Liu Ye, Molchanov Vladimir, Zhao Yaguang, Lu Di, Liu Huadie, Jang H Josh, Yang Tao
Department of Cell Biology, Van Andel Institute, Grand Rapids, MI 49503, USA.
Department of Epigenetics, Van Andel Institute, Grand Rapids, MI 49503, USA.
Osteoarthritis Cartilage. 2025 Jan;33(1):128-133. doi: 10.1016/j.joca.2024.08.004. Epub 2024 Aug 15.
This study aims to link aberrant endogenous retroviruses (ERVs) activation and osteoarthritis (OA) progression by comparing the chromatin accessibility and transcriptomic landscapes of diseased or intact joint tissues of OA patients.
We performed ERVs-centric analysis on published ATAC-seq and RNA-seq data from OA patients' cartilage tissues. Here, we compared the outer region of the lateral tibial plateau, representing intact cartilage, to the inner region of the medial tibial plateau, representing damaged cartilage. In addition, cartilage tissue sections from OA patients and post-traumatic OA mouse models were assayed for global H3K9me3 abundance through immunohistochemistry staining.
Chromatin accessibility and transcription of ERVs, particularly from evolutionarily "intermediate age" ERVs families (ERV1 and ERVL), were enriched and elevated in OA cartilage. This integrative analysis suggests that H3K9me3-related heterochromatin loss might be mechanistically connected to ERV activation in OA tissue. We further verified that global H3K9me3 levels were reduced in diseased cartilage relative to intact tissue in OA patients and injury-induced OA mice.
The findings suggest a compelling hypothesis that the loss of H3K9me3, either due to aging or cellular stressors, may lead to ERVs reactivation that contributes to tissue inflammation and OA progression. This study unveils the intricate relationship between epigenetic alterations, ERVs activation, and OA, paving the way for potential therapeutic interventions targeting these pathogenic mechanisms.
本研究旨在通过比较骨关节炎（OA）患者患病或完整关节组织的染色质可及性和转录组图谱，将异常内源性逆转录病毒（ERVs）激活与骨关节炎进展联系起来。
我们对已发表的OA患者软骨组织的ATAC-seq和RNA-seq数据进行了以ERVs为中心的分析。在此，我们将代表完整软骨的胫骨外侧平台外部区域与代表受损软骨的胫骨内侧平台内部区域进行了比较。此外，通过免疫组织化学染色检测了OA患者和创伤后骨关节炎小鼠模型的软骨组织切片中整体H3K9me3丰度。
ERVs的染色质可及性和转录，特别是来自进化上“中年”ERVs家族（ERV1和ERVL）的，在OA软骨中富集并升高。这种综合分析表明，H3K9me3相关的异染色质丢失可能在机制上与OA组织中的ERV激活有关。我们进一步证实，与完整组织相比，OA患者和损伤诱导的骨关节炎小鼠患病软骨中的整体H3K9me3水平降低。
这些发现提出了一个令人信服的假设，即由于衰老或细胞应激源导致的H3K9me3缺失可能导致ERVs重新激活，从而促进组织炎症和OA进展。本研究揭示了表观遗传改变、ERVs激活与OA之间的复杂关系，为针对这些致病机制的潜在治疗干预铺平了道路。
