Department of Pathology and Laboratory Medicine and David Geffen School of Medicine at the University of California Los Angeles, Los Angeles, CA 90095-1732, USA.
J Bone Miner Res. 2010 Nov;25(11):2460-9. doi: 10.1002/jbmr.148.
Osteoporosis, which contributes to morbidity and mortality, often coexists with cardiovascular disease, especially atherosclerosis. We have reported recently that in vitro exposure of human T-lymphocytes to oxidized lipids induced expression of a key osteoclastogenic cytokine, receptor activator of NF-κB ligand (RANKL). Our previous studies have shown that mice fed an atherogenic high-fat diet developed osteopenia and that bone marrow preosteoclasts from these hyperlipidemic mice have increased osteoclastic potential. To investigate the role of T-lymphocytes in the diet-induced bone loss, C57BL/6 mice were fed either chow or a high-fat diet, and bone parameters and T-lymphocyte activation were assessed at 6 and 11 months. Consistent with our previous findings, peripheral quantitative computed tomographic (pQCT) analysis showed that mice in the high-fat group had lower bone mineral content than mice in the chow group. Furthermore, histomorphometric analysis showed decreased structural parameters in the high-fat group. Coculture studies showed that bone marrow cells isolated from the high-fat group, which contained increased levels of activated memory T-lymphocytes compared with bone marrow cells from the chow mice, supported osteoclastic differentiation of RAW 264.7 cells. Additionally, RANKL expression was upregulated significantly in the T-lymphocytes isolated from the bone marrow of the high-fat group. Splenic T-lymphocytes isolated from the high-fat group also had increased expression of transcripts for the receptor for oxidized lipids (LOX-1) as well as for inflammatory and osteoclastogenic cytokines, including RANKL, interleukin 6 (IL-6), tumor necrosis factor α (TNF-α), IL-1β, and interferon γ (IFN-γ). Together these findings suggest that T-lymphocytes play a key role in the osteoclastogenesis induced by a high-fat diet and may contribute to the bone loss associated with diet-induced osteopenia.
骨质疏松症可导致发病率和死亡率升高，常与心血管疾病共存，尤其是动脉粥样硬化。我们最近报道称，人 T 淋巴细胞在体外接触氧化脂质后会诱导表达关键的破骨细胞生成细胞因子，核因子 κB 配体受体激活剂（RANKL）。我们之前的研究表明，喂食动脉粥样硬化高脂肪饮食的小鼠会出现骨质疏松症，并且这些高脂血症小鼠的骨髓前破骨细胞具有增强的破骨细胞潜能。为了研究 T 淋巴细胞在饮食诱导的骨丢失中的作用，将 C57BL/6 小鼠喂食标准饮食或高脂肪饮食，并在 6 个月和 11 个月时评估骨参数和 T 淋巴细胞活化情况。与我们之前的发现一致，外周定量计算机断层扫描（pQCT）分析显示，高脂肪组小鼠的骨矿物质含量低于标准饮食组小鼠。此外，组织形态计量学分析显示高脂肪组的结构参数降低。共培养研究表明，与标准饮食组小鼠的骨髓细胞相比，从高脂肪组小鼠分离的骨髓细胞中含有更多的活化记忆 T 淋巴细胞，可支持 RAW 264.7 细胞的破骨细胞分化。此外，高脂肪组骨髓分离的 T 淋巴细胞中 RANKL 表达显著上调。从高脂肪组分离的脾 T 淋巴细胞也增加了氧化脂质受体（LOX-1）以及炎症和破骨细胞生成细胞因子（包括 RANKL、白细胞介素 6（IL-6）、肿瘤坏死因子 α（TNF-α）、白细胞介素 1β（IL-1β）和干扰素 γ（IFN-γ））的转录物表达。这些发现表明 T 淋巴细胞在高脂肪饮食诱导的破骨细胞生成中起关键作用，并可能导致与饮食诱导的骨质疏松症相关的骨丢失。
