that exhibits many key features of HIV disease including HIV-1-induced changes in bone mineral density (BMD). A key determinant in the rate of bone loss is the differentiation of osteoclasts, the cells responsible for bone resorption. We found HIV-1 transgenic osteoclast precursors (OCP) express higher levels of suppressor of cytokine signaling-1 (SOCS-1) and TNF receptor-associated factor 6 (TRAF6) and are resistant to interferon-gamma (IFN-γ) mediated suppression of osteoclast differentiation. Our data suggest that dysregulated SOCS-1 expression by HIV-1 transgenic OCP promotes osteoclastogenesis leading to the accelerated bone loss observed in this animal model. We propose that elevated SOCS-1 expression in OCP antagonizes the inhibitory effects of IFN-γ and enhances receptor activator of NF-kB ligand (RANKL) signaling that drives osteoclast differentiation and activation. Understanding the molecular mechanisms of HIV-associated BMD changes has the potential to detect and treat bone metabolism disturbances early and improve the quality of life in patients.