Feng Naibo, Liu Chungeng, Zhu Yuan, Cai Shuqiong, Xie Yongheng, Wang Zhenmin, Wang Hua, Xiao Guozhi, Long Houqing, Peng Songlin
Division of Spine, Department of Orthopedic Surgery, Shenzhen People's Hospital, The Second Clinical Medical College, Jinan University; The First Affiliated Hospital, Southern University of Science and Technology, Shenzhen, China.
Department of Trauma Orthopedics, Weifang People's Hospital, Shandong Second Medical University, Weifang, China.
Exp Mol Med. 2025 Jul 23. doi: 10.1038/s12276-025-01503-3.
Rheumatoid arthritis (RA) is a chronic autoimmune disorder characterized by synovitis and presenting as symmetrical arthritis that primarily affects the small joints of the limbs. PIWI-interacting RNAs, a class of small noncoding RNAs, have garnered significant attention due to their critical involvement in various pathological conditions, including reproductive diseases, cancers and other disorders. Here we observe elevated levels of macrophage-derived piENOX2 in the synovial tissues of both patients with RA and mice with collagen-induced arthritis (CIA). It was found that transfection with a piENOX2 mimic promoted M1 macrophage polarization, while a piENOX2 inhibitor facilitated M2 polarization. In vivo, a piENOX2 inhibitor significantly alleviated disease progression, reduced systemic inflammation and preserved the integrity of articular cartilage in CIA mice. Mechanistic analyses indicated that the piENOX2 effects were due to its targeting Alkbh5 mRNA for degradation. In a Alkbh5 conditional-knockout mouse model of CIA, the therapeutic effects of a piENOX2 inhibitor, including inflammation suppression and cartilage protection, were reduced compared with control mice. A comprehensive analyses using methylated RNA immunoprecipitation sequencing and methylated RNA immunoprecipitation and quantitative PCR revealed that piENOX2 regulated ALKBH5-mediated mA modification of Itga4 mRNA, thereby influencing macrophage polarization through the PI3K-AKT signaling pathway. These findings provide important insights into the complex roles of PIWI-interacting RNAs in RA progression and indicate potential avenues for therapeutic intervention.
类风湿性关节炎（RA）是一种慢性自身免疫性疾病，其特征为滑膜炎，表现为对称性关节炎，主要影响四肢小关节。PIWI相互作用RNA（PIWI-interacting RNAs）是一类小的非编码RNA，由于它们在包括生殖疾病、癌症和其他疾病在内的各种病理状况中起关键作用而备受关注。在此，我们观察到RA患者和胶原诱导性关节炎（CIA）小鼠的滑膜组织中巨噬细胞衍生的piENOX2水平升高。研究发现，转染piENOX2模拟物可促进M1巨噬细胞极化，而piENOX2抑制剂则促进M2极化。在体内，piENOX2抑制剂可显著减轻CIA小鼠的疾病进展，减轻全身炎症并维持关节软骨的完整性。机制分析表明，piENOX2的作用是由于其靶向Alkbh5 mRNA进行降解。在CIA的Alkbh5条件性敲除小鼠模型中，与对照小鼠相比，piENOX2抑制剂的治疗效果（包括炎症抑制和软骨保护）降低。使用甲基化RNA免疫沉淀测序以及甲基化RNA免疫沉淀和定量PCR进行的综合分析表明，piENOX2调节ALKBH5介导的Itga4 mRNA的mA修饰，从而通过PI3K-AKT信号通路影响巨噬细胞极化。这些发现为PIWI相互作用RNA在RA进展中的复杂作用提供了重要见解，并指出了潜在的治疗干预途径。
