Liver X Receptors Orchestrate Osteoblast/Osteoclast Crosstalk and Counteract Pathologic Bone Loss
Liver X Receptors Orchestrate Osteoblast/Osteoclast Crosstalk and Counteract Pathologic Bone Loss
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DOI：
10.1002/jbmr.1702
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发表时间：
2012-12-01
影响因子：
6.2
通讯作者：
Kroenke, Gerhard
中科院分区：
文献类型：
--
作者：
Kleyer, Arnd;Scholtysek, Carina;Kroenke, Gerhard
骨质疏松症的特点是骨吸收破骨细胞分化增强，导致功能性骨小梁迅速丧失。成骨细胞和成骨细胞衍生的骨细胞通过提供 NF-κ B 配体 (RANKL) 的促破骨细胞因子受体激活剂及其天然诱饵受体骨保护素 (OPG)，在破骨细胞发育的调节中发挥关键作用。通过调节 RANKL/OPG 比率，成骨细胞决定破骨细胞分化和骨转换的速率。在这里，我们描述了肝脏 X 受体 (LXR) 在骨形成成骨细胞和骨吸收破骨细胞串扰过程中的新作用。通过使用成骨细胞/破骨细胞共培养系统，我们将 LXR 确定为成骨细胞中 RANKL 表达和 RANKL/OPG 比率的调节剂。 LXR 的激活显着降低了 RANKL/OPG 比率，并干扰了体外成骨细胞介导的破骨细胞分化。在卵巢切除术 (OVX) 诱导的绝经后骨质疏松模型中，LXR 激动剂的应用改变了体内 RANKL/OPG 比率，改善了增强的破骨细胞分化，并提供了针对 OVX 诱导的骨质流失的完全保护。这些结果揭示了 LXR 意外地参与骨转换的调节，并强调了 LXR 作为治疗骨质疏松症和相关疾病的新靶点的潜在作用。 (C) 2012 年美国骨与矿物质研究学会。
Osteoporosis is characterized by enhanced differentiation of bone-resorbing osteoclasts, resulting in a rapid loss of functional trabecular bone. Bone-forming osteoblasts and osteoblast-derived osteocytes perform a key role in the regulation of osteoclast development by providing both the pro-osteoclastogenic cytokine receptor activator of NF-kappa B ligand (RANKL) and its natural decoy receptor osteoprotegerin (OPG). By regulating the RANKL/OPG ratio, osteoblasts hence determine the rate of both osteoclast differentiation and bone turnover. Here, we describe a novel role for liver X receptors (LXRs) during the crosstalk of bone-forming osteoblasts and bone-resorbing osteoclasts. By using a system of osteoblast/osteoclast cocultures, we identify LXRs as regulator of RANKL expression and the RANKL/OPG ratio in osteoblasts. Activation of LXRs drastically reduced the RANKL/OPG ratio and interfered with osteoblast-mediated osteoclast differentiation in vitro. During an ovariectomy (OVX)-induced model of postmenopausal osteoporosis, the application of an LXR agonist shifted the RANKL/OPG ratio in vivo, ameliorated the enhanced osteoclast differentiation, and provided complete protection from OVX-induced bone loss. These results reveal an unexpected involvement of LXRs in the regulation of bone turnover and highlight a potential role for LXRs as novel targets in the treatment of osteoporosis and related diseases. (C) 2012 American Society for Bone and Mineral Research.