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

骨吸收破骨细胞在关键的破骨细胞因子受体的影响下形成 NF-κB配体激活因子（RANKL），由其生理性诱饵受体骨保护素调节 （OPG）。免疫系统对生理性和病理性骨转换都具有强有力的影响。下 基础条件B-细胞，分泌OPG和淋巴细胞因此保护骨骼。然而，激活 B细胞和T细胞可分泌RANKL，导致骨丢失。艾滋病毒感染会严重破坏 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是 在艾滋病毒感染中得到承认。有趣的是，无论方案如何，抗逆转录病毒疗法（ART）进一步 在治疗的前2年内加重骨丢失。最后的结果是， 骨折在HIV患者，一个重大的公共卫生问题，高发病率，死亡率，和戏剧性的 医疗保健费用。然而，HIV感染和ART驱动骨质流失的机制很差 定义了我们最近报道了一种HIV感染的动物模型--HIV转基因大鼠的骨丢失， 减少基础B细胞OPG的产生有利于增加RANKL的表达。这是复杂的， 破骨细胞前体对RANKL的敏感性增加。重要的是，在最近出版的翻译 我们的临床研究证实了HIV感染ART初治患者中OPG和RANKL产生的B细胞失衡 发现B细胞RANKL/OPG比值与骨矿物质显著负相关， 骨密度（BMD）。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，我们检测了IL-4对鼠和人B细胞的作用， 发现IL-4有效地促进B细胞产生OPG，但抑制RANKL。此外，IL-4是 已知可降低破骨细胞前体对RANKL的敏感性。IL-4敲除小鼠具有显著的 BMD下降，骨吸收增加，血清OPG浓度不足。我们建议 在两个特定目标中进一步定义驱动HIV和ART相关骨丢失的机制。具体目标1 将量化IL-4在改变B细胞OPG和RANKL以及增强骨吸收相关的 在急性ART期间和之后开始ART之前和之后， 诱导骨丢失期。具体目标2将采用最先进的动物模型来确定来源， IL-4通过直接作用于破骨细胞在维持生理骨量中的机制作用 通过OPG的间接行动。

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.