小柯机器人

美国纽约大学格罗斯曼医学院Chuan-ju Liu和美国耶鲁大学医学院Stephen G. Waxman共同合作，近期取得重要工作进展。他们研究提出，Na_v1.7可以作为软骨细胞调节剂和骨关节炎的治疗靶点。相关研究成果2024年1月3日在线发表于《自然》杂志上。

据介绍，骨关节炎（OA）是最常见的关节疾病。目前还没有有效的方法可以同时防止关节退化和减轻疼痛。尽管有限的证据表明软骨细胞中存在电压门控钠通道（VGSC），但它们在软骨细胞和OA中的表达和功能基本上未知。

研究人员将Na_v1.7鉴定为OA相关的VGSC，并证明人类OA软骨细胞表达功能性Na_v1.7通道，密度为每µm² 0.1至0.15个通道，每细胞350至525个通道。Na_v1.7在多个小鼠模型中的连续基因消融表明，在背根神经节神经元中表达的Na_v1.7与疼痛有关，而软骨细胞中的Na_v1.7调节OA的进展。选择性或临床使用的泛Na_v通道阻滞剂对Na_v1.7的药理学阻断可显著改善结构性关节损伤的进展，并减少OA疼痛行为。从机制上讲，Na_v1.7阻断剂调节细胞内Ca²⁺信号传导和软骨细胞分泌组，进而影响软骨细胞生物学和OA进展。

总之，Na_v1.7作为一种新的软骨细胞表达的OA相关通道的鉴定揭示了开发OA疾病改良和非阿片类镇痛治疗的双重靶点。

附：英文原文

Title: Nav1.7 as a chondrocyte regulator and therapeutic target for osteoarthritis

Author: Fu, Wenyu, Vasylyev, Dmytro, Bi, Yufei, Zhang, Mingshuang, Sun, Guodong, Khleborodova, Asya, Huang, Guiwu, Zhao, Libo, Zhou, Renpeng, Li, Yonggang, Liu, Shujun, Cai, Xianyi, He, Wenjun, Cui, Min, Zhao, Xiangli, Hettinghouse, Aubryanna, Good, Julia, Kim, Ellen, Strauss, Eric, Leucht, Philipp, Schwarzkopf, Ran, Guo, Edward X., Samuels, Jonathan, Hu, Wenhuo, Attur, Mukundan, Waxman, Stephen G., Liu, Chuan-ju

Issue&Volume: 2024-01-03

Abstract: Osteoarthritis (OA) is the most common joint disease. Currently there are no effective methods that simultaneously prevent joint degeneration and reduce pain1. Although limited evidence suggests the existence of voltage-gated sodium channels (VGSCs) in chondrocytes2, their expression and function in chondrocytes and in OA remain essentially unknown. Here we identify Nav1.7 as an OA-associated VGSC and demonstrate that human OA chondrocytes express functional Nav1.7 channels, with a density of 0.1 to 0.15 channels per μm2 and 350 to 525 channels per cell. Serial genetic ablation of Nav1.7 in multiple mouse models demonstrates that Nav1.7 expressed in dorsal root ganglia neurons is involved in pain, whereas Nav1.7 in chondrocytes regulates OA progression. Pharmacological blockade of Nav1.7 with selective or clinically used pan-Nav channel blockers significantly ameliorates the progression of structural joint damage, and reduces OA pain behaviour. Mechanistically, Nav1.7 blockers regulate intracellular Ca2+ signalling and the chondrocyte secretome, which in turn affects chondrocyte biology and OA progression. Identification of Nav1.7 as a novel chondrocyte-expressed, OA-associated channel uncovers a dual target for the development of disease-modifying and non-opioid pain relief treatment for OA.

DOI: 10.1038/s41586-023-06888-7

Source: https://www.nature.com/articles/s41586-023-06888-7

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