title: Dioxin Exposure Impairs BMP-2-Mediated Spinal Fusion in a Rat Arthrodesis Model.
abstract: 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Orthopaedic Surgery, Northwestern University, 676 North Saint Claire Street, Suite #1350, Chicago, IL 60611. E-mail address for E.L. Hsu: Email: erinkhsu@gmail.com.
authors.forename: Erin L
authors.initials: EL
authors.lastname: Hsu
authors.affiliation: Department of Orthopaedic Surgery, Northwestern University, 676 North Saint Claire Street, Suite #1350, Chicago, IL 60611. E-mail address for E.L. Hsu: Email: erinkhsu@gmail.com.
authors.forename: Kevin
authors.initials: K
authors.lastname: Sonn
authors.affiliation: Department of Orthopaedic Surgery, Northwestern University, 676 North Saint Claire Street, Suite #1350, Chicago, IL 60611. E-mail address for E.L. Hsu: Email: erinkhsu@gmail.com.
authors.forename: Abhishek
authors.initials: A
authors.lastname: Kannan
authors.affiliation: Department of Orthopaedic Surgery, Northwestern University, 676 North Saint Claire Street, Suite #1350, Chicago, IL 60611. E-mail address for E.L. Hsu: Email: erinkhsu@gmail.com.
authors.forename: Sharath
authors.initials: S
authors.lastname: Bellary
authors.affiliation: Department of Orthopaedic Surgery, Northwestern University, 676 North Saint Claire Street, Suite #1350, Chicago, IL 60611. E-mail address for E.L. Hsu: Email: erinkhsu@gmail.com.
authors.forename: Chawon
authors.initials: C
authors.lastname: Yun
authors.affiliation: Department of Orthopaedic Surgery, Northwestern University, 676 North Saint Claire Street, Suite #1350, Chicago, IL 60611. E-mail address for E.L. Hsu: Email: erinkhsu@gmail.com.
authors.forename: Sohaib
authors.initials: S
authors.lastname: Hashmi
authors.affiliation: Department of Orthopaedic Surgery, Northwestern University, 676 North Saint Claire Street, Suite #1350, Chicago, IL 60611. E-mail address for E.L. Hsu: Email: erinkhsu@gmail.com.
authors.forename: John
authors.initials: J
authors.lastname: Nelson
authors.affiliation: Department of Orthopaedic Surgery, Northwestern University, 676 North Saint Claire Street, Suite #1350, Chicago, IL 60611. E-mail address for E.L. Hsu: Email: erinkhsu@gmail.com.
authors.forename: Marco
authors.initials: M
authors.lastname: Mendoza
authors.affiliation: Department of Orthopaedic Surgery, Northwestern University, 676 North Saint Claire Street, Suite #1350, Chicago, IL 60611. E-mail address for E.L. Hsu: Email: erinkhsu@gmail.com.
authors.forename: Michael
authors.initials: M
authors.lastname: Nickoli
authors.affiliation: Department of Orthopaedic Surgery, Northwestern University, 676 North Saint Claire Street, Suite #1350, Chicago, IL 60611. E-mail address for E.L. Hsu: Email: erinkhsu@gmail.com.
authors.forename: Jason
authors.initials: J
authors.lastname: Ghodasra
authors.affiliation: Department of Orthopaedic Surgery, Northwestern University, 676 North Saint Claire Street, Suite #1350, Chicago, IL 60611. E-mail address for E.L. Hsu: Email: erinkhsu@gmail.com.
authors.forename: Christian
authors.initials: C
authors.lastname: Park
authors.affiliation: Department of Orthopaedic Surgery, Northwestern University, 676 North Saint Claire Street, Suite #1350, Chicago, IL 60611. E-mail address for E.L. Hsu: Email: erinkhsu@gmail.com.
authors.forename: Sean
authors.initials: S
authors.lastname: Mitchell
authors.affiliation: Department of Orthopaedic Surgery, Northwestern University, 676 North Saint Claire Street, Suite #1350, Chicago, IL 60611. E-mail address for E.L. Hsu: Email: erinkhsu@gmail.com.
authors.forename: Amruta
authors.initials: A
authors.lastname: Ashtekar
authors.affiliation: Department of Orthopaedic Surgery, Northwestern University, 676 North Saint Claire Street, Suite #1350, Chicago, IL 60611. E-mail address for E.L. Hsu: Email: erinkhsu@gmail.com.
authors.forename: Anjan
authors.initials: A
authors.lastname: Ghosh
authors.affiliation: Department of Orthopaedic Surgery, Northwestern University, 676 North Saint Claire Street, Suite #1350, Chicago, IL 60611. E-mail address for E.L. Hsu: Email: erinkhsu@gmail.com.
authors.forename: Akshay
authors.initials: A
authors.lastname: Jain
authors.affiliation: Department of Orthopaedic Surgery, Northwestern University, 676 North Saint Claire Street, Suite #1350, Chicago, IL 60611. E-mail address for E.L. Hsu: Email: erinkhsu@gmail.com.
authors.forename: Stuart R
authors.initials: SR
authors.lastname: Stock
authors.affiliation: Department of Orthopaedic Surgery, Northwestern University, 676 North Saint Claire Street, Suite #1350, Chicago, IL 60611. E-mail address for E.L. Hsu: Email: erinkhsu@gmail.com.
authors.forename: Wellington K
authors.initials: WK
authors.lastname: Hsu
mesh_terms: D000818:Animals; D055396:Bone Morphogenetic Protein 2 / Q000187:drug effects* / Q000502:physiology*; D001861:Bone Regeneration / Q000187:drug effects; D004147:Dioxins / Q000009:adverse effects*; D005260:Female; D023421:Models, Animal; D051381:Rats; D020318:Rats, Long-Evans; D013123:Spinal Fusion
chemical_list: D055396:Bone Morphogenetic Protein 2; D004147:Dioxins