Novel role of estrogen receptor-α on regulating chondrocyte phenotype and response to mechanical loading,Osteoarthritis and Cartilage

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Novel role of estrogen receptor-α on regulating chondrocyte phenotype and response to mechanical loading
Osteoarthritis and Cartilage ( IF 7 ) Pub Date : 2021-11-09 , DOI: 10.1016/j.joca.2021.11.002
N Wang ₁ , X Zhang ₁ , B B Rothrauff ₂ , M R Fritch ₂ , A Chang ₃ , Y He ₁ , M Yeung ₄ , S Liu ₅ , K E Lipa ₄ , G Lei ₆ , P G Alexander ₇ , H Lin ₈

Affiliation

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.
Department of Bioinformatics, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15219, USA.
Department of Orthopaedic Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15219, USA; Department of Bioengineering, University of Pittsburgh Swanson School of Engineering, 15219, USA.
Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15219, USA.
Department of Orthopaedic Surgery, Xiangya Hospital, Central South University, Changsha, Hunan, China.
Department of Orthopaedic Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15219, USA; McGowan Institute for Regenerative Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15219, USA.
Department of Orthopaedic Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15219, USA; Department of Bioengineering, University of Pittsburgh Swanson School of Engineering, 15219, USA; McGowan Institute for Regenerative Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15219, USA.

Objective

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.

Methods

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.

Results

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.

Conclusion

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.

中文翻译：

雌激素受体-α在调节软骨细胞表型和对机械负荷反应中的新作用

客观的

在骨关节炎 (OA) 患者的膝关节软骨中，观察到保留的软骨和受损的软骨。在这项研究中，我们旨在比较保存的软骨和受损的软骨，以确定可能导致软骨退化内机械负荷诱导差异的分子。

方法

从同一个 OA 膝关节采集保存的和受损的软骨。进行 RNA 测序以检查保存的和受损的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检测其功能。通过以应变控制的方式压缩载有软骨细胞的水凝胶来检查 ERα 在介导软骨细胞对机械负荷的反应中的作用。人类样本研究的结果在动物模型中得到验证。

结果

与保存的软骨相比，受损软骨中的雌激素受体α (ERα) 水平显着降低，这在人类和小鼠样本中均观察到。敲除编码 ERα 的基因ESR1导致软骨细胞中衰老和 OA 相关标志物的上调。相反，敲入ESR1部分逆转了 OA 软骨细胞的骨关节炎和衰老表型。使用三维 (3D) 培养模型，我们证明机械过载显着抑制软骨细胞中的 ERα 水平，同时上调骨关节炎表型。当ESR1表达受到抑制时，机械负荷会增强肥大和成骨转变。