Inhibition of IKKβ/NF-κB signaling facilitates tendinopathy healing by rejuvenating inflamm-aging induced tendon-derived stem/progenitor cell senescence.
Inhibition of IKKβ/NF-κB signaling facilitates tendinopathy healing by rejuvenating inflamm-aging induced tendon-derived stem/progenitor cell senescence.
复制标题
抑制 IKKβ/NF-κB 信号传导可通过恢复炎症老化诱导的肌腱干细胞/祖细胞衰老来促进肌腱病愈合
DOI：
10.1016/j.omtn.2021.12.026
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发表时间：
2022-03-08
期刊：
影响因子：
--
通讯作者：
He Y
中科院分区：
文献类型：
--
作者：
Wang C;Zhou Z;Song W;Cai Z;Ding Z;Chen D;Xia F;He Y
退行性肩袖肌腱病（RCT）是一种由退行性变和炎症引起的慢性肌腱疾病，常见于老年人。间充质干细胞衰老被认为是许多与年龄相关的骨骼疾病的重要病理生理机制。在此，我们从退行性冈上肌腱中收集了人肌腱源性干细胞/祖细胞（TSPC），发现TSPC衰老与RCT密切相关。我们进一步发现核因子κB （NF-κB）通路激活参与退行性RCT的年龄相关炎症（炎症老化）。此外，全基因组RNA测序结果显示，体外抑制I κB激酶β (IKKβ)/NF-κB信号通路可以逆转衰老的TSPC表型，减少TSPC的衰老，增加TSPC的衰老潜能。为了实现对IKKβ/NF-κB信号的有效体内抑制，我们制备了装载IKKβ小干扰RNA （siRNA）的金纳米簇（AuNC-siRNA），以实现IKKβ siRNA高效便捷的关节内递送。我们发现，在退行性RCT衰老大鼠模型中，AuNC-siRNA可阻止炎症老化诱导的TSPC衰老和功能障碍。综上所述，这些数据表明，炎症老化通过诱导TSPC衰老导致RCT退行性，而TSPC衰老可以通过阻断IKKβ/NF-κB通路在体内逆转。因此，我们的研究通过使用aunc在关节内递送IKKβ siRNA为退行性随机对照试验提供了一种有希望的治疗策略。抑制IKKβ/NF-κB信号通过恢复炎症老化诱导的肌腱源性干细胞/祖细胞衰老来预防退行性肌腱套肌腱病。
Degenerative rotator cuff tendinopathy (RCT) is a chronic tendon disease caused by degeneration and inflammation, which often affects the elderly population. Mesenchymal stem cell senescence is generally recognized as an important pathophysiological mechanism in many age-related skeletal diseases. Herein, we collected human tendon-derived stem/progenitor cells (TSPCs) from degenerative supraspinatus tendons and found that TSPC senescence is closely related to RCT. We further identified that nuclear factor κB (NF-κB) pathway activation is involved in age-related inflammation (inflamm-aging) of degenerative RCT. Moreover, whole genome RNA sequencing revealed that in vitro inhibition of the I kappa B kinase β (IKKβ)/NF-κB signaling pathway could reverse the aged TSPC phenotype with decreased TSPC senescence and increased tenogenic potential. To achieve effective in vivo inhibition of IKKβ/NF-κB signaling, we fabricated IKKβ small interfering RNA (siRNA)-loaded gold nanoclusters (AuNC-siRNA) for efficient and convenient intra-articular delivery of IKKβ siRNA. We found that AuNC-siRNA prevented inflamm-aging-induced TSPC senescence and dysfunction in a degenerative RCT aged rat model. Together, these data show that inflamm-aging causes degenerative RCT through inducing TSPC senescence, which can be reversed by blocking the IKKβ/NF-κB pathway in vivo. Thus, our study provides a promising therapeutic strategy for degenerative RCT via intra-articular delivery of IKKβ siRNA using AuNCs. The inhibition of IKKβ/NF-κB signaling prevents degenerative rotator cuff tendinopathy by rejuvenating inflamm-aging-induced tendon-derived stem/progenitor cell senescence.
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影响因子：
7.8
作者：
Kohler J;Popov C;Klotz B;Alberton P;Prall WC;Haasters F;Müller-Deubert S;Ebert R;Klein-Hitpass L;Jakob F;Schieker M;Docheva D
通讯作者：
Docheva D
影响因子：
27.4
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影响因子：
4.8
作者：
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影响因子：
82.9
作者：
Bi, Yanming;Ehirchiou, Driss;Young, Marian F.
通讯作者：
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影响因子：
3
作者：
Swan, Malcolm A.;Sato, Eugene;Galatz, Leesa M.;Thomopoulos, Stavros;Ward, Samuel R.
通讯作者：
Ward, Samuel R.