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

IL-4，HIV 和 ART 中骨转换的关键调节因子

• 批准号: 9759768
• 负责人: Ighovwerha Ofotokun
• 金额: $ 61.89万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-20 至 2021-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9759768
• 关键词: AIDS therapy; AIDS/HIV problem; Ablation; Acute; Aging; Animal Model; Animals; Automobile Driving; B-Lymphocytes; Bone Density; Bone Resorption; CD4 Positive T Lymphocytes; Catabolism; Cell physiology; Cells; Cellular Metabolic Process; Chronic; Clinical; Clinical Research; Communicable Diseases; Complication; Cytokine Receptors; Data; Disease; Drops; Failure; Fracture; Functional disorder; Future; Grant; HIV; HIV Infections; HIV antiretroviral; HIV therapy; HIV-1; Health Care Costs; Hip region structure; Human; Humoral Immunities; Immune; Immune system; Immunology; Impairment; In Vitro; Individual; Infection; Inflammatory; Interleukin 4 Receptor; Interleukin-4; Knockout Mice; Ligands; Link; Lymphocyte; Maintenance; Morbidity - disease rate; Mus; Osteoblasts; Osteoclasts; Osteogenesis; Pathologic; Patients; Phenotype; Physiological; Production; Public Health; Publishing; Rattus; Receptors, Antigen, B-Cell; Recovery; Regimen; Regulation; Reporting; Risk; Role; Serum; Site; Skeletal system; Skeleton; Source; Specialist; T-Cell Depletion; T-Lymphocyte; TRANCE protein; Th2 Cells; Time; Transgenic Organisms; Tumor necrosis factor receptor 11b; Viral; Women’s Interagency HIV Study; antiretroviral therapy; assault; bone; bone health; bone loss; bone mass; bone turnover; clinical translation; cytokine; design; fracture risk; in vivo; knowledge translation; mortality; novel therapeutics; osteoclastogenesis; osteoimmunology; preservation; prevent; programs; prospective; receptor; receptor binding; response; skeletal; therapy development

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.

骨吸收破骨细胞在关键破骨细胞因子受体的影响下形成 NF-κB 配体 (RANKL) 的激活剂，由其生理诱饵受体骨保护素调节 (OPG)。免疫系统对生理和病理性骨转换都有强大的影响。 基础条件 B 细胞、分泌 OPG 和淋巴细胞因此对骨骼有保护作用。 B 细胞和 T 细胞可以分泌 RANKL，导致骨质流失，HIV 感染会导致骨质流失的严重破坏。 免疫-骨骼界面，攻击 T 细胞和 B 细胞功能 毫不奇怪，骨质流失长期以来一直存在。 在 HIV 感染中，无论采用何种治疗方案，都需要进一步进行抗逆转录病毒治疗 (ART)。 治疗前 2 年内骨质流失加剧，最终结果是风险增加高达 9 倍。 HIV 患者骨折是一个重大的公共卫生问题，其发病率、死亡率和发病率都很高 然而，艾滋病毒感染和抗逆转录病毒治疗导致骨质流失的机制尚不清楚。 我们最近报道了 HIV 转基因大鼠（一种 HIV 感染动物模型）的骨质流失。 基础 B 细胞 OPG 产生的减少有利于 RANKL 表达的增加。 重要的是，在最近发表的翻译中，破骨细胞前体对 RANKL 的敏感性增加。 临床研究中，我们验证了 HIV 感染的 ART 初治者中 B 细胞 OPG 和 RANKL 产生的不平衡 对患者进行研究，发现 B 细胞 RANKL/OPG 比值与骨矿物质呈显着负相关 然而，驱动 B 细胞代谢改变的潜在机制仍然未知。 由于 IL-4 是体液免疫的关键调节剂，我们检查了 IL-4 对小鼠和人类 B 细胞的作用，并 发现 IL-4 有效促进 B 细胞产生 OPG，但抑制 RANKL。此外，IL-4 还具有抑制作用。 已知可降低破骨细胞前体对 RANKL 敲除小鼠的敏感性。 我们建议骨密度下降、骨吸收增加以及血清中 OPG 浓度不足。 在两个具体目标 1 中进一步明确驱动 HIV 和 ART 相关骨质流失的机制。 将量化 IL-4 在 B 细胞 OPG 和 RANKL 改变以及相关骨吸收增强中的作用 在急性 ART 期间和之后，在 ART 开始之前和之后，对初次接受 ART 的 HIV 感染者进行治疗 具体目标 2 将采用最先进的动物模型来定义来源和 IL-4通过直接作用于破骨细胞维持生理骨量的机制功能 以及通过 OPG 采取的间接行动。