Division of Endocrinology & Metabolism, Georgetown University, Washington, DC, 20007, USA.
Division of Endocrinology & Metabolism, Georgetown University, Washington, DC, 20007, USA.
Mol Cell Endocrinol. 2022 Aug 20;554:111724. doi: 10.1016/j.mce.2022.111724. Epub 2022 Jul 14.
Growing evidence indicates that chronic hyponatremia represents a significant risk for bone loss, osteoporosis, and fractures in our aging population. Our prior studies on a rat model of the syndrome of inappropriate antidiuretic hormone secretion indicated that chronic hyponatremia causes osteoporosis by increasing osteoclastic bone resorption, thereby liberating stored sodium from bone. Moreover, studies in RAW264.7 pre-osteoclastic cells showed increased osteoclast formation and resorptive activity in response to low extracellular fluid sodium ion concentration (low [Na]). These studies implicated a direct stimulatory effect of low [Na] rather than the low osmolality on cultured osteoclastic cells. In the present cellular studies, we explored gene expression changes triggered by low [Na] using RNA sequencing and gene ontology analysis. Results were confirmed by mouse whole genome microarray, and quantitative RT-PCR. Findings confirmed gene expression changes supporting osteoclast growth and differentiation through stimulation of receptor activator of nuclear factor kappa-B ligand (RANKL), and PI3K/Akt pathways, and revealed additional pathways. New findings on low [Na]-induced upregulation of lysosomal genes, mitochondrial energy production, MMP-9 expression, and osteoclast motility have supported the significance of osteoclast transcriptomic responses. Functional assays demonstrated that RANL and low [Na] independently enhance osteoclast functions. Understanding the molecular mechanisms of hyponatremia-induced osteoporosis provides the basis for future studies identifying sodium-sensing mechanisms in osteoclasts, and potentially other bone cells, and developing strategies for treatment of bone fragility in the vulnerable aging population most affected by both chronic hyponatremia and osteoporosis. ISSUE SECTIONS: Signaling Pathways; Parathyroid, Bone, and Mineral Metabolism.
越来越多的证据表明，慢性低钠血症代表了我们老龄化人口中骨丢失、骨质疏松症和骨折的重大风险。我们之前关于抗利尿激素分泌不当综合征大鼠模型的研究表明，慢性低钠血症通过增加破骨细胞的骨吸收导致骨质疏松症，从而从骨骼中释放储存的钠。此外，在 RAW264.7 前破骨细胞中进行的研究表明，低细胞外液钠离子浓度（低 [Na]）下破骨细胞形成和吸收活性增加。这些研究表明低 [Na] 对培养破骨细胞具有直接的刺激作用，而不是低渗透压。在目前的细胞研究中，我们使用 RNA 测序和基因本体分析探讨了低 [Na] 触发的基因表达变化。通过小鼠全基因组微阵列和定量 RT-PCR 对结果进行了确认。研究结果证实了支持破骨细胞生长和分化的基因表达变化，这些变化通过刺激核因子 kappa-B 配体受体激活剂（RANKL）和 PI3K/Akt 途径，以及揭示其他途径来实现。关于低 [Na] 诱导溶酶体基因、线粒体能量产生、MMP-9 表达和破骨细胞迁移的上调的新发现，支持了破骨细胞转录组反应的重要性。功能测定表明，RANKL 和低 [Na] 独立增强破骨细胞的功能。了解低钠血症性骨质疏松症的分子机制为未来研究提供了基础，这些研究确定了破骨细胞中钠感应机制，以及其他潜在的骨细胞，并为受慢性低钠血症和骨质疏松症影响最大的脆弱老龄化人口的骨脆性治疗制定策略。问题领域：信号通路；甲状旁腺、骨骼和矿物质代谢。
