Institute of Orthopedics and Traumatology, Foshan Hospital of Traditional Chinese Medicine, Foshan 528000, China.
Center for Translation Medicine Research and Development, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China; Key Laboratory of Structure-Based Drug Design & Discovery, Ministry of Education; Shenyang Pharmaceutical University, Shenyang 110016, China.
Phytomedicine. 2023 Jan;108:154506. doi: 10.1016/j.phymed.2022.154506. Epub 2022 Nov 17.
C-X-C chemokine receptor type 4 (CXCR4) inhibition protects cartilage in osteoarthritis (OA) animal models. Therefore, CXCR4 has becoming a novel target for OA drug development. Since dietary and herbal supplements have been widely used for joint health, we hypothesized that some supplements exhibit protective effects on OA cartilage through inhibiting CXCR4 signaling.
The single-cell RNA sequencing data of OA patients (GSE152805) was re-analyzed by Scanpy 1.9.0. The docking screening of CXCR4 antagonists was conducted by Autodock Vina 1.2.0. The CXCR4 antagonistic activity was evaluated by calcium response in THP-1 cells. Signaling pathway study was conducted by bulk RNA sequencing and western blot analysis in human C28/I2 chondrocytes. The anti-OA activity was evaluated in monosodium iodoacetate (MIA)-induced rats.
Astragaloside IV (ASN IV), the predominate phytochemical in Astragalus membranaceus, has been identified as a novel CXCR4 antagonist. ASN IV reduced CXCL12-induced ADAMTS4,5 overexpression in chondrocytes through blocking Akt signaling pathway. Furthermore, ASN IV administration significantly repaired the damaged cartilage and subchondral bone in MIA-induced rats.
The blockade of CXCR4 signaling by ASN IV could explain anti-OA activities of Astragalus membranaceus by protection of cartilage degradation in OA patients. Since ASN IV as an antiviral has been approved by China National Medical Products Administration for testing in people, repurposing of ASN IV as a joint protective agent might be a promising strategy for OA drug development.
C-X-C 趋化因子受体 4（CXCR4）抑制可保护骨关节炎（OA）动物模型中的软骨。因此，CXCR4 已成为 OA 药物开发的新靶点。由于膳食和草药补充剂已广泛用于关节健康，我们假设某些补充剂通过抑制 CXCR4 信号来发挥对 OA 软骨的保护作用。
使用 Scanpy 1.9.0 对 OA 患者的单细胞 RNA 测序数据（GSE152805）进行重新分析。使用 Autodock Vina 1.2.0 对 CXCR4 拮抗剂进行对接筛选。通过 THP-1 细胞中的钙反应评估 CXCR4 拮抗活性。通过人 C28/I2 软骨细胞的批量 RNA 测序和 Western blot 分析研究信号通路。通过碘酸钠（MIA）诱导的大鼠评估抗 OA 活性。
黄芪甲苷（ASN IV），黄芪中的主要植物化学物质，已被鉴定为新型 CXCR4 拮抗剂。ASN IV 通过阻断 Akt 信号通路减少 CXCL12 诱导的软骨细胞中 ADAMTS4,5 的过表达。此外，ASN IV 给药可显著修复 MIA 诱导的大鼠受损的软骨和软骨下骨。
ASN IV 阻断 CXCR4 信号可能通过保护 OA 患者的软骨降解来解释黄芪的抗 OA 活性。由于 ASN IV 作为抗病毒药物已被中国国家药品监督管理局批准用于人体测试，将 ASN IV 重新用作关节保护剂可能是 OA 药物开发的有前途的策略。
