Yiang Giou-Teng, Su Wen-Lin, Zheng Cai-Mei, Liao Min-Tser, Cheng Tong-Hong, Lu Chien-Lin, Lu Kuo-Cheng
School of Medicine, Tzu Chi University, Hualien, Taiwan.
Department of Emergency Medicine, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, New Taipei, Taiwan.
Tzu Chi Med J. 2023 Dec 13;36(1):38-45. doi: 10.4103/tcmj.tcmj_212_23. eCollection 2024 Jan-Mar.
Uremic toxins play a crucial role in the development of low bone turnover disease in chronic kidney disease (CKD) through the induction of oxidative stress. This oxidative stress disrupts the delicate balance between bone formation and resorption, resulting in a decline in both bone quantity and quality. Reactive oxygen species (ROS) activate nuclear factor kappa-B and mitogen-activated protein kinase signaling pathways, promoting osteoclastogenesis. Conversely, ROS hinder osteoblast differentiation by facilitating the binding of Forkhead box O proteins (FoxOs) to β-catenin, triggering apoptosis through FoxOs-activating kinase phosphorylation. This results in increased osteoblastic receptor activator of nuclear factor kappa-B ligand (RANKL) expression and decreased nuclear factor erythroid 2-related factor 2 levels, compromising antioxidant defenses against oxidative damage. As CKD progresses, the accumulation of protein-bound uremic toxins such as indoxyl sulfate (IS) and p-cresyl sulfate (PCS) intensifies oxidative stress, primarily affecting osteoblasts. IS and PCS directly inhibit osteoblast viability, induce apoptosis, decrease alkaline phosphatase activity, and impair collagen 1 and osteonectin, impeding bone formation. They also reduce cyclic adenosine 3',5'-monophosphate (cAMP) production and lower parathyroid hormone (PTH) receptor expression in osteoblasts, resulting in PTH hyporesponsiveness. In summary, excessive production of ROS by uremic toxins not only reduces the number and function of osteoblasts but also induces PTH hyporesponsiveness, contributing to the initiation and progression of low bone turnover disease in CKD.
尿毒症毒素通过诱导氧化应激在慢性肾脏病（CKD）低骨转换疾病的发生发展中起关键作用。这种氧化应激破坏了骨形成与骨吸收之间的微妙平衡，导致骨量和骨质量下降。活性氧（ROS）激活核因子κB和丝裂原活化蛋白激酶信号通路，促进破骨细胞生成。相反，ROS通过促进叉头框O蛋白（FoxOs）与β-连环蛋白的结合来阻碍成骨细胞分化，通过FoxOs激活激酶磷酸化触发细胞凋亡。这导致成骨细胞中核因子κB受体活化因子配体（RANKL）表达增加，核因子红细胞2相关因子2水平降低，损害了对抗氧化损伤的抗氧化防御能力。随着CKD的进展，蛋白结合型尿毒症毒素如硫酸吲哚酚（IS）和对甲酚硫酸盐（PCS）的蓄积加剧了氧化应激，主要影响成骨细胞。IS和PCS直接抑制成骨细胞活力，诱导细胞凋亡，降低碱性磷酸酶活性，并损害Ⅰ型胶原和骨连接蛋白，阻碍骨形成。它们还减少环磷酸腺苷（cAMP）生成，降低成骨细胞中甲状旁腺激素（PTH）受体表达，导致PTH反应性降低。总之，尿毒症毒素过量产生ROS不仅减少了成骨细胞数量和功能，还诱导了PTH反应性降低，促进了CKD低骨转换疾病的发生和发展。
