Dept. Biomedical Data Sciences, Section Molecular Epidemiology, Leiden University Medical Center, Einthovenweg 20, 2333 ZC, Leiden, The Netherlands.
Washington University, Saint Louis, MO, USA.
Clin Epigenetics. 2024 May 10;16(1):64. doi: 10.1186/s13148-024-01676-0.
Osteoarthritis (OA) is a complex, age-related multifactorial degenerative disease of diarthrodial joints marked by impaired mobility, joint stiffness, pain, and a significant decrease in quality of life. Among other risk factors, such as genetics and age, hyper-physiological mechanical cues are known to play a critical role in the onset and progression of the disease (Guilak in Best Pract Res Clin Rheumatol 25:815-823, 2011). It has been shown that post-mitotic cells, such as articular chondrocytes, heavily rely on methylation at CpG sites to adapt to environmental cues and maintain phenotypic plasticity. However, these long-lasting adaptations may eventually have a negative impact on cellular performance. We hypothesize that hyper-physiologic mechanical loading leads to the accumulation of altered epigenetic markers in articular chondrocytes, resulting in a loss of the tightly regulated balance of gene expression that leads to a dysregulated state characteristic of the OA disease state.
We showed that hyper-physiological loading evokes consistent changes in CpGs associated with expression changes (ML-tCpGs) in ITGA5, CAV1, and CD44, among other genes, which together act in pathways such as anatomical structure morphogenesis (GO:0009653) and response to wound healing (GO:0042060). Moreover, by comparing the ML-tCpGs and their associated pathways to tCpGs in OA pathophysiology (OA-tCpGs), we observed a modest but particular interconnected overlap with notable genes such as CD44 and ITGA5. These genes could indeed represent lasting detrimental changes to the phenotypic state of chondrocytes due to mechanical perturbations that occurred earlier in life. The latter is further suggested by the association between methylation levels of ML-tCpGs mapped to CD44 and OA severity.
Our findings confirm that hyper-physiological mechanical cues evoke changes to the methylome-wide landscape of chondrocytes, concomitant with detrimental changes in positional gene expression levels (ML-tCpGs). Since CAV1, ITGA5, and CD44 are subject to such changes and are central and overlapping with OA-tCpGs of primary chondrocytes, we propose that accumulation of hyper-physiological mechanical cues can evoke long-lasting, detrimental changes in set points of gene expression that influence the phenotypic healthy state of chondrocytes. Future studies are necessary to confirm this hypothesis.
骨关节炎（OA）是一种复杂的、与年龄相关的多因素退行性关节疾病，其特征是运动能力受损、关节僵硬、疼痛以及生活质量显著下降。除了遗传和年龄等其他风险因素外，超生理机械线索已知在疾病的发生和进展中起着关键作用（Guilak 在 Best Pract Res Clin Rheumatol 25:815-823, 2011）。已经表明，有丝分裂后细胞，如关节软骨细胞，严重依赖于 CpG 位点的甲基化来适应环境线索并保持表型可塑性。然而，这些持久的适应可能最终对细胞性能产生负面影响。我们假设超生理机械负荷导致关节软骨细胞中异常表观遗传标记的积累，导致基因表达的紧密调控平衡丧失，从而导致 OA 疾病状态的失调状态。
我们表明，超生理负荷引起与 ITGA5、CAV1 和 CD44 等基因的表达变化相关的 CpG （ML-tCpGs）的一致变化，这些基因共同作用于形态发生（GO：0009653）和对伤口愈合的反应（GO：0042060）等途径。此外，通过将 ML-tCpGs 及其相关途径与 OA 病理生理学中的 tCpGs（OA-tCpGs）进行比较，我们观察到与 CD44 和 ITGA5 等显著基因有适度但特殊的相互重叠。这些基因确实可能代表由于生命早期发生的机械干扰而对软骨细胞表型状态的持久不利变化。这进一步由 CD44 中映射到 ML-tCpGs 的甲基化水平与 OA 严重程度之间的关联所表明。
我们的研究结果证实，超生理机械线索引起软骨细胞全基因组甲基化景观的变化，同时位置基因表达水平（ML-tCpGs）也发生有害变化。由于 CAV1、ITGA5 和 CD44 受到这种变化的影响，并且是初级软骨细胞中 OA-tCpGs 的核心和重叠，我们提出，超生理机械线索的积累可以引起影响软骨细胞表型健康状态的基因表达设定点的持久、有害变化。需要进一步的研究来证实这一假设。
