IntroductionEmerging evidence suggests long non‐coding RNA (lncRNA) H19 is associated with osteoarthritis (OA) pathology. However, how H19 contributes to OA has not been reported. This study aims to investigate the biological function of H19 in OA subchondral bone remodeling and OA progression.MethodsClinical joint samples and OA animal models induced by medial meniscus destabilization (DMM) surgery were used to verify the causal relationship between osteocyte H19 and OA subchondral bone and cartilage changes. MLO‐Y4 osteocyte cells subjected to fluid shear stress were used to verify the mechanism underlying H19‐mediated mechano‐response. Finally, the antisense oligonucleotide (ASO) against H19 was delivered to mice knee joints by magnetic metal‐organic framework (MMOF) nanoparticles in order to develop a site‐specific delivery method for targeting osteocyte H19 for OA treatment.ResultsBoth clinical OA subchondral bone and wildtype mice with DMM‐induced OA exhibit aberrant higher subchondral bone mass with more H19 expressing osteocytes. On the contrary, osteocyte‐specific deletion of H19 mice is less vulnerable to DMM‐induced OA phenotype. In MLO‐Y4 cells, H19‐mediated osteocyte mechano‐response through PI3K/AKT/GSK3 signals activation by EZH2‐induced H3K27me3 regulation on PP2A inhibition. Targeted inhibition of H19 (using ASO‐loaded MMOF) substantially alleviates subchondral bone remodeling and OA phenotype.DiscussionIn summary, our results provide new evidence that the elevated H19 expression in osteocytes may contribute to aberrant subchondral bone remodeling and OA progression. H19 appears to be required for the osteocyte response to mechanical stimulation, and targeting H19 represents a new promising approach for OA treatment.image

中文翻译：

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靶向软骨下骨细胞中的长链非编码 RNA H19 可减轻骨关节炎中的软骨降解


引言新出现的证据表明，长链非编码 RNA （lncRNA） H19 与骨关节炎 （OA） 病理学有关。然而，H19 如何导致 OA 尚未见报道。本研究旨在探讨 H19 在 OA 软骨下骨重塑和 OA 进展中的生物学功能。方法采用临床关节标本和内侧半月板不稳定 （DMM） 手术诱导的 OA 动物模型验证骨细胞 H19 与 OA 软骨下骨和软骨变化之间的因果关系。使用经受液体剪切应力的 MLO-Y4 骨细胞来验证 H19 介导的机械反应机制。最后，通过磁性金属有机框架 （MMOF） 纳米颗粒将针对 H19 的反义寡核苷酸 （ASO） 递送至小鼠膝关节，以开发一种靶向骨细胞 H19 治疗 OA 的位点特异性递送方法。结果临床 OA 软骨下骨和患有 DMM 诱导的 OA 的野生型小鼠均表现出异常较高的软骨下骨量和更多 H19 表达的骨细胞。相反，H19 小鼠的骨细胞特异性缺失不太容易受到 DMM 诱导的 OA 表型的影响。在 MLO-Y4 细胞中，H19 通过 PI3K/AKT/GSK3 介导的骨细胞机械反应信号激活 EZH2 诱导的 H3K27me3 对 PP2A 抑制的调节。靶向抑制 H19 （使用 ASO 负载的 MMOF） 可显著缓解软骨下骨重塑和 OA 表型。讨论总之，我们的结果提供了新的证据，表明骨细胞中 H19 表达升高可能导致异常的软骨下骨重塑和 OA 进展。H19 似乎是骨细胞对机械刺激的反应所必需的，靶向 H19 代表了 OA 治疗的一种很有前途的新方法。