Anti-Inflammatory Peptide Attenuates Edema and Promotes BMP-2-Induced Bone Formation in Spine Fusion
Anti-Inflammatory Peptide Attenuates Edema and Promotes BMP-2-Induced Bone Formation in Spine Fusion
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DOI：
10.1089/ten.tea.2017.0512
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发表时间：
2018-07-03
影响因子：
4.1
通讯作者：
Bae, Hyun W.
中科院分区：
文献类型：
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作者：
Glaeser, Juliane D.;Salehi, Khosrowdad;Bae, Hyun W.
载有重组人骨形态发生蛋白-2（BMP-2）的可吸收胶原海绵（ACS）已成功用于增强骨形成并诱导人类脊柱融合。然而，副作用，如软组织水肿和炎症，已被报道。NEMO结合结构域肽（NBD）抑制活化的B细胞（NF-B）的核因子κ轻链增强子（NF-κ-轻链增强子）的活化，NF-κ-轻链增强子是免疫应答的中枢调节因子。在这项研究中，我们研究了NBD在不影响BMP-2介导的大鼠脊柱融合的情况下减少BMP-2诱导的软组织炎症的潜力。为了评价软组织炎症，将含有BMP-2、BMP-2+NBD、NBD或仅ACS的ACS植入32只大鼠的肌内脊柱旁部位。术后第2天，使用磁共振成像评估植入部位的水肿形成。与BMP-2+NBD、NBD和ACS组相比，BMP-2组的T2加权弛豫时间（T2-RT）值增加。在BMP-2+NBD与NBD和ACS对照之间未检测到T2-RT值的差异。处死后，植入物周围区域的组织学分析显示，与BMP-2+NBD和对照组相比，BMP-2组的单核细胞浸润增加。与对照组相比，BMP-2的存在增加了相对NF-B结合和炎症标志物白细胞介素（IL）1、IL 6、IL 18和趋化因子配体（CCL）2和CCL 3的基因表达。在BMP-2+NBD组中，细胞因子表达被阻断。BMP-2+NBD组与对照组之间无差异。为了评价脊柱融合，对16只大鼠进行了后外侧横突间腰椎融合术。ACS负载有BMP-2或BMP-2+NBD。在第12周处死后，融合部位的显微计算机断层扫描评估发现，与BMP-2相比，BMP-2+NBD组的骨体积更高，骨小梁间距更小。组织学分析未显示新形成骨微结构的任何差异。总之，在大鼠中，将NBD添加到负载BMP-2的ACS中减少了BMP-2诱导的软组织水肿形成和单核细胞浸润，减少了NF-B结合，从而阻断了NF-B调节的细胞因子的转录。此外，NBD刺激BMP-2介导的脊柱融合中的骨形成，可能是通过NF-B通路与其他通路的串扰。本研究结果为开发BMP-2和NBD联合应用于脊柱融合的新的治疗性植骨方法提供了依据。
Recombinant human bone morphogenic protein-2 (BMP-2)-loaded absorbable collagen sponges (ACS) have been successfully used to enhance bone formation and to induce spinal fusion in humans. However, side effects, such as soft tissue edema and inflammation, have been reported. NEMO binding domain peptide (NBD) inhibits activation of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-B), a central regulator of immune response. In this study, we investigated NBD's potential to reduce BMP-2-induced soft tissue inflammation without affecting BMP-2-mediated spinal fusion in rat. For evaluation of soft tissue inflammation, ACS containing BMP-2, BMP-2+NBD, NBD, or ACS only were implanted into intramuscular paraspinal sites of 32 rats. At day 2 postsurgery, edema formation at the implant sites was assessed using magnetic resonance imaging. T2-weighted relaxation time (T2-RT) values were increased in the BMP-2 group compared with BMP-2+NBD, NBD, and ACS groups. No difference in T2-RT values was detected between BMP-2+NBD versus NBD and ACS controls. Postsacrifice, histological analysis of the implant-surrounding zones showed increased mononuclear cell infiltration in the BMP-2 group compared with BMP-2+NBD and controls. The presence of BMP-2 increased relative NF-B binding and gene expression of inflammatory markers, interleukin (IL)1, IL6, IL18, and chemokine ligand (CCL)2 and CCL3 compared with controls. In the BMP-2+NBD group, cytokine expression was blocked. No differences were found between BMP-2+NBD and control groups. For evaluation of spinal fusion, posterolateral intertransverse lumbar fusion procedures were performed on 16 rats. ACS were loaded with BMP-2 or BMP-2+NBD. After sacrifice at week 12, microcomputed tomographic assessment of the fusion site detected a higher bone volume and reduced trabecular spacing in the BMP-2+NBD group compared with BMP-2. Histological analysis did not show any differences in newly formed bone microarchitecture. In summary, addition of NBD to BMP-2-loaded ACS reduces BMP-2-induced soft tissue edema formation and mononuclear cell infiltration, diminishes NF-B binding, and thus blocks transcription of NF-B-regulated cytokines in rat. Furthermore, NBD stimulates bone formation in BMP-2-mediated spinal fusion, possibly through crosstalk of the NF-B pathway with other pathways. The results of this study might provide the basis to develop new therapeutic bone grafting approaches with combinatory administration of BMP-2 and NBD for spinal fusion.