Department of Orthopaedic Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15219, USA; Department of Orthopaedic Surgery, Xiangya Hospital, Central South University, Changsha, Hunan, China; Xiangya Third Hospital, Central South University, Changsha, Hunan, China.
Department of Orthopaedic Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15219, USA.
Osteoarthritis Cartilage. 2022 Feb;30(2):302-314. doi: 10.1016/j.joca.2021.11.002. Epub 2021 Nov 9.
In knee cartilage from patients with osteoarthritis (OA), both preserved cartilage and damaged cartilage are observed. In this study, we aim to compare preserved with damaged cartilage to identify the molecule(s) that may be responsible for the mechanical loading-induced differences within cartilage degradation.
Preserved and damaged cartilage were harvested from the same OA knee joint. RNA Sequencing was performed to examine the transcriptomic differences between preserved and damaged cartilage cells. Estrogen receptor-α (ERα) was identified, and its function of was tested through gene knockin and knockout. The role of ERα in mediating chondrocyte response to mechanical loading was examined via compression of chondrocyte-laded hydrogel in a strain-controlled manner. Findings from the studies on human samples were verified in animal models.
Level of estrogen receptor α (ERα) was significantly reduced in damaged cartilage compared to preserved cartilage, which were observed in both human and mice samples. Knockdown of ESR1, the gene encoding ERα, resulted in an upregulation of senescence- and OA-relevant markers in chondrocytes. Conversely, knockin of ESR1 partially reversed the osteoarthritic and senescent phenotype of OA chondrocytes. Using a three-dimensional (3D) culture model, we demonstrated that mechanical overload significantly suppressed ERα level in chondrocytes with concomitant upregulation of osteoarthritic phenotype. When ESR1 expression was suppressed, mechanical loading enhanced hypertrophic and osteogenic transition.
Our study demonstrates a new estrogen-independent role of ERα in mediating chondrocyte phenotype and its response to mechanical loading, and suggests that enhancing ERα level may represent a new method to treat osteoarthritis.
在骨关节炎（OA）患者的膝关节软骨中，既存在正常软骨，也存在受损软骨。本研究旨在比较正常软骨和受损软骨，以确定可能导致软骨降解过程中机械加载诱导差异的分子。
从同一 OA 膝关节中采集正常和受损的软骨。通过 RNA 测序检测正常和受损软骨细胞之间的转录组差异。鉴定出雌激素受体-α（ERα），并通过基因敲入和敲除测试其功能。通过应变控制方式压缩负载软骨细胞的水凝胶来研究 ERα在介导软骨细胞对机械加载的反应中的作用。通过动物模型验证了来自人类样本的研究结果。
与正常软骨相比，受损软骨中雌激素受体α（ERα）的水平明显降低，这在人类和小鼠样本中均观察到。ESR1（编码 ERα 的基因）的敲低导致软骨细胞中衰老和 OA 相关标志物的上调。相反，ESR1 的敲入部分逆转了 OA 软骨细胞的 OA 和衰老表型。使用三维（3D）培养模型，我们证明机械过载会显著抑制软骨细胞中的 ERα 水平，同时伴随 OA 表型的上调。当抑制 ESR1 表达时，机械加载会增强肥大和成骨转化。
我们的研究表明 ERα 在介导软骨细胞表型及其对机械加载的反应中具有新的雌激素非依赖性作用，并表明增强 ERα 水平可能代表治疗骨关节炎的一种新方法。
