title: Elevated suppressor of cytokine signaling-1 (SOCS-1): a mechanism for dysregulated osteoclastogenesis in HIV transgenic rats.
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.
authors.affiliation: Division of Basic Science and Vaccine Research, Institute of Human Virology, University of Maryland School of Medicine, Baltimore, MD, 21201, USA; Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, MD, 21201, USA.
authors.forename: Mark K
authors.initials: MK
authors.lastname: Lafferty
authors.forename: Lori
authors.initials: L
authors.lastname: Fantry
authors.forename: Joseph
authors.initials: J
authors.lastname: Bryant
authors.forename: Odell
authors.initials: O
authors.lastname: Jones
authors.forename: Dima
authors.initials: D
authors.lastname: Hammoud
authors.forename: M Neale
authors.initials: MN
authors.lastname: Weitzmann
authors.forename: George K
authors.initials: GK
authors.lastname: Lewis
authors.forename: Alfredo
authors.initials: A
authors.lastname: Garzino-Demo
authors.forename: William
authors.initials: W
authors.lastname: Reid
mesh_terms: D000818:Animals; D001851:Bone Diseases, Metabolic / Q000209:etiology; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D015497:HIV-1 / Q000502:physiology*; D054884:Host-Pathogen Interactions; D006801:Humans; D010010:Osteoclasts / Q000502:physiology*; D055647:Rats, Transgenic; D015398:Signal Transduction; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000096:biosynthesis*
chemical_list: D016207:Cytokines; C491589:Socs1 protein, rat; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins
keywords: HIV-1; SOCS-1; osteoclast; osteoporosis