Laboratory of Tissue Homeostasis and Disease, Skeletal Biology and Engineering Research Center, Department of Development and Regeneration, KU Leuven, Leuven, Belgium.
Division of Trauma Surgery, University Hospitals Leuven, Leuven, Belgium.
JCI Insight. 2021 Dec 22;6(24):e150451. doi: 10.1172/jci.insight.150451.
Osteoarthritis is the most prevalent joint disease worldwide, and it is a leading source of pain and disability. To date, this disease lacks curative treatment, as underlying molecular mechanisms remain largely unknown. The histone methyltransferase DOT1L protects against osteoarthritis, and DOT1L-mediated H3K79 methylation is reduced in human and mouse osteoarthritic joints. Thus, restoring DOT1L function seems to be critical to preserve joint health. However, DOT1L-regulating molecules and networks remain elusive, in the joint and beyond. Here, we identified transcription factors and networks that regulate DOT1L gene expression using a potentially novel bioinformatics pipeline. Thereby, we unraveled a possibly undiscovered link between the hypoxia pathway and DOT1L. We provide evidence that hypoxia enhanced DOT1L expression and H3K79 methylation via hypoxia-inducible factor-1 α (HIF1A). Importantly, we demonstrate that DOT1L contributed to the protective effects of hypoxia in articular cartilage and osteoarthritis. Intra-articular treatment with a selective hypoxia mimetic in mice after surgical induction of osteoarthritis restored DOT1L function and stalled disease progression. Collectively, our data unravel a molecular mechanism that protects against osteoarthritis with hypoxia inducing DOT1L transcription in cartilage. Local treatment with a selective hypoxia mimetic in the joint restores DOT1L function and could be an attractive therapeutic strategy for osteoarthritis.
骨关节炎是全球最普遍的关节疾病，也是疼痛和残疾的主要来源。迄今为止，这种疾病缺乏有效的治疗方法，因为其潜在的分子机制在很大程度上仍不清楚。组蛋白甲基转移酶 DOT1L 可预防骨关节炎，并且在人类和小鼠的骨关节炎关节中，DOT1L 介导的 H3K79 甲基化减少。因此，恢复 DOT1L 的功能对于保持关节健康似乎至关重要。然而，DOT1L 调节分子和网络在关节内外仍然难以捉摸。在这里，我们使用一种潜在的新型生物信息学管道，确定了调节 DOT1L 基因表达的转录因子和网络。由此，我们揭示了缺氧途径和 DOT1L 之间可能未被发现的联系。我们提供的证据表明，缺氧通过缺氧诱导因子-1α（HIF1A）增强 DOT1L 的表达和 H3K79 甲基化。重要的是，我们证明 DOT1L 有助于缺氧在关节软骨和骨关节炎中的保护作用。在手术诱导骨关节炎后，向小鼠关节内注射选择性缺氧模拟物进行治疗，恢复了 DOT1L 的功能并阻止了疾病的进展。总的来说，我们的数据揭示了一种分子机制，通过在软骨中诱导 DOT1L 转录来预防骨关节炎。在关节内局部使用选择性缺氧模拟物恢复 DOT1L 的功能可能是治疗骨关节炎的一种有吸引力的治疗策略。
