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IL-4 Correlates With Bone Mineral Density in Men, and IL-4 Depletion May Drive Bone Loss in Men With HIV
Ighovwerha Ofotokun1,2, Kehmia Titanji3, Sadaf Dabeer3,4
1Division of Infectious Diseases, Department of Medicine, School of Medicine, Emory University.
Insights
Interleukin 4 (IL-4) is lower in people with HIV (PWH) not on treatment. Higher IL-4 levels correlate with better bone mineral density (BMD) in men, suggesting IL-4 protects the male skeleton in HIV.
Area of Science:
- Immunology and Bone Metabolism
- HIV/AIDS Research
Background:
- Fractures are prevalent in people with HIV (PWH).
- Interleukin 4 (IL-4), crucial for bone health, is depleted in PWH.
- The role of IL-4 in skeletal deterioration among PWH remains unclear.
Purpose of the Study:
- To investigate the association between IL-4 levels and bone health markers in PWH.
- To compare IL-4 levels in antiretroviral therapy (ART)-naive PWH, ART-experienced PWH, and people without HIV (PWoH).
Main Methods:
- Measured IL-4, bone resorption (β-CTx), bone formation (osteocalcin), and osteoclast regulators (RANKL, OPG) using ELISAs.
- Assessed bone mineral density (BMD) via bone densitometry.
- Analyzed data using Spearman correlation and multivariable linear regression, stratified by sex and HIV status.
Main Results:
- IL-4 levels were lower in ART-naive PWH compared to PWoH, and higher in ART-experienced PWH versus ART-naive PWH.
- In combined PWoH and ART-naive PWH, IL-4 inversely correlated with bone resorption markers and RANKL/OPG ratio in both sexes.
- IL-4 was associated with higher BMD in males but not females when combining PWoH and ART-naive PWH.
Conclusions:
- Reduced IL-4 in treatment-naive PWH and elevated levels with ART suggest a dynamic relationship.
- IL-4 positively correlates with BMD in men, indicating a protective role for the male skeleton.
- Declining IL-4 may contribute to bone loss in men living with HIV.
Background:
Fractures are common in people with HIV (PWH). Interleukin 4 (IL-4), an antiosteoclastogenic product of CD4 Th2 T cells, becomes depleted in PWH; however, its role in skeletal deterioration in PWH is unknown. We therefore examined associations between IL-4 and bone mineral density (BMD), bone resorption and formation markers (β-C-terminal telopeptide of type I collagen and osteocalcin), and the osteoclastogenic regulators receptor activator of NF-κB ligand (RANKL) and osteoprotegerin in PWH who were antiretroviral therapy (ART) naive and people without HIV (PWoH).
Methods:
Commercial enzyme-linked immunosorbent assays were used to measure factors in a cohort of 37 ART-naive PWH and 28 PWoH and in an independent cohort of 29 ART-experienced PWH. BMD was quantified by bone densitometry, and IL-4 associations were analyzed by sex and HIV status via Spearman correlation and multivariable linear regression.
Results:
IL-4 was significantly lower in ART-naive PWH as compared with PWoH and higher in ART-experienced PWH vs ART-naive PWH. With ART-naive PWH and PWoH combined, IL-4 correlated inversely with β-C-terminal telopeptide of type I collagen, RANKL, and RANKL/osteoprotegerin ratio in males and females, individually and when aggregated, but not in ART-naive PWH or PWoH individually. In PWoH and ART-naive PWH combined, IL-4 was significantly associated with higher lumbar spine Z score and most femoral BMD T and Z scores in males but not females.
Conclusions:
IL-4 levels are reduced in treatment-naive PWH and higher in ART-experienced PWH. IL-4 positively correlates with BMD in men but not women, suggesting that IL-4 protects the male skeleton and that IL-4 decline may contribute to bone loss in men with HIV.
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