Department of Orthopaedic Surgery, School of Medicine, Stanford University, Stanford, CA 94305, USA.
Boston University, Boston, MA 02215, USA.
Sci Transl Med. 2020 Apr 15;12(539). doi: 10.1126/scitranslmed.aax2332.
Osteoarthritis (OA) is a degenerative disease of the joint, which results in pain, loss of mobility, and, eventually, joint replacement. Currently, no disease-modifying drugs exist, partly because of the multiple levels at which cartilage homeostasis is disrupted. Recent studies have highlighted the importance of epigenetic dysregulation in OA, sparking interest in the epigenetic modulation for this disease. In our previous work, we characterized a fivefold increase in cytosine hydroxymethylation (5hmC), an oxidized derivative of cytosine methylation (5mC) associated with gene activation, accumulating at OA-associated genes. To test the role of 5hmC in OA, here, we used a mouse model of surgically induced OA and found that OA onset was accompanied by a gain of ~40,000 differentially hydroxymethylated sites before the notable histological appearance of disease. We demonstrated that ten-eleven-translocation enzyme 1 (TET1) mediates the 5hmC deposition because 98% of sites enriched for 5hmC in OA were lost in mice. Loss of TET1-mediated 5hmC protected the mice from OA development, including degeneration of the cartilage surface and osteophyte formation, by directly preventing the activation of multiple OA pathways. Loss of in human OA chondrocytes reduced the expression of the matrix metalloproteinases and and multiple inflammatory cytokines. Intra-articular injections of a dioxygenases inhibitor, 2-hydroxyglutarate, on mice after surgical induction of OA stalled disease progression. Treatment of human OA chondrocytes with the same inhibitor also phenocopied loss. Collectively, these data demonstrate that TET1-mediated 5hmC deposition regulates multiple OA pathways and can be modulated for therapeutic intervention.
骨关节炎（OA）是一种关节退行性疾病，可导致疼痛、活动能力丧失，最终需要进行关节置换。目前，尚无疾病修饰药物，部分原因是软骨动态平衡受到多个层面的破坏。最近的研究强调了表观遗传失调在 OA 中的重要性，激发了人们对这种疾病的表观遗传调节的兴趣。在我们之前的工作中，我们描述了细胞嘧啶羟甲基化（5hmC）增加了五倍，这是与基因激活相关的胞嘧啶甲基化（5mC）的氧化衍生物，在与 OA 相关的基因中积累。为了测试 5hmC 在 OA 中的作用，我们在这里使用了手术诱导 OA 的小鼠模型，发现 OA 发病伴随着约 40,000 个差异羟甲基化位点的增加，这些位点在疾病明显出现之前就已经出现了。我们证明，ten-eleven-translocation 酶 1（TET1）介导了 5hmC 的沉积，因为在 OA 中富集 5hmC 的 98%的位点在 缺失的小鼠中丢失。TET1 介导的 5hmC 的缺失通过直接阻止多个 OA 途径的激活，保护了 缺失的小鼠免受 OA 的发展，包括软骨表面的退化和骨赘的形成。在人 OA 软骨细胞中缺失 降低了基质金属蛋白酶和多个炎症细胞因子的表达。在手术诱导 OA 后，向小鼠关节内注射双加氧酶抑制剂 2-羟基戊二酸，可阻止疾病进展。用相同的抑制剂处理人 OA 软骨细胞也可模拟 缺失的表型。总之，这些数据表明，TET1 介导的 5hmC 沉积调节多个 OA 途径，可以进行治疗干预。
