Department of Orthopaedic Surgery, Northwestern University, 676 North Saint Claire Street, Suite #1350, Chicago, IL 60611. E-mail address for E.L. Hsu: Email:
J Bone Joint Surg Am. 2015 Jun 17;97(12):1003-10. doi: 10.2106/JBJS.N.01311.
Cigarette smoking inhibits bone-healing and leads to increased rates of pseudarthrosis. However, the mechanisms behind these effects are controversial. Dioxin (2,3,7,8-tetrachlorodibenzo-p-dioxin)--a cigarette smoke constituent and potent activator of the aryl hydrocarbon receptor (Ahr)--negatively impacts bone quality and osteoblast differentiation. We hypothesized that activation of the Ahr by dioxin would inhibit bone morphogenetic protein (BMP)-2-mediated spinal fusion in a rat arthrodesis model.
Female Long-Evans rats were pretreated with dioxin or vehicle in six weekly doses, followed by bilateral posterior lumbar spinal fusion across the L4-L5 transverse processes using recombinant human BMP (rhBMP)-2. Treatments continued until sacrifice at four weeks postoperatively. A third group was treated with dioxin for six weeks, followed by a recovery period of four elimination half-lives to assess the reversible effects of dioxin exposure on spinal fusion capacity. Bone formation and fusion capacity were evaluated using fusion scoring, radiography, micro-computed tomography, and histologic analysis.
Fusion scores for dioxin-treated and dioxin-recovery rats were significantly lower than those for controls. Although fusion rates were also significantly reduced in dioxin-treated animals relative to controls (50% versus 100%, respectively), rates were not significantly reduced in dioxin-recovery animals (80%).
Dioxin treatment significantly inhibited spinal fusion in a rat arthrodesis model, and a prolonged cessation of dioxin exposure facilitated only a partial recovery of bone-healing capacity. This finding indicates that, although the effects of dioxin are persistent, an extended recovery from exposure could potentially restore bone regeneration in vivo.
Development of a pharmacologic agent that reduces the adverse effects of cigarette smoke on bone-healing could prove useful to orthopaedic surgeons. Since dioxin and other similar cigarette smoke toxins exert their effects through Ahr pathway activation, the receptor represents a potential therapeutic target to improve spinal fusion rates in patients who smoke.
吸烟会抑制骨骼愈合，并导致假关节形成率增加。然而，这些影响的机制仍存在争议。二恶英（2,3,7,8-四氯二苯并对二恶英）——一种香烟烟雾成分，也是芳烃受体（Ahr）的有效激活剂——会对骨质量和成骨细胞分化产生负面影响。我们假设，二恶英激活 Ahr 会抑制骨形态发生蛋白（BMP）-2 介导的大鼠关节融合模型中的脊柱融合。
雌性长耳大白鼠经六次每周剂量的二恶英或载体预处理，然后在 L4-L5 横突之间用重组人 BMP（rhBMP）-2 进行双侧后路腰椎融合。治疗一直持续到术后四周处死。第三组大鼠用二恶英治疗六周，然后进行四个消除半衰期的恢复期，以评估二恶英暴露对脊柱融合能力的可逆影响。使用融合评分、放射学、微计算机断层扫描和组织学分析评估骨形成和融合能力。
二恶英治疗组和二恶英恢复期大鼠的融合评分明显低于对照组。尽管与对照组相比，二恶英治疗组的融合率也显著降低（分别为 50%和 100%），但在二恶英恢复期组中，融合率并未显著降低（80%）。
二恶英治疗显著抑制了大鼠关节融合模型中的脊柱融合，而长时间停止二恶英暴露仅促进了骨愈合能力的部分恢复。这一发现表明，尽管二恶英的影响是持久的，但从暴露中恢复可能有潜力在体内恢复骨再生。
开发一种能够减少香烟烟雾对骨愈合不利影响的药物可能对骨科医生有用。由于二恶英和其他类似的香烟烟雾毒素通过 Ahr 途径激活发挥作用，因此该受体代表了改善吸烟患者脊柱融合率的潜在治疗靶点。
