Dioxin exposure impairs BMP-2-mediated spinal fusion in a rat arthrodesis model

Erin L Hsu, Kevin Sonn, Abhishek Kannan, Sharath Bellary, Chawon Yun, Sohaib Hashmi, John Nelson, Marco Mendoza, Michael Nickoli, Jason Ghodasra, Christian Park, Sean Mitchell, Amruta Ashtekar, Anjan Ghosh, Akshay Jain, Stuart R Stock, Wellington K Hsu

Research output: Contribution to journalArticle

8 Citations (Scopus)

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. 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.

Original languageEnglish (US)
Pages (from-to)1003-1010
Number of pages8
JournalJournal of Bone and Joint Surgery - American Volume
Volume97
Issue number12
DOIs
StatePublished - Jan 1 2015

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Bone Morphogenetic Protein 2
Spinal Fusion
Dioxins
Arthrodesis
Aryl Hydrocarbon Receptors
Smoke
Tobacco Products
Bone and Bones
Long Evans Rats
Pseudarthrosis
Bone Regeneration
Osteoblasts
Osteogenesis
Radiography

ASJC Scopus subject areas

  • Surgery
  • Orthopedics and Sports Medicine

Cite this

Hsu, Erin L ; Sonn, Kevin ; Kannan, Abhishek ; Bellary, Sharath ; Yun, Chawon ; Hashmi, Sohaib ; Nelson, John ; Mendoza, Marco ; Nickoli, Michael ; Ghodasra, Jason ; Park, Christian ; Mitchell, Sean ; Ashtekar, Amruta ; Ghosh, Anjan ; Jain, Akshay ; Stock, Stuart R ; Hsu, Wellington K. / Dioxin exposure impairs BMP-2-mediated spinal fusion in a rat arthrodesis model. In: Journal of Bone and Joint Surgery - American Volume. 2015 ; Vol. 97, No. 12. pp. 1003-1010.
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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. 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.",
author = "Hsu, {Erin L} and Kevin Sonn and Abhishek Kannan and Sharath Bellary and Chawon Yun and Sohaib Hashmi and John Nelson and Marco Mendoza and Michael Nickoli and Jason Ghodasra and Christian Park and Sean Mitchell and Amruta Ashtekar and Anjan Ghosh and Akshay Jain and Stock, {Stuart R} and Hsu, {Wellington K}",
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Hsu, EL, Sonn, K, Kannan, A, Bellary, S, Yun, C, Hashmi, S, Nelson, J, Mendoza, M, Nickoli, M, Ghodasra, J, Park, C, Mitchell, S, Ashtekar, A, Ghosh, A, Jain, A, Stock, SR & Hsu, WK 2015, 'Dioxin exposure impairs BMP-2-mediated spinal fusion in a rat arthrodesis model', Journal of Bone and Joint Surgery - American Volume, vol. 97, no. 12, pp. 1003-1010. https://doi.org/10.2106/JBJS.N.01311

Dioxin exposure impairs BMP-2-mediated spinal fusion in a rat arthrodesis model. / Hsu, Erin L; Sonn, Kevin; Kannan, Abhishek; Bellary, Sharath; Yun, Chawon; Hashmi, Sohaib; Nelson, John; Mendoza, Marco; Nickoli, Michael; Ghodasra, Jason; Park, Christian; Mitchell, Sean; Ashtekar, Amruta; Ghosh, Anjan; Jain, Akshay; Stock, Stuart R; Hsu, Wellington K.

In: Journal of Bone and Joint Surgery - American Volume, Vol. 97, No. 12, 01.01.2015, p. 1003-1010.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Dioxin exposure impairs BMP-2-mediated spinal fusion in a rat arthrodesis model

AU - Hsu, Erin L

AU - Sonn, Kevin

AU - Kannan, Abhishek

AU - Bellary, Sharath

AU - Yun, Chawon

AU - Hashmi, Sohaib

AU - Nelson, John

AU - Mendoza, Marco

AU - Nickoli, Michael

AU - Ghodasra, Jason

AU - Park, Christian

AU - Mitchell, Sean

AU - Ashtekar, Amruta

AU - Ghosh, Anjan

AU - Jain, Akshay

AU - Stock, Stuart R

AU - Hsu, Wellington K

PY - 2015/1/1

Y1 - 2015/1/1

N2 - 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.

AB - 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.

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