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.

在关键破骨细胞因子受体的影响下形成骨头吸收破骨细胞。 NF-κB配体（RANKL）的激活剂，其物理诱饵受体骨蛋白蛋白蛋白会调节 （OPG）。免疫系统对物理和病理骨转换都有潜在的影响。在下面 基本条件B细胞，秘密OPG和淋巴细胞受到骨骼的保护。但是，被激活 B-和T细胞可以秘密rank虫，导致骨质流失。艾滋病毒感染导致急剧破坏 免疫 - 骨骼接口，攻击T-和B细胞功能。毫不奇怪，骨质流失长期以来一直存在 在HIV感染中识别。有趣的是，无论采用抗逆转录病毒疗法（ART）方案如何 在治疗的头两年内加剧了骨质流失。净结果是最多增加9倍的风险 艾滋病毒患者的骨折，高发，死亡率和剧烈的公共卫生问题 医疗保健费用。然而，艾滋病毒感染和艺术驱动骨质流失的机制很差 定义。我们最近报道了HIV转基因大鼠的骨质流失，这是HIV感染动物模型，因此 基本的B细胞OPG产生减少，有利于增加RANKL表达。这是由 破骨细胞前体对RANKL的敏感性提高。重要的是，在最近发表的翻译中 临床研究，我们验证了这种B细胞不平衡的OPG和RANKL产生的HIV感染的Art-Nothe 患者，发现B细胞RANKL/OPG比与骨头尖塔显着相关 密度（BMD）。但是，推动B细胞代谢改变的基本机制仍然未知。 由于IL-4是体液免疫学的关键调节剂，因此我们检查了IL-4对鼠和人类B细胞的作用，以及 发现IL-4可能会促进OPG的B细胞产生，但抑制了RANKL的B细胞产生。另外，IL-4是 已知可以降低破骨细胞前体对RANKL的敏感性。 IL-4基因敲除小鼠有很大的 BMD的下降，骨骼分辨率的增加和OPG浓度中的血清防御。我们建议 进一步定义了在两个特定目标中驱动HIV和与艺术相关的骨质流失的机制。具体目标1 将量化IL-4在改变的B细胞OPG和RANKL中的作用，并增强骨分辨率 在急性艺术期间和之外，有未经艺术的艾滋病毒感染的受试者 诱发骨质流失期。具体目标2将采用最新动物模型来定义来源和 IL-4通过直接作用破骨细胞来维持物理骨质量的机械功能 和间接的动作虽然OPG。