PTEN inhibitor VO-OHpic attenuates GC-associated endothelial progenitor cell dysfunction and osteonecrosis of the femoral head via activating Nrf2 signaling and inhibiting mitochondrial apoptosis pathway.

PTEN 抑制剂 VO-OHpic 通过激活 Nrf2 信号和抑制线粒体凋亡途径减轻 GC 相关的内皮祖细胞功能障碍和股骨头坏死。

  • 影响因子:4.83
  • DOI:10.1186/s13287-020-01658-y
  • 作者列表:"Yao X","Yu S","Jing X","Guo J","Sun K","Guo F","Ye Y
  • 发表时间:2020-03-30

BACKGROUND:Glucocorticoid (GC)-associated osteonecrosis of the femoral head (ONFH) is the most common in non-traumatic ONFH. Despite a strong relationship between GC and ONFH, the detailed mechanisms have remained elusive. Recent studies have shown that GC could directly injure the blood vessels and reduce blood supply in the femoral head. Endothelial progenitor cells (EPCs), which were inhibited quantitatively and functionally during ONFH, play an important role in maintaining the normal structure and function of vascular endothelium. Phosphatase and tensin homolog (PTEN) is a tumor suppressor gene that promotes cell apoptosis, and its expression was found to be elevated in GC-associated ONFH patients. However, whether direct inhibition of PTEN attenuates GC-associated apoptosis and dysfunction of the EPCs remains largely unknown. METHODS:We investigated the effect of, VO-OHpic, a potent inhibitor of PTEN, in attenuating GC-associated apoptosis and dysfunction of EPCs and the molecular mechanism. SD rats were used to study the effect of VO-OHpic on angiogenesis and osteonecrosis in vivo. RESULTS:The results revealed that methylprednisolone (MPS) obviously inhibit angiogenesis of EPCs by inducing apoptosis, destroying the normal mitochondrial structure, and disrupting function of mitochondria. VO-OHpic treatment is able to reverse the harmful effects by inhibiting the mitochondrial apoptosis pathway and activating the NF-E2-related factor 2 (Nrf2) signaling. Si-Nrf2 transfection significantly reduced the protective effects of VO-OHpic on EPCs. Our in vivo studies also showed that intraperitoneal injection of VO-OHpic obviously attenuates the osteonecrosis of the femoral head induced by MPS and potently increases the blood supply in the femoral head. CONCLUSION:Taken together, the data suggests that inhibition of PTEN with VO-OHpic attenuates apoptosis and promotes angiogenesis of EPCs in vitro via activating Nrf2 signaling pathway and inhibiting the mitochondrial apoptosis pathway. Moreover, VO-OHpic also mitigates GC-associated ONFH and potentiates angiogenesis in the femoral head.


背景: 糖皮质激素 (GC) 相关性股骨头坏死 (ONFH) 是非创伤性 ONFH 中最常见的。尽管 GC 和 ONFH 之间有很强的关系,但详细的机制仍然难以捉摸。最近的研究表明,GC 可以直接损伤血管,减少股骨头的血液供应。内皮祖细胞 (EPCs) 在 ONFH 过程中受到定量和功能抑制,在维持血管内皮的正常结构和功能中起重要作用。磷酸酶和张力蛋白同源物 (PTEN) 是一种促进细胞凋亡的抑癌基因,在 GC 相关的 ONFH 患者中发现其表达升高。然而,直接抑制 PTEN 是否减弱 GC 相关的 EPCs 凋亡和功能障碍在很大程度上仍然未知。 方法: 我们研究了 PTEN 的有效抑制剂 VO-OHpic 在减轻 GC 相关的 EPCs 凋亡和功能障碍中的作用及其分子机制。SD 大鼠用于体内研究 VO-OHpic 对血管生成和骨坏死的影响。 结果: 甲基强的松龙 (MPS) 通过诱导 EPCs 凋亡,破坏正常线粒体结构,破坏线粒体功能,明显抑制 EPCs 的血管生成。VO-OHpic 治疗能够通过抑制线粒体凋亡途径和激活 NF-E2-related 因子 2 (Nrf2) 信号来逆转有害作用。Si-Nrf2 转染显著降低了 VO-OHpic 对 EPCs 的保护作用。我们的体内研究还表明,腹腔注射 VO-OHpic 可明显减轻 MPS 引起的股骨头坏死,有力地增加股骨头的血供。 结论: 联合应用 VO-OHpic 抑制 PTEN 可通过激活 Nrf2 信号通路和抑制线粒体凋亡通路,减轻 EPCs 的凋亡,促进血管新生。此外,VO-OHpic 还可减轻 GC 相关的 ONFH,并增强股骨头的血管生成。



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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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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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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