# IL-4, a key regulator of bone turnover in HIV and ART

> **NIH NIH R01** · EMORY UNIVERSITY · 2020 · $606,817

## Abstract

Bone resorbing osteoclasts form under the influence of the key osteoclastogenic cytokine Receptor
activator of NF-κB ligand (RANKL), which is moderated by its physiological decoy receptor Osteoprotegerin
(OPG). The immune system has a potent effect on both physiological and pathological bone turnover. Under
basal conditions B-cells, secrete OPG and lymphocytes are thus protective of the skeleton. However, activated
B- and T-cells can secrete RANKL leading to bone loss. HIV-infection causes dramatic disruptions of the
immuno-skeletal interface, assaulting both T- and B-cell functions. Not surprisingly, bone loss has long been
recognized in HIV-infection. Interestingly, regardless of regimen, antiretroviral therapy (ART) further
exacerbates bone loss within the first 2 years of therapy. The net result is an up to 9-fold increase in the risk of
bone fractures in HIV patients, a significant public health concern with high morbidity, mortality, and dramatic
health care costs. The mechanisms by which HIV-infection and ART drive bone loss are however poorly
defined. We recently reported bone loss in the HIV transgenic rat, an animal model of HIV-infection, as a result
of diminished basal B-cell OPG production in favor of increased RANKL expression. This was compounded by
an increased sensitivity of osteoclast precursors to RANKL. Importantly, in a recently published translational
clinical study we validated this B-cell imbalance in OPG and RANKL production in HIV-infected ART-naïve
patients and found that the B cell RANKL/OPG ratio was significantly inversely correlated with bone mineral
density (BMD). However, the underlying mechanisms driving alterations in B-cell metabolism remain unknown.
As IL-4 is a key regulator of humoral immunity, we examined IL-4 action on murine and human B-cells and
found that IL-4 potently promotes B-cell production of OPG, but suppresses that of RANKL. In addition, IL-4 is
known to decrease the sensitivity of osteoclast-precursors to RANKL. IL-4 knockout mice have a significant
decline in BMD and an increase in bone resorption and a serum deficit in OPG concentrations. We propose to
further define the mechanisms driving HIV- and ART-associated bone loss in two specific aims. Specific Aim 1
will quantify the role of IL-4 in the altered B-cell OPG and RANKL and enhanced bone resorption associated
with ART-naïve HIV-infected subjects before and after ART initiation during and beyond the acute ART-
induced bone loss period. Specific Aim 2 will employ state-of the-art animal models to define the sources and
mechanistic functions of IL-4 in the maintenance of physiological bone mass by direct actions on osteoclasts
and indirect actions though OPG.

## Key facts

- **NIH application ID:** 10005026
- **Project number:** 5R01AR070091-05
- **Recipient organization:** EMORY UNIVERSITY
- **Principal Investigator:** Ighovwerha Ofotokun
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $606,817
- **Award type:** 5
- **Project period:** 2016-09-20 → 2022-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10005026

## Citation

> US National Institutes of Health, RePORTER application 10005026, IL-4, a key regulator of bone turnover in HIV and ART (5R01AR070091-05). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10005026. Licensed CC0.

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