Dysregulated B Cell Expression of RANKL and OPG Correlates with Loss of Bone Mineral Density in HIV Infection

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.

Loss of marginal zone B-cells in SHIVSF162P4 challenged rhesus macaques despite control of viremia to low or undetectable levels in chronic infection

“…4A). However as reported for HIV infected humans (Chagnon-Choquet et al, 2014; Titanji et al, 2014) we saw significant skewing of memory B-cell subsets between healthy and chronically infected animals (Fig. 4B).…”

“…Compared to the partial reversal of CD4 + T-cell loss in the periphery and gut mucosa by ART therapy, B-cell dysregulation is not fully reversed (D’Orsogna et al, 2007; Moir and Fauci, 2009; Regidor et al, 2011), although early ART may help prevent it (Moir et al, 2010). B-cell dysregulation occurs early after HIV and SIV infection, usually before CD4 + T-cells decline, and strikingly manifests itself by skewing memory populations (Chagnon-Choquet et al, 2014; Kuhrt et al, 2010; Titanji et al, 2010; Titanji et al, 2014). Additional broader effects of HIV infection on B-cells have been recently reviewed (Moir and Fauci, 2009).…”

High Prevalence of Low Bone Mineral Density and Substantial Bone Loss over 4 Years Among HIV-Infected Persons in the Era of Modern Antiretroviral Therapy

“…5,[17][18][19] Chronic immune activation and inflammation, in turn, have been linked with bone loss associated with HIV infection. 20 In this analysis, we did not find an independent association of osteoporosis with metabolic risk factors that have been previously associated with osteoporosis in HIV-infected persons (e.g., vitamin D deficiency).…”

“…24 In the general population, the association of unemployment with risk of osteoporotic fracture has been described. 25 Low socioeconomic status, as evidenced by unemployment and low income, is strongly (57) 214 (64) 27 (43) Black, non-Hispanic 188 (29) 83 (33) 82 (24) 23 (37) Hispanic 64 (10) 21 (8) 31 (9) 12 (19) 22 (18) 10 (14) 11 (25) 1 (20) HIV-related factors Time since HIV diagnosis in years 57 (22) 78 (23) 20 (32) Nadir CD4 count (cells/mm 177 (88) 230 (89) 48 (91) (continued) 136 (54) 197 (59) 34 (54) Any use of NNRTI 362 (55) 141 (56) 182 (54) 39 (62) Any use of NRTI 574 (88) 225 (89) 292 (87) 57 (90) Any use of stavudine 171 (26) 52 (20) 96 (29) b 23 (37) b Any use of tenofovir 297 (45) 117 (46) 146 (43) 34 (54) Current use tenofovir 257 (39) 103 (41) 122 (36) 32 ( (13) 21 (9) 42 (13) 15 ( linked to poorer health outcomes, including increased allcause mortality. <...>…”

Mechanism of enhanced antiosteoporosis effect of&nbsp;circinal&ndash;icaritin by self-assembled nanomicelles&nbsp;in vivo with suet oil and sodium deoxycholate

“…Postmenopausal estrogen deficiency leads to an increase in osteoclast activity and bone resorption, which manifests as a decrease in serum OPG level. 26 Serum OCN is synthesized and secreted by OCN, which may reflect the activity of osteoblasts. In the process of postmenopausal osteoporosis, OCN can significantly increase.…”