Department of Orthopaedics, School of Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan.
Department of Orthopaedics, Shuang Ho Hospital, Taipei Medical University, New Taipei City 23561, Taiwan.
Int J Mol Sci. 2022 Jun 24;23(13):7043. doi: 10.3390/ijms23137043.
Osteoarthritis (OA) is most prevalent in older individuals and exerts a heavy social and economic burden. However, an effective and noninvasive approach to OA treatment is currently not available. Chondrocyte senescence has recently been proposed as a key pathogenic mechanism in the etiology of OA. Furthermore, senescent chondrocytes (SnCCs) can release various proinflammatory cytokines, proteolytic enzymes, and other substances known as the senescence-associated secretory phenotype (SASP), allowing them to connect with surrounding cells and induce senesce. Studies have shown that the pharmacological elimination of SnCCs slows the progression of OA and promotes regeneration. Growth differentiation factor 15 (GDF15), a member of the tumor growth factor (TGF) superfamily, has recently been identified as a possible aging biomarker and has been linked to a variety of clinical conditions, including coronary artery disease, diabetes, and multiple cancer types. Thus, we obtained data from a publicly available single-cell sequencing RNA database and observed that GDF15, a critical protein in cellular senescence, is highly expressed in early OA. In addition, GDF15 is implicated in the senescence and modulation of MAPK14 in OA. Tissue and synovial fluid samples obtained from OA patients showed overexpression of GDF15. Next, we treated C20A4 cell lines with interleukin (IL)-1β with or without shGDF15 then removed the conditioned medium, and cultured C20A4 and HUVEC cell lines with the aforementioned media. We observed that C20A4 cells treated with IL-1β exhibited increased GDF15 secretion and that chondrocytes cultured with media derived from IL-1β-treated C20A4 exhibited senescence. HUVEC cell migration and tube formation were enhanced after culturing with IL-1β-treated chondrocyte media; however, decreased HUVEC cell migration and tube formation were noted in HUVEC cells cultured with GDF15-loss media. We tested the potential of inhibiting GDF15 by using a GDF15 neutralizing antibody, GDF15-nAb. GDF15-nAb exerted a similar effect, resulting in the molecular silencing of GDF15 in vivo and in vitro. Our results reveal that GDF15 is a driver of SnCCs and can contribute to OA progression by inducing angiogenesis.
骨关节炎（OA）在老年人中最为常见，给社会和经济带来沉重负担。然而，目前还没有有效的非侵入性 OA 治疗方法。最近提出软骨细胞衰老（SnCCs）是 OA 发病机制中的关键致病机制。此外，衰老的软骨细胞（SnCCs）可以释放各种促炎细胞因子、蛋白水解酶和其他被称为衰老相关分泌表型（SASP）的物质，使它们能够与周围细胞连接并诱导衰老。研究表明，药理学消除 SnCCs 可减缓 OA 的进展并促进再生。生长分化因子 15（GDF15）是肿瘤生长因子（TGF）超家族的一个成员，最近被确定为一种可能的衰老生物标志物，与多种临床情况有关，包括冠状动脉疾病、糖尿病和多种癌症类型。因此，我们从一个公开的单细胞测序 RNA 数据库中获取数据，观察到细胞衰老过程中的关键蛋白 GDF15 在早期 OA 中高表达。此外，GDF15 与 OA 中的 MAPK14 衰老和调节有关。从 OA 患者获得的组织和滑液样本显示 GDF15 过度表达。接下来，我们用白细胞介素（IL）-1β处理 C20A4 细胞系，并用 shGDF15 处理或不处理，然后去除条件培养基，并用上述培养基培养 C20A4 和 HUVEC 细胞系。我们观察到用 IL-1β 处理的 C20A4 细胞中 GDF15 分泌增加，用 IL-1β 处理的 C20A4 软骨细胞培养的培养基培养的软骨细胞发生衰老。用 IL-1β 处理的软骨细胞培养基培养的 HUVEC 细胞迁移和管形成增强，但在用 GDF15 缺失培养基培养的 HUVEC 细胞中，HUVEC 细胞迁移和管形成减少。我们用 GDF15 中和抗体 GDF15-nAb 测试了抑制 GDF15 的潜力。GDF15-nAb 发挥了类似的作用，导致体内和体外 GDF15 的分子沉默。我们的结果表明，GDF15 是 SnCCs 的驱动因子，通过诱导血管生成促进 OA 进展。
