Dioxin Exposure Impairs BMP-2-Mediated Spinal Fusion in a Rat Arthrodesis Model

• Published in: Journal of bone and joint surgery. American volume Vol. 97; no. 12; pp. 1003 - 1010
• Main Authors: Hsu, Erin L., PhD, Sonn, Kevin, MD, Kannan, Abhishek, BS, Bellary, Sharath, MD, Yun, Chawon, PhD, Hashmi, Sohaib, MD, Nelson, John, MD, Mendoza, Marco, MD, Nickoli, Michael, MD, Ghodasra, Jason, MD, Park, Christian, BS, Mitchell, Sean, BS, Ashtekar, Amruta, MS, Ghosh, Anjan, Jain, Akshay, BS, Stock, Stuart R., PhD, Hsu, Wellington K., MD
• Format: Journal Article
• Language: English
• Published: United States Copyright by The Journal of Bone and Joint Surgery, Incorporated 17-06-2015
• Subjects: Animals; Bone Morphogenetic Protein 2 - drug effects; Bone Morphogenetic Protein 2 - physiology; Bone Regeneration - drug effects; Dioxins - adverse effects; Female; Models, Animal; Orthopedics; Rats; Rats, Long-Evans; Spinal Fusion
• ISSN: 0021-9355; 1535-1386
• DOI: 10.2106/JBJS.N.01311

Background 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. Methods 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. Results 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%). Conclusions 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. Clinical Relevance 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.