Pharmacological inhibition of DKK1 promotes spine fusion in an ovariectomized rat model.
Pharmacological inhibition of DKK1 promotes spine fusion in an ovariectomized rat model.
复制标题
DKK1 的药理学抑制可促进卵巢切除大鼠模型中的脊柱融合。
DOI：
10.1016/j.bone.2022.116456
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发表时间：
2022
期刊：
影响因子：
4.1
通讯作者：
James,AaronW
中科院分区：
文献类型：
--
作者：
Li,Zhao;Xing,Xin;Gomez-Salazar,MarioArmando;Xu,Mingxin;Negri,Stefano;Xu,Jiajia;James,AaronW
骨质疏松症在接受脊柱手术的患者中很常见，并且有相当大的不良后果风险。在骨质疏松的情况下，积极影响骨再生和脊柱融合的新方法将是有意义的。中和抗dickkopf -1 （DKK1）抗体已被用作骨合成代谢剂，最近我们的小组报道了它有助于干细胞介导的阑尾骨再生。在这里，设计了一种小分子作为DKK1抑制剂WAY-262611，用于诱导去卵巢大鼠模型的后外侧脊柱融合。在体外，DKK1的药理抑制增强了大鼠骨髓源性干细胞（BMSCs）的成骨和Wnt信号活性。在体内，WAY-262611全身治疗促进了脊柱融合部位的软骨形成和成骨，并最终通过XR、微ct、组织学和手触诊评估显著改善了腰椎融合。未检测到对破骨细胞数量或融合部位血管生成的显著影响，提示对植入部位间充质细胞的主要直接影响。最后，来自人干细胞/基质细胞的证据进一步表明，DKK1的药物抑制促进了体外成骨分化。综上所述，我们的研究结果表明，靶向DKK1促进局部骨形成，并为骨质疏松性骨修复提供了潜在的临床价值。
Osteoporosis is common in patients undergoing spine surgery, and carries a considerable risk of adverse outcomes. New methods to positively influence bone regeneration and spine fusion under osteoporotic conditions would be impactful. Neutralizing anti–Dickkopf-1 (DKK1) antibodies has been used as a bone anabolic agent, and recently reported by our group to aid in stem cell-mediated appendicular bone regeneration. Here, a small molecule designed as a DKK1 inhibitor, WAY-262611, was used to induce posterolateral spine fusion in an ovariectomized rat model. In vitro, pharmacological inhibition of DKK1 enhanced osteogenesis and Wnt signaling activity among rat bone marrow-derived stem/stromal cells (BMSCs). In vivo, systemic treatment with WAY-262611 promoted both chondrogenesis and osteogenesis within the spinal fusion site, and ultimately led to significant improvements in lumbar fusion as assessed by XR, μCT, histology and manual palpation assessments. No significant effect on osteoclast numbers or fusion site angiogenesis was detected, suggesting a primary direct effect on mesenchymal cells of the implantation site. Finally, evidence from human stem/stromal cells further demonstrated that pharmacologic inhibition of DKK1 promoted osteogenic differentiation in vitro. Taken together, our results suggest that targeting DKK1 promotes local bone formation and suggests potential clinical value for osteoporotic bone repair.