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Dysregulated B cell expression of RANKL and OPG correlates with loss of bone mineral density in HIV infection.

Titanji K, Vunnava A, Sheth AN, Delille C, Lennox JL, Sanford SE, Foster A, Knezevic A, Easley KA, Weitzmann MN, Ofotokun I - PLoS Pathog. (2014)

Bottom Line: HIV infection is associated with high rates of osteopenia and osteoporosis, but the mechanisms involved are unclear.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.

View Article: PubMed Central - PubMed

Affiliation: Division of Endocrinology, Metabolism and Lipids, Emory University School of Medicine, Atlanta, Georgia, United States of America.

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.

No MeSH data available.


Related in: MedlinePlus

Differential B cell subset RANKL and OPG expression in HIV-negative and HIV-positive individuals.Representative histograms (alternate top panels) of B cell subset staining for RANKL (A) and OPG (B) for HIV negative individuals (solid line) and HIV positive individuals (dashed line). Scatter plots (alternate bottom panels) represent cumulative data for B cell subset RANKL (A) or OPG (B) expression from individual HIV-negative (HIV−, N = 17) or seropositive (HIV+, N = 15) individuals with bars at the mean (parametric data) or median [non-parametric data, RANKL: tissue-like memory (HIV-); OPG: All HIV- subsets]. Comparisons were done using two-way ANOVA, followed by pairwise comparisons of individual B cell subsets using student's t-test (parametric data) or Wilcoxon rank sum test (non-parametric data).
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ppat-1004497-g003: Differential B cell subset RANKL and OPG expression in HIV-negative and HIV-positive individuals.Representative histograms (alternate top panels) of B cell subset staining for RANKL (A) and OPG (B) for HIV negative individuals (solid line) and HIV positive individuals (dashed line). Scatter plots (alternate bottom panels) represent cumulative data for B cell subset RANKL (A) or OPG (B) expression from individual HIV-negative (HIV−, N = 17) or seropositive (HIV+, N = 15) individuals with bars at the mean (parametric data) or median [non-parametric data, RANKL: tissue-like memory (HIV-); OPG: All HIV- subsets]. Comparisons were done using two-way ANOVA, followed by pairwise comparisons of individual B cell subsets using student's t-test (parametric data) or Wilcoxon rank sum test (non-parametric data).

Mentions: To examine how B cell subset OPG and RANKL expression is affected by HIV infection, we compared B cell subsets from uninfected and HIV-infected and HIV-negative subjects. Higher proportions of RANKL-expressing cells were observed in all four subsets in the HIV-positive compared to the HIV-negative. These differences were statistically significant for all but the activated memory B cell subset (Figure 3A). These data suggest that the increased expression of RANKL by total B cells (Figure 1B) is likely the consequence of a significant increase in RANKL-expressing B cell subpopulations (particularly activated and exhausted tissue-like memory B cells) in the context of HIV infection.


Dysregulated B cell expression of RANKL and OPG correlates with loss of bone mineral density in HIV infection.

Titanji K, Vunnava A, Sheth AN, Delille C, Lennox JL, Sanford SE, Foster A, Knezevic A, Easley KA, Weitzmann MN, Ofotokun I - PLoS Pathog. (2014)

Differential B cell subset RANKL and OPG expression in HIV-negative and HIV-positive individuals.Representative histograms (alternate top panels) of B cell subset staining for RANKL (A) and OPG (B) for HIV negative individuals (solid line) and HIV positive individuals (dashed line). Scatter plots (alternate bottom panels) represent cumulative data for B cell subset RANKL (A) or OPG (B) expression from individual HIV-negative (HIV−, N = 17) or seropositive (HIV+, N = 15) individuals with bars at the mean (parametric data) or median [non-parametric data, RANKL: tissue-like memory (HIV-); OPG: All HIV- subsets]. Comparisons were done using two-way ANOVA, followed by pairwise comparisons of individual B cell subsets using student's t-test (parametric data) or Wilcoxon rank sum test (non-parametric data).
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4231117&req=5

ppat-1004497-g003: Differential B cell subset RANKL and OPG expression in HIV-negative and HIV-positive individuals.Representative histograms (alternate top panels) of B cell subset staining for RANKL (A) and OPG (B) for HIV negative individuals (solid line) and HIV positive individuals (dashed line). Scatter plots (alternate bottom panels) represent cumulative data for B cell subset RANKL (A) or OPG (B) expression from individual HIV-negative (HIV−, N = 17) or seropositive (HIV+, N = 15) individuals with bars at the mean (parametric data) or median [non-parametric data, RANKL: tissue-like memory (HIV-); OPG: All HIV- subsets]. Comparisons were done using two-way ANOVA, followed by pairwise comparisons of individual B cell subsets using student's t-test (parametric data) or Wilcoxon rank sum test (non-parametric data).
Mentions: To examine how B cell subset OPG and RANKL expression is affected by HIV infection, we compared B cell subsets from uninfected and HIV-infected and HIV-negative subjects. Higher proportions of RANKL-expressing cells were observed in all four subsets in the HIV-positive compared to the HIV-negative. These differences were statistically significant for all but the activated memory B cell subset (Figure 3A). These data suggest that the increased expression of RANKL by total B cells (Figure 1B) is likely the consequence of a significant increase in RANKL-expressing B cell subpopulations (particularly activated and exhausted tissue-like memory B cells) in the context of HIV infection.

Bottom Line: HIV infection is associated with high rates of osteopenia and osteoporosis, but the mechanisms involved are unclear.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.

View Article: PubMed Central - PubMed

Affiliation: Division of Endocrinology, Metabolism and Lipids, Emory University School of Medicine, Atlanta, Georgia, United States of America.

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.

No MeSH data available.


Related in: MedlinePlus