Wang Rongliang, Mehrjou Babak, Dehghan-Banian Dorsa, Wang Belle Yu Hsuan, Li Qiangqiang, Deng Shuai, Liu Chuanhai, Zhang Zhe, Zhu Yanlun, Wang Haixing, Li Dan, Lu Xiaomin, Cheng Jack Chun Yiu, Ong Michael Tim Yun, Chan Hon Fai, Li Gang, Chu Paul K, Lee Wayne Yuk Wai
Department of Orthopaedics and Traumatology, Faculty of Medicine, Prince of Wales Hospital, The Chinese University of Hong Kong, Shatin, Hong Kong SAR, China; Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Shatin, Hong Kong SAR, China; SH Ho Scoliosis Research Laboratory, Joint Scoliosis Research Center of the Chinese University of Hong Kong and Nanjing University, The Chinese University of Hong Kong, Shatin, Hong Kong SAR, China; and State Key Laboratory of Pharmaceutical Biotechnology, Division of Sports Medicine and Adult Reconstructive Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China.
Department of Physics, Department of Materials Science and Engineering, Department of Biomedical Engineering, City University of Hong Kong, Tat Chee Avenue, Kowloon, Hong Kong SAR, China.
Arthritis Rheumatol. 2025 Mar;77(3):283-297. doi: 10.1002/art.43028. Epub 2025 Jan 8.
Emerging evidence suggests long noncoding RNA H19 is associated with osteoarthritis (OA) pathology. However, how H19 contributes to OA has not been reported. This study aims to investigate the biologic function of H19 in OA subchondral bone remodeling and OA progression.
Clinical joint samples and OA animal models induced by surgical destabilization of the medial meniscus (DMM) 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 mechanoresponse. Finally, the antisense oligonucleotide (ASO) against H19 was delivered to mice knee joints by magnetic metal-organic framework (MMOF) nanoparticles to develop a site-specific delivery method for targeting osteocyte H19 for OA treatment.
Both clinical OA subchondral bone and wildtype mice with DMM-induced OA exhibit aberrant higher subchondral bone mass, with more H19 mice expressing osteocytes. On the contrary, mice with osteocyte-specific deletion of H19 are less vulnerable to DMM-induced OA phenotype. In MLO-Y4 cells, H19-mediated osteocyte mechanoresponse through PI3K/AKT/GSK3 signal activation by EZH2-induced H3K27me3 regulation on protein phosphatase 2A inhibition. Targeted inhibition of H19 (using ASO-loaded MMOF) substantially alleviates subchondral bone remodeling and OA phenotype.
In 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.
新出现的证据表明长链非编码RNA H19与骨关节炎（OA）病理相关。然而，H19如何促成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。
采用临床关节样本和通过内侧半月板手术不稳定（DMM）诱导的OA动物模型，以验证骨细胞H19与OA软骨下骨及软骨变化之间的因果关系。对承受流体剪切应力的MLO-Y4骨细胞进行实验，以验证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，以开发一种针对骨细胞H19的OA治疗位点特异性递送方法。
临床OA软骨下骨和DMM诱导的OA野生型小鼠均表现出异常高的软骨下骨量，且有更多表达H19的骨细胞。相反，骨细胞特异性缺失H19的小鼠对DMM诱导的OA表型的易感性较低。在MLO-Y4细胞中，H19通过EZH2诱导的H3K27me3对蛋白磷酸酶2A抑制的调控，经PI3K/AKT/GSK3信号激活介导骨细胞机械反应。对H19的靶向抑制（使用负载ASO的MMOF）可显著减轻软骨下骨重塑和OA表型。
总之，我们的数据提供了新的证据，表明骨细胞中H19表达升高可能促成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反应所必需的，靶向H19代表了一种新的有前景的OA治疗方法。
