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

• 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
• Journal Title: Pathogens and Disease
• Volume: Volume 71, Number 1
• Publisher: Oxford University Press (OUP): Policy B - Oxford Open Option D | 2014-06-01, Pages 81-89
• Type of Work: Article | Post-print: After Peer Review
• Publisher DOI: http://doi.org/10.1111/2049-632X.12117
• Subjects: Biology, Virology; Biology, Cell; Health Sciences, Medicine and Surgery
• Keywords: Science & Technology; Life Sciences & Biomedicine; Immunology; Infectious Diseases; Microbiology; SOCS-1; HIV-1; osteoclast; osteoporosis; BONE-MINERAL DENSITY; VIRUS-INFECTED WOMEN; B LIGAND RANKL; ANTIRETROVIRAL THERAPY; T-CELLS; RECEPTOR ACTIVATOR; IFN-GAMMA; OSTEOPROTEGERIN LIGAND; INHIBITORY FACTOR; CROSS-TALK

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.