Dysregulated B cell expression of RANKL and OPG correlates with loss of bone mineral density in HIV infection.
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.
Division of Endocrinology, Metabolism and Lipids, Emory University School of Medicine, Atlanta, Georgia, United States of America.
Kehmia
K
Titanji
Division of Infectious Diseases, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia, United States of America.
Aswani
A
Vunnava
Division of Infectious Diseases, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia, United States of America.
Anandi N
AN
Sheth
Division of Infectious Diseases, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia, United States of America.
Cecile
C
Delille
Division of Infectious Diseases, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia, United States of America.
Jeffrey L
JL
Lennox
Division of Infectious Diseases, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia, United States of America.
Sara E
SE
Sanford
Division of Infectious Diseases, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia, United States of America.
Antonina
A
Foster
Department of Biostatistics and Bioinformatics, Rollins School of Public Health, Emory University, Atlanta, Georgia, United States of America.
Andrea
A
Knezevic
Department of Biostatistics and Bioinformatics, Rollins School of Public Health, Emory University, Atlanta, Georgia, United States of America.
Kirk A
KA
Easley
Division of Endocrinology, Metabolism and Lipids, Emory University School of Medicine, Atlanta, Georgia, United States of America; Atlanta VA Medical Center, Decatur, Georgia, United States of America; Winship Cancer Institute, Emory University, Atlanta, Georgia, United States of America.
M Neale
MN
Weitzmann
Division of Infectious Diseases, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia, United States of America.
Ighovwerha
I
Ofotokun
D000328:Adult; D001402:B-Lymphocytes / Q000378:metabolism*; D015519:Bone Density; D003430:Cross-Sectional Studies; D016207:Cytokines / Q000378:metabolism; D005260:Female; D015658:HIV Infections / Q000150:complications / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D016328:NF-kappa B / Q000378:metabolism; D010024:Osteoporosis / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D053244:Osteoprotegerin / Q000378:metabolism*; D053245:RANK Ligand / Q000378:metabolism*
D016207:Cytokines; D016328:NF-kappa B; D053244:Osteoprotegerin; D053245:RANK Ligand; C505688:TNFSF11 protein, human