腺苷 A2A 受体激活减少软骨细胞衰老,The FASEB Journal

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腺苷 A2A 受体激活减少软骨细胞衰老
The FASEB Journal ( IF 4.4 ) Pub Date : 2023-03-08 , DOI: 10.1096/fj.202201212rr
Benjamin Friedman _{1,

2} , Ane Larranaga-Vera ₂ , Cristina M Castro ₂ , Carmen Corciulo ₂ , Piul Rabbani _{1,

3} , Bruce N Cronstein _{1,

2}

Affiliation

骨关节炎 (OA) 发病机制与软骨细胞稳态降低和软骨细胞衰老水平增加有关。软骨衰老是软骨衰老的发展，随着关节老化而增加并破坏软骨细胞稳态，并与 OA 相关。腺苷 A2A 受体 (A2AR) 通过关节内注射脂质体 A2AR 激动剂脂质体-CGS21680 在软骨中激活，导致体内软骨再生和软骨细胞稳态。A2AR 基因敲除小鼠发育为早期 OA 分离的软骨细胞，表明细胞衰老和衰老相关基因的表达上调。基于这些观察，我们假设 A2AR 激活会改善软骨衰老。我们发现 A2AR 对软骨细胞的刺激减少了 β-半乳糖苷酶染色，并在体外调节了人类 TC28a2 软骨细胞系中常见衰老介质 p21 和 p16 的水平和细胞定位。体内分析同样显示，与野生型小鼠相比，A2AR 激活减少注射脂质体-CGS21680 的肥胖诱导的 OA 小鼠的核 p21 和 p16，并增加 A2AR 敲除小鼠软骨细胞的核 p21 和 p16。A2AR 激动剂还通过增强核 Sirt1 定位和上调 T172 磷酸化（活性）AMPK 蛋白水平来增加软骨细胞 Sirt1/AMPK 能量感应通路的活性。最后，TC28a2 和原代人软骨细胞中的 A2AR 激活减少了野生型 p53，同时增加了 p53 可变剪接，导致抗衰老 p53 变体 Δ133p53α 增加。

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Adenosine A2A receptor activation reduces chondrocyte senescence

Osteoarthritis (OA) pathogenesis is associated with reduced chondrocyte homeostasis and increased levels of cartilage cellular senescence. Chondrosenescence is the development of cartilage senescence that increases with aging joints and disrupts chondrocyte homeostasis and is associated with OA. Adenosine A2A receptor (A2AR) activation in cartilage via intra-articular injection of liposomal A2AR agonist, liposomal-CGS21680, leads to cartilage regeneration in vivo and chondrocyte homeostasis. A2AR knockout mice develop early OA isolated chondrocytes demonstrate upregulated expression of cellular senescence and aging-associated genes. Based on these observations, we hypothesized that A2AR activation would ameliorate cartilage senescence. We found that A2AR stimulation of chondrocytes reduced beta-galactosidase staining and regulated levels and cell localization of common senescence mediators p21 and p16 in vitro in the human TC28a2 chondrocyte cell line. In vivo analysis similarly showed A2AR activation reduced nuclear p21 and p16 in obesity-induced OA mice injected with liposomal-CGS21680 and increased nuclear p21 and p16 in A2AR knockout mouse chondrocytes compared to wild-type mice. A2AR agonism also increased activity of the chondrocyte Sirt1/AMPK energy-sensing pathway by enhancing nuclear Sirt1 localization and upregulating T172-phosphorylated (active) AMPK protein levels. Lastly, A2AR activation in TC28a2 and primary human chondrocytes reduced wild-type p53 and concomitantly increased p53 alternative splicing leading to increase in an anti-senescent p53 variant, Δ133p53α. The results reported here indicate that A2AR signaling promotes chondrocyte homeostasis in vitro and reduces OA cartilage development in vivo by reducing chondrocyte senescence.

更新日期：2023-03-08

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