Graham Lucia S, Parhami Farhad, Tintut Yin, Kitchen Christina M R, Demer Linda L, Effros Rita B
Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at UCLA, 10833 Le Conte Avenue, Los Angeles, CA 90095-1732, USA.
Clin Immunol. 2009 Nov;133(2):265-75. doi: 10.1016/j.clim.2009.07.011. Epub 2009 Aug 22.
Osteoporosis is a systemic disease that is associated with increased morbidity, mortality and health care costs. Whereas osteoclasts and osteoblasts are the main regulators of bone homeostasis, recent studies underscore a key role for the immune system, particularly via activation-induced T lymphocyte production of receptor activator of NFkappaB ligand (RANKL). Well-documented as a mediator of T lymphocyte/dendritic cell interactions, RANKL also stimulates the maturation and activation of bone-resorbing osteoclasts. Given that lipid oxidation products mediate inflammatory and metabolic disorders such as osteoporosis and atherosclerosis, and since oxidized lipids affect several T lymphocyte functions, we hypothesized that RANKL production might also be subject to modulation by oxidized lipids. Here, we show that short term exposure of both unstimulated and activated human T lymphocytes to minimally oxidized low density lipoprotein (LDL), but not native LDL, significantly enhances RANKL production and promotes expression of the lectin-like oxidized LDL receptor-1 (LOX-1). The effect, which is also observed with 8-iso-Prostaglandin E2, an inflammatory isoprostane produced by lipid peroxidation, is mediated via the NFkappaB pathway, and involves increased RANKL mRNA expression. The link between oxidized lipids and T lymphocytes is further reinforced by analysis of hyperlipidemic mice, in which bone loss is associated with increased RANKL mRNA in T lymphocytes and elevated RANKL serum levels. Our results suggest a novel pathway by which T lymphocytes contribute to bone changes, namely, via oxidized lipid enhancement of RANKL production. These findings may help elucidate clinical associations between cardiovascular disease and decreased bone mass, and may also lead to new immune-based approaches to osteoporosis.
骨质疏松症是一种全身性疾病，与发病率、死亡率及医疗费用增加相关。破骨细胞和成骨细胞是骨稳态的主要调节因子，而最近的研究强调了免疫系统的关键作用，特别是通过活化诱导的T淋巴细胞产生核因子κB受体活化因子配体（RANKL）。RANKL作为T淋巴细胞/树突状细胞相互作用的介质已得到充分证明，它还能刺激骨吸收破骨细胞的成熟和活化。鉴于脂质氧化产物介导诸如骨质疏松症和动脉粥样硬化等炎症和代谢紊乱，并且由于氧化脂质会影响多种T淋巴细胞功能，我们推测RANKL的产生也可能受到氧化脂质的调节。在此，我们表明，未刺激和活化的人T淋巴细胞短期暴露于轻度氧化的低密度脂蛋白（LDL）而非天然LDL，可显著增强RANKL的产生并促进凝集素样氧化LDL受体-1（LOX-1）的表达。脂质过氧化产生的炎症异前列腺素8-异前列腺素E2也可观察到这种效应，它是通过核因子κB途径介导的，并且涉及RANKL mRNA表达增加。对高脂血症小鼠的分析进一步加强了氧化脂质与T淋巴细胞之间的联系，其中骨质流失与T淋巴细胞中RANKL mRNA增加及血清RANKL水平升高相关。我们的结果提示了T淋巴细胞导致骨变化的一条新途径，即通过氧化脂质增强RANKL的产生。这些发现可能有助于阐明心血管疾病与骨量减少之间的临床关联，也可能导致基于免疫的骨质疏松症新疗法。
