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Contribution of T cells to RANKL/OPG
imbalance and bone loss in HIV infection
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Download the PDF Here
Reported by Jules Levin
Durban IAC 2016 July 18-22
Kehmia Titanji1, Aswani Vunnava2, Antonina Foster2, Anandi N. Sheth2, C. Delille Lahiri2,Ighovwerha Ofotokun2, M. Neale Weitzmann1,3
1Division of Endocrinology, 2Division of Infectious Diseases, Department of Medicine, Emory University School of Medicine, Atlanta, GA; 3Atlanta VA Medical Center, Decatur, GA
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Dysregulated B Cell Expression of RANKL and OPG Correlates with Loss of Bone Mineral Density in HIV Infection
http://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1004497
Abstract
HIV infection is associated with high rates of osteopenia and osteoporosis, but the mechanisms involved are unclear. We recently reported that bone loss in the HIV transgenic rat model was associated with upregulation of B cell expression of the key osteoclastogenic cytokine receptor-activator of NF-κB ligand (RANKL), compounded by a simultaneous decline in expression of its physiological moderator, osteoprotegerin (OPG). To clinically translate these findings we performed cross-sectional immuno-skeletal profiling of HIV-uninfected and antiretroviral therapy-naïve HIV-infected individuals. Bone resorption and osteopenia were significantly higher in HIV-infected individuals. B cell expression of RANKL was significantly increased, while B cell expression of OPG was significantly diminished, conditions favoring osteoclastic bone resorption. The B cell RANKL/OPG ratio correlated significantly with total hip and femoral neck bone mineral density (BMD), T- and/or Z-scores in HIV infected subjects, but revealed no association at the lumbar spine. B cell subset analyses revealed significant HIV-related increases in RANKL-expressing naïve, resting memory and exhausted tissue-like memory B cells. By contrast, the net B cell OPG decrease in HIV-infected individuals resulted from a significant decline in resting memory B cells, a population containing a high frequency of OPG-expressing cells, concurrent with a significant increase in exhausted tissue-like memory B cells, a population with a lower frequency of OPG-expressing cells. These data validate our pre-clinical findings of an immuno-centric mechanism for accelerated HIV-induced bone loss, aligned with B cell dysfunction.
Author Summary
HIV infection causes significant bone loss and skeletal deterioration, leading to fractures that are often devastating and incur significant financial burden on patients and their families. HIV-infected individuals have up to a five-fold higher risk of bone fractures, and the increasing average age of people living with HIV/AIDS has triggered fears of an impending epidemic of bone fractures in this population. Antiretroviral therapy, used to manage HIV infection, fails to prevent, but rather paradoxically accelerates skeletal decline. The underlying mechanisms of HIV-induced bone loss are poorly understood. The aim of this study was to clarify the mechanisms of bone loss in HIV-infected patients, in an effort to better understand how bone loss and fractures occur, and consequently how it can be prevented in this population. The cytokine RANKL (Receptor Activator of Nuclear Factor kappa-B Ligand) helps induce bone loss. We show that RANKL expression was increased in immune cells in HIV-infected individuals. Another cytokine, osteoprotegerin (OPG), counteracts the activity of RANKL, and therefor helps prevent bone loss. OPG expression by the same immune cells was decreased in HIV-infected individuals. We conclude that disrupted immune cell expression of RANKL and OPG in HIV-infected patients contributes to bone loss.
In conclusion, our data confirm a significant imbalance in circulating B cell RANKL and OPG expression consistent with enhanced osteoclastic bone resorption and establish a potential immunocentric basis for bone loss (summarized diagrammatically in Figure 4). This imbalance in the immuno-skeletal interface may ultimately contribute to higher rates of fracture incidence in HIV-infected individuals.
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