Rahman Md Mizanur, Bhattacharya Arunabh, Fernandes Gabriel
Department of Medicine, Division of Clinical Immunology and Rheumatology, University of Texas Health Science Center at San Antonio, 78229-3900, USA.
J Lipid Res. 2006 Aug;47(8):1739-48. doi: 10.1194/jlr.M600151-JLR200. Epub 2006 May 15.
Bone destruction is a pathological hallmark of several chronic inflammatory diseases, including rheumatoid arthritis, periodontitis, and osteoporosis. Inflammation-induced bone loss of this sort results from increased numbers of bone-resorbing osteoclasts. Numerous studies have indicated that conjugated linoleic acid (CLA) positively influences calcium and bone metabolism. Gene-deletion studies have shown that receptor activator of nuclear factor-kappaB ligand (RANKL) is one of the critical mediators of osteoclastogenesis. In this report, we examine the ability of CLA to suppress RANKL signaling and osteoclastogenesis in RAW264.7 cells, a murine monocytic cell line. Treatment of these cells with RANKL activated nuclear factor-kappaB (NF-kappaB), and preexposure of the cells to CLA significantly suppressed RANKL-induced NF-kappaB activation, including phosphorylation of I-kappaBalpha, degradation of I-kappaBalpha, and nuclear translocation of p65. RANKL induced osteoclastogenesis in these monocytic cells, and CLA inhibited RANKL-induced tumor necrosis factor-alpha production and osteoclast differentiation, including osteoclast-specific genes such as tartrate-resistant acid phosphatase, cathepsin K, calcitonin receptor, and matrix metalloproteinase-9 expression and osteoclast-specific transcription factors such as c-Fos, nuclear factor of activated T-cells expression, and bone resorption pit formation. CLA also inhibited RANKL-induced activation of mitogen-activated protein kinase p38 but had little effect on c-Jun N-terminal kinase activation. Collectively, these data demonstrate for the first time that CLA inhibits osteoclastogenesis by modulating RANKL signaling. Thus, CLA may have important therapeutic implications for the treatment of bone diseases associated with enhanced bone resorption by excessive osteoclastogenesis.
骨破坏是包括类风湿性关节炎、牙周炎和骨质疏松症在内的几种慢性炎症性疾病的病理标志。这种由炎症引起的骨质流失是由于骨吸收破骨细胞数量增加所致。大量研究表明，共轭亚油酸（CLA）对钙和骨代谢有积极影响。基因缺失研究表明，核因子κB受体活化剂配体（RANKL）是破骨细胞生成的关键介质之一。在本报告中，我们研究了CLA抑制RAW264.7细胞（一种小鼠单核细胞系）中RANKL信号传导和破骨细胞生成的能力。用RANKL处理这些细胞可激活核因子κB（NF-κB），而预先将细胞暴露于CLA可显著抑制RANKL诱导的NF-κB活化，包括I-κBα的磷酸化、I-κBα的降解以及p65的核转位。RANKL诱导这些单核细胞中的破骨细胞生成，而CLA抑制RANKL诱导的肿瘤坏死因子-α产生和破骨细胞分化，包括破骨细胞特异性基因如抗酒石酸酸性磷酸酶、组织蛋白酶K、降钙素受体和基质金属蛋白酶-9的表达以及破骨细胞特异性转录因子如c-Fos、活化T细胞核因子的表达和骨吸收坑的形成。CLA还抑制RANKL诱导的丝裂原活化蛋白激酶p38的活化，但对c-Jun N端激酶活化影响很小。总体而言，这些数据首次证明CLA通过调节RANKL信号传导来抑制破骨细胞生成。因此，CLA可能对治疗因破骨细胞过度生成导致骨吸收增强相关的骨疾病具有重要的治疗意义。
