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

破骨细胞在关键的破骨细胞因子受体作用下形成的骨吸收破骨细胞 受生理诱骗受体骨保护素调节的核因子-κB配体激活剂 (OPG)。免疫系统对生理性和病理性的骨转换都有很大的影响。在……下面 基础条件B细胞、分泌的OPG和淋巴细胞因此对骨骼具有保护作用。但是，已激活 B细胞和T细胞可以分泌RANKL，导致骨质丢失。艾滋病毒感染会导致人类的 免疫骨骼界面，攻击T细胞和B细胞功能。并不令人惊讶的是，长期以来，骨质流失 在艾滋病毒感染中被认可。有趣的是，无论方案如何，抗逆转录病毒疗法(ART)进一步 在治疗的头两年内加剧骨质流失。最终结果是患病风险增加了9倍。 HIV患者的骨折是一个重大的公共卫生问题，具有很高的发病率、死亡率和戏剧性 医疗保健费用。然而，艾滋病毒感染和抗逆转录病毒治疗导致骨丢失的机制尚不清楚。 已定义。我们最近报道了HIV转基因大鼠的骨质丢失，这是一种HIV感染的动物模型 基础B细胞OPG产生减少有利于RANKL表达增加。这是一个复杂的问题 破骨细胞前体对RANKL的敏感性增加。重要的是，在最近出版的一份翻译版本中 我们在HIV感染的ART患者中证实了B细胞在OPG和RANKL产生方面的不平衡 并发现B细胞RANKL/OPG比值与骨矿物质呈显著负相关 密度(BMD)。然而，驱动B细胞代谢改变的潜在机制仍不清楚。 由于IL-4是体液免疫的关键调节因子，我们检测了IL-4对小鼠和人B细胞的作用以及 发现IL-4有效地促进了OPG的B细胞产生，但抑制了RANKL的产生。此外，IL-4是 已知会降低破骨细胞前体对RANKL的敏感性。IL-4基因敲除小鼠有显著的 BMD下降，骨吸收增加，血清OPG浓度不足。我们建议 在两个具体目标中进一步定义导致艾滋病毒和抗逆转录病毒治疗相关骨丢失的机制。具体目标1 将量化IL-4在改变的B细胞OPG和RANKL以及相关的骨吸收增强中的作用 在ART开始之前和之后，在急性ART期间和之后，对于ART天真的HIV感染者- 诱导性骨丢失期。特定目标2将使用最先进的动物模型来定义来源和 IL-4直接作用于破骨细胞维持生理性骨量的机制 以及通过OPG采取的间接行动。

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.