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Bone regenerative potential of the selective sphingosine 1-phosphate receptor modulator siponimod: In vitro characterisation using osteoblast and endothelial cells.

选择性 1-磷酸鞘氨醇受体调节剂 siponimod 的骨再生潜能: 使用成骨细胞和内皮细胞的体外表征。

  • 影响因子:3.24
  • DOI:10.1016/j.ejphar.2020.173262
  • 作者列表:"Sartawi Z","Ryan KB","Waeber C
  • 发表时间:2020-06-10

:The repair of critical bone defects remains a significant therapeutic challenge. While the implantation of drug-eluting scaffolds is an option, a drug with the optimal pharmacological properties has not yet been identified. Agents acting at sphingosine 1-phosphate (S1P) receptors have been considered, but those investigated so far do not discriminate between the five known S1P receptors. This work was undertaken to investigate the potential of the specific S1P1/5 modulator siponimod as a bone regenerative agent, by testing in vitro its effect on cell types critical to the bone regeneration process. hFOB osteoblasts and HUVEC endothelial cells were treated with siponimod and other S1P receptor modulators and investigated for changes in intracellular cyclic AMP content, viability, proliferation, differentiation, attachment and cellular motility. Siponimod showed no effect on the viability and proliferation of osteoblasts and endothelial cells, but increased osteoblast differentiation (as shown by increased alkaline phosphatase activity). Furthermore, siponimod significantly increased endothelial cell motility in scratch and transwell migration assays. These effects on osteoblast differentiation and endothelial cell migration suggest that siponimod may be a potential agent for the stimulation of localised differentiation of osteoblasts in critical bone defects.


: 关键骨缺损的修复仍然是一个重大的治疗挑战。虽然植入药物洗脱支架是一种选择,但具有最佳药理学性质的药物尚未确定。已经考虑了作用于 1-磷酸鞘氨醇 (S1P) 受体的药物,但迄今为止研究的药物没有区分 5 种已知的 S1P 受体。这项工作是为了研究特异性 S1P1/5 调节剂 siponimod 作为骨再生剂的潜力,通过体外测试其对骨再生过程关键的细胞类型的影响。用 siponimod 和其他 S1P 受体调节剂处理 hFOB 成骨细胞和 HUVEC 内皮细胞,研究细胞内环 AMP 含量、活力、增殖、分化、附着和细胞运动的变化。Siponimod 对成骨细胞和内皮细胞的活力和增殖没有影响,但增加了成骨细胞分化 (如碱性磷酸酶活性增加所示)。此外,siponimod 在划痕和 transwell 迁移试验中显著增加内皮细胞运动性。这些对成骨细胞分化和内皮细胞迁移的影响表明,siponimod 可能是关键骨缺损中成骨细胞局部分化刺激的潜在剂。



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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