BACKGROUND Intra-articular injections of hyaluronic acid (HA), the United States Food and Drug Administration approved treatment and widely utilized to delay or reserve the progression of the osteoarthritis (OA) involves. However, this treatment has shown controversial results through various clinical practice guidelines and meta-analysis evaluations, warrants more advanced researches on its safety and effectiveness. METHODS A novel strategy of integrating medical informatics and bioinformatics was utilized. An updated meta-analysis of 16 randomized controlled trials (RCTs) out of 1820 articles was conducted, in combination with a high throughput body-wide-organ-transcriptomic (BOT) RNA-sequencing (RNA-seq) and in vitro and vivo experiments to evaluate the effect of HA at local and systemic levels, revealing the underlying mechanism. RESULTS A sensitivity analysis was performed restricting to high quality RCTs, no significant effect of HA treatment was found on pain relief and functional improvement. Descriptive analysis of RNA-seq using Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway analysis revealed biological process related to innate immune responses and apoptosis; BOT analysis revealed differential gene expressions (DEGs) in cartilage, lymph node, spleen, kidney, and liver, with immune cell proliferation in immune-related organs. In vitro, HA-coated plates were shown to induce macrophage responses; in vivo histological images revealed knee joint, liver, and kidney with damaged/abnormal morphologies, while immune cell proliferation was observed in the lymph node and spleen and it was found that there was no significant difference in the treatment effect for OA animal model. CONCLUSION Conclusively, integration of meta-analysis with bioinformatics analysis exhibited that HA induces inflammatory responses both locally and systematically and not benefit for OA treatment, thus limiting the regeneration and leading to some organ-specific pathogenesis. The strategy and findings will be of important for guiding future long-term clinical studies. THE TRANSLATIONAL POTENTIAL OF THIS ARTICLE This study illustrated that the administered HA activated both systemic and local pro-inflammatory immune responses, possibly limiting its efficacy. This novel unique strategy proposed in this study can be utilized and adapted for future meta-analysis and bioinformatics study.

中文翻译：

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透明质酸治疗骨关节炎的炒作或希望：多器官转录组学的综合临床证据合成。

背景技术透明质酸(HA)的关节内注射是美国食品和药物管理局批准的治疗方法，并广泛用于延缓或保留骨关节炎(OA)所涉及的进展。然而，这种治疗方法通过各种临床实践指南和荟萃分析评估显示出有争议的结果，需要对其安全性和有效性进行更深入的研究。方法 采用整合医学信息学和生物信息学的新策略。结合高通量全身器官转录组 (BOT) RNA 测序 (RNA-seq) 和体外和体内实验，对 1820 篇文章中的 16 篇随机对照试验 (RCT) 进行了更新的荟萃分析评估 HA 在局部和全身水平的作用，揭示潜在机制。结果 对高质量 RCT 进行了敏感性分析，没有发现 HA 治疗对疼痛缓解和功能改善有显着影响。使用基因本体论和京都基因百科全书和基因组通路分析对 RNA-seq 进行描述性分析，揭示了与先天免疫反应和细胞凋亡相关的生物学过程；BOT 分析揭示了软骨、淋巴结、脾脏、肾脏和肝脏中的差异基因表达 (DEG)，以及免疫相关器官中的免疫细胞增殖。在体外，HA 涂层板显示出诱导巨噬细胞反应。体内组织学图像显示膝关节、肝脏和肾脏具有受损/异常的形态，而在淋巴结和脾脏中观察到免疫细胞增殖，发现对OA动物模型的治疗效果没有显着差异。结论 总之，荟萃分析与生物信息学分析的整合表明，HA 可局部和系统地诱导炎症反应，但对 OA 治疗无益，从而限制再生并导致某些器官特异性发病机制。该策略和发现对于指导未来的长期临床研究具有重要意义。本文的翻译潜力 本研究表明，施用的 HA 激活了全身和局部促炎免疫反应，可能会限制其功效。