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The PI3K/AKT pathway promotes fracture healing through its crosstalk with Wnt/β-catenin.

PI3K/AKT 通路通过与 Wnt/β-catenin 的串扰促进骨折愈合。

  • 影响因子:3.21
  • DOI:10.1016/j.yexcr.2020.112137
  • 作者列表:"Dong J","Xu X","Zhang Q","Yuan Z","Tan B
  • 发表时间:2020-06-10
Abstract

:PI3K/AKT is one of the key pathways that regulate cell behaviors including apoptosis, proliferation, and differentiation. Although previous studies have demonstrated that this pathway is a crucial regulator of osteoblasts, the role of PI3K/AKT in fracture healing remains unclear. It is well known that the Wnt/β-catenin pathway plays an essential role in bone regeneration. However, whether there exists crosstalk between Wnt/β-catenin and PI3K/AKT in regulating osteoblasts and bone repair has not been reported. To address these issues, we establish a stabilized fracture model in mice and show that PI3K inhibitor LY294002 substantially inhibits the bone healing process, suggesting that PI3K/AKT promotes fracture repair. More importantly, we report that PI3K/AKT increases phosphorylation of GSK-3β at Ser9 and phosphorylation of β-catenin at Ser552 in fracture callus and murine osteoblastic MC3T3-E1 cells, both of which lead to β-catenin stabilization, nuclear translocation, as well as β-catenin-mediated TCF-dependent transcription, suggesting that β-catenin is activated downstream of PI3K/AKT. Furthermore, we show that ICG001, the inhibitor of β-catenin transcriptional activity, attenuates PI3K/AKT-induced osteoblast proliferation, differentiation, and mineralization, indicating that the PI3K/AKT/β-catenin axis is functional in regulating osteoblasts. Notably, the PI3K/AKT pathway is also activated by Wnt3a and is involved in Wnt3a-induced osteoblast proliferation and differentiation. Hence, our results reveal the existence of a Wnt/PI3K/AKT/β-catenin signaling nexus in osteoblasts, highlighting complex crosstalk between PI3K/AKT and Wnt/β-catenin pathways that are critically implicated in fracture healing.

摘要

: PI3K/AKT 是调控细胞行为包括凋亡、增殖和分化的关键通路之一。尽管先前的研究已经证明该通路是成骨细胞的关键调节因子,但 PI3K/AKT 在骨折愈合中的作用仍不清楚。众所周知,Wnt/β-catenin 通路在骨再生中起着至关重要的作用。然而,Wnt/β-catenin 和 PI3K/AKT 在调控成骨细胞和骨修复方面是否存在串扰尚未见报道。为了解决这些问题,我们在小鼠中建立了一个稳定的骨折模型,并显示 PI3K 抑制剂 LY294002 实质上抑制了骨愈合过程,提示 PI3K/AKT 促进骨折修复。更重要的是,我们报道在骨折愈伤组织和鼠成骨 MC3T3-E1 细胞中,PI3K/AKT 增加 gsk-3 β 在 Ser9 的磷酸化和 β-catenin 在 Ser552 的磷酸化,两者均导致 β-catenin 稳定、核转位以及 β-catenin 介导的 TCF 依赖性转录,提示 β-catenin 在 PI3K/AKT 下游被激活。此外,我们发现 β-catenin 转录活性抑制剂 ICG001 可减弱 PI3K/AKT 诱导的成骨细胞增殖、分化和矿化,表明 PI3K/AKT/β-catenin 轴在调节成骨细胞中具有功能。值得注意的是,PI3K/AKT 通路也被 Wnt3a 激活,并参与成骨细胞增殖和分化 Wnt3a-induced。因此,我们的结果揭示了成骨细胞中 Wnt/PI3K/AKT/β-catenin 信号连接的存在,强调 PI3K/AKT 和 Wnt/β-catenin 通路之间复杂的串扰,这些通路与骨折愈合密切相关。

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影响因子:3.28
发表时间:2020-01-30
DOI:10.1007/s00167-019-05842-3
作者列表:["Ghosh, Koushik","Salmon, Lucy J.","Heath, Emma","Pinczewski, Leo A.","Roe, Justin P."]

METHODS:Purpose To determine outcomes of transphyseal ACL reconstruction using a living parental hamstring tendon allograft in a consecutive series of 100 children. Methods One hundred consecutive juveniles undergoing ACL reconstruction with a living parental hamstring allograft were recruited prospectively and reviewed 2 years after ACL reconstruction with IKDC Knee Ligament Evaluation, and KT1000 instrumented laxity testing. Skeletally immature participants obtained annual radiographs until skeletal maturity, and long leg alignment radiographs at 2 years. Radiographic Posterior tibial slope was recorded. Results Of 100 juveniles, the median age was 14 years (range 8–16) and 68% male. At surgery, 30 juveniles were graded Tanner 1 or 2, 21 were Tanner 3 and 49 were Tanner 4 or 5. There were no cases of iatrogenic physeal injury or leg length discrepancy on long leg radiographs at 2 years, despite a median increase in height of 8 cm. Twelve patients had an ACL graft rupture and 9 had a contralateral ACL injury. Of those without further ACL injury, 82% returned to competitive sports, IKDC ligament evaluation was normal in 52% and nearly normal in 48%. The median side to side difference on manual maximum testing with the KT1000 was 2 mm (range − 1 to 5). A radiographic PTS of 12° or more was observed in 49%. Conclusions ACL reconstruction in the juvenile with living parental hamstring tendon allograft is a viable procedure associated with excellent clinical stability, patient-reported outcomes and return to sport over 2 years. Further ACL injury to the reconstructed and the contralateral knee remains a significant risk, with identical prevalence observed between the reconstructed and contralateral ACL between 12 and 24 months after surgery. Level of evidence III (Cohort Study).

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影响因子:2.44
发表时间:2020-01-29
DOI:10.1007/s00264-020-04485-1
作者列表:["Skvortsov, D.","Kaurkin, S.","Goncharov, E.","Akhpashev, A."]

METHODS:Purpose The purpose of the study was to investigate the biomechanics of walking and of the knee joint in the acute phase of ACL injury. Methods We examined 18 patients with acute ACL injuries and 20 healthy adults as controls. The biomechanics of the knee joint and of walking was assessed by 5 inertial sensors fixed with special cuffs to the lower back, the lower third of the thigh, and the lower third of the shank of the right and left legs. The movements and temporal characteristics were recorded while the subject was walking 10 m at a comfortable pace. Based on the results of examination, the patients were divided into two groups: with severe function impairment (6 patients) and with moderate function impairment (12 patients). Results It was found that in the first days post-trauma, not only the knee function was reduced, but the function of the entire lower limb as well. This led to a functional asymmetry. The kinematics of movements in the joints changed in accordance with slower walking. The walking became not only slower, but it was also associated with a decreased impact load in the weight acceptance phase. At later dates, the functional impairments were less pronounced. The total range of flexion motion did not exceed 20 degrees in the first group and 55 degrees in the second one. The injured joint developed functional immobilization within the first days post-injury. This was a guarding response by additional muscle strain to prevent unusual and limit physiological movements in the knee joint. The movements in the knee joint while walking were of small amplitude, rocking, and occurred only under load. The amplitude of the main flexion in the swing phase was reduced. Conclusion The stage of an ACL injury should be assessed not only based on the time post-trauma, but also taking account of the functional parameter—the knee range of flexion while walking. According to our findings, the only factor that had influenced the functional condition of the KJ was the duration of joint immobilization after trauma.

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影响因子:2.21
发表时间:2020-01-24
DOI:10.1007/s00402-020-03350-5
作者列表:["Theopold, Jan","Schleifenbaum, Stefan","Georgi, Alexander","Schmidt, Michael","Henkelmann, Ralf","Osterhoff, Georg","Hepp, Pierre"]

METHODS:Purpose Numerous techniques have been described for the tibial-sided graft preparation in anterior cruciate ligament (ACL) reconstruction. The use of less suture material for graft preparation is thought to improve ingrowth and to reduce the risk for infection. At the same time, the suture construct should be strong enough to resist the surgeon’s pull during tensioning of the transplant. Methods In total, 39 fresh-frozen procine deep flexor tendons were used and prepared as four-strand grafts. In the three-suture group ( n  = 19), graft preparation was performed using three tibial-sided sutures, with each tendon end sutured separately. In the one-suture group ( n  = 20), a modified graft preparation using only one tibial-sided suture was applied. Each sample underwent load-to-failure testing ( N _max) after cyclic pre-loading. To estimate intraoperative tension forces acting on the tibial-sided suture constructs, the maximal tension force of 26 volunteers on such a construct was measured using a load cell. Results The biomechanical testing of the two different suture constructs showed a significantly higher load-to-failure for the three-suture group (711 N ± 91 N) compared to the one-suture group (347 N ± 24 N) ( p  = 0.0001). In both groups, the mode of failure was a tear of the suture in all samples. A failure of the suture–tendon interface was not observed in any case. The median maximal tension force on the construct applied by the 26 volunteers was 134 N (range 73–182 N). Conclusion The presented single-suture tendon graft preparation resisted to smaller failure loads than the conventional three-suture technique. However, no failures in the suture–tendon interface were seen and the failure loads observed were far beyond the tension forces that can be expected intraoperatively. Hence, the single-suture graft preparation technique may be a valuable alternative to the conventional technique.

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