Enhanced Tendon-to-Bone Healing via IKKβ Inhibition in a Rat Rotator Cuff Model.
Enhanced Tendon-to-Bone Healing via IKKβ Inhibition in a Rat Rotator Cuff Model.
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在大鼠肩袖模型中通过抑制IKKβ促进腱-骨愈合
DOI：
10.1177/0363546520985203
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发表时间：
2021-03
期刊：
影响因子：
--
通讯作者：
Thomopoulos S
中科院分区：
文献类型：
--
作者：
Golman M;Li X;Skouteris D;Abraham AA;Song L;Abu-Amer Y;Thomopoulos S
每年有超过45万例肩袖修复手术，但肌腱与骨的愈合往往失败。这种失败的根源在于纤维血管愈合反应，其不能再生天然附着位点。在修复后的早期针对炎症可以实现更好的愈合结果。目前的研究不是广泛抑制炎症，这可能会损害愈合，而是利用分子靶向方法抑制IKKβ，仅关闭核因子κB（NF-κB）信号通路的炎症臂。在临床相关的大鼠肩袖修复模型中评价IKKβ抑制的治疗潜力。对照实验室研究。在体外验证IKKβ抑制剂的疗效后，在大鼠肩袖修复模型中，术后每天一次口服IKKβ抑制剂，持续7天。在愈合3天和2、4和8周后，使用基因表达、生物力学、骨形态测定和组织学评估治疗对减轻炎症和改善修复质量的影响。抑制IKKβ可在体外减弱细胞因子和趋化因子的产生，证明了该抑制剂在体内减轻炎症的潜力。与未治疗组相比，口服IKKβ抑制剂治疗第3天可使NF-κB靶基因表达降低80%，其中一部分基因在14天内受到抑制。此外，IKKβ抑制剂导致增强的肌腱生成和细胞外基质产生，如基因表达和组织学分析所示。在4周时，与溶剂对照相比，抑制剂处理导致韧性增加，对破坏载荷和强度没有影响，并且刚度和模量降低。在第8周，与对照组动物相比，IKKβ抑制剂治疗导致韧性、破坏载荷和强度增加。IKKβ抑制剂治疗防止了对照修复中发生的肌腱附着附近的骨丢失。在大鼠模型中，IKKβ的药理学抑制成功抑制了肩袖修复后的过度炎症并增强了腱-骨愈合。NF-κB通路是提高肩袖修复术后疗效的一个有前景的靶点。
More than 450,000 rotator cuff repairs are performed annually, yet healing of tendon to bone often fails. This failure is rooted in the fibrovascular healing response, which does not regenerate the native attachment site. Better healing outcomes may be achieved by targeting inflammation during the early period after repair. Rather than broad inhibition of inflammation, which may impair healing, the current study utilized a molecularly targeted approach to suppress IKKβ, shutting down only the inflammatory arm of the nuclear factor κB (NF-κB) signaling pathway. To evaluate the therapeutic potential of IKKβ inhibition in a clinically relevant model of rat rotator cuff repair. Controlled laboratory study. After validating the efficacy of the IKKβ inhibitor in vitro, it was administered orally once a day for 7 days after surgery in a rat rotator cuff repair model. The effect of treatment on reducing inflammation and improving repair quality was evaluated after 3 days and 2, 4, and 8 weeks of healing, using gene expression, biomechanics, bone morphometry, and histology. Inhibition of IKKβ attenuated cytokine and chemokine production in vitro, demonstrating the potential for this inhibitor to reduce inflammation in vivo. Oral treatment with IKKβ inhibitor reduced NF-κB target gene expression by up to 80% compared with a nontreated group at day 3, with a subset of these genes suppressed through 14 days. Furthermore, the IKKβ inhibitor led to enhanced tenogenesis and extracellular matrix production, as demonstrated by gene expression and histological analyses. At 4 weeks, inhibitor treatment led to increased toughness, no effects on failure load and strength, and decreases in stiffness and modulus when compared with vehicle control. At 8 weeks, IKKβ inhibitor treatment led to increased toughness, failure load, and strength compared with control animals. IKKβ inhibitor treatment prevented the bone loss near the tendon attachment that occurred in repairs in control. Pharmacological inhibition of IKKβ successfully suppressed excessive inflammation and enhanced tendon-to-bone healing after rotator cuff repair in a rat model. The NF-κB pathway is a promising target for enhancing outcomes after rotator cuff repair.
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影响因子：
1.8
作者：
Berglund, M.;Hart, D. A.;Wiig, M.
通讯作者：
Wiig, M.
影响因子：
5.3
作者：
Colvin, Alexis Chiang;Egorova, Natalia;Flatow, Evan L.
通讯作者：
Flatow, Evan L.
DOI：
10.1073/pnas.1018501108
发表时间：
2011-01-25
影响因子：
11.1
作者：
Glass, Graeme E.;Chan, James K.;Nanchahal, Jagdeep
通讯作者：
Nanchahal, Jagdeep
影响因子：
4.8
作者：
Azzam, Michael G.;Dugas, Jeffrey R.;Cain, E. Lyle, Jr.
通讯作者：
Cain, E. Lyle, Jr.
影响因子：
7
作者：
Grothe, K.;Flechsenhar, K.;Rudolphi, K.
通讯作者：
Rudolphi, K.