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

Hsu, Erin L.; Sonn, Kevin A.; Kannan, Abhishek; Bellary, Sharath; Yun, Chawon; Hashmi, Salman; Nelson, John T.; Mendoza, Marco; Nickoli, Michael S.; Ghodasra, Jason H.; Park, Christian; Mitchell, Sean M.; Ashtekar, Amruta; Ghosh, Anjan; Jain, Anubha; Stock, Stuart R.; Hsu, Wellington K.

doi:10.2106/jbjs.n.01311

Cited by 22 publications

(23 citation statements)

References 51 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Dioxin, a minor hydrocarbon constituent of cigarette smoke but potent activator of the AhR, is thought to exert its effects almost exclusively through the receptor [ 20 , 21 ]. Because of its extremely high affinity for the receptor, dioxin is frequently used as a prototypical ligand to investigate the effects of the AhR pathway involvement in biological processes.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Aryl Hydrocarbon Receptor Antagonists Mitigate the Effects of Dioxin on Critical Cellular Functions in Differentiating Human Osteoblast-Like Cells

Yun

Katchko

Schallmo

et al. 2018

IJMS

Self Cite

View full text Add to dashboard Cite

The inhibition of bone healing in humans is a well-established effect associated with cigarette smoking, but the underlying mechanisms are still unclear. Recent work using animal cell lines have implicated the aryl hydrocarbon receptor (AhR) as a mediator of the anti-osteogenic effects of cigarette smoke, but the complexity of cigarette smoke mixtures makes understanding the mechanisms of action a major challenge. 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD, dioxin) is a high-affinity AhR ligand that is frequently used to investigate biological processes impacted by AhR activation. Since there are dozens of AhR ligands present in cigarette smoke, we utilized dioxin as a prototype ligand to activate the receptor and explore its effects on pro-osteogenic biomarkers and other factors critical to osteogenesis using a human osteoblast-like cell line. We also explored the capacity for AhR antagonists to protect against dioxin action in this context. We found dioxin to inhibit osteogenic differentiation, whereas co-treatment with various AhR antagonists protected against dioxin action. Dioxin also negatively impacted cell adhesion with a corresponding reduction in the expression of integrin and cadherin proteins, which are known to be involved in this process. Similarly, the dioxin-mediated inhibition of cell migration correlated with reduced expression of the chemokine receptor CXCR4 and its ligand, CXCL12, and co-treatment with antagonists restored migratory capacity. Our results suggest that AhR activation may play a role in the bone regenerative response in humans exposed to AhR activators, such as those present in cigarette smoke. Given the similarity of our results using a human cell line to previous work done in murine cells, animal models may yield data relevant to the human setting. In addition, the AhR may represent a potential therapeutic target for orthopedic patients who smoke cigarettes, or those who are exposed to secondhand smoke or other environmental sources of aryl hydrocarbons.

show abstract

Section: Discussionmentioning

confidence: 99%

“…Previously, we found that chronic exposure to dioxin inhibited bone morphogenetic protein 2 (BMP-2) mediated bone regeneration and posterolateral (L4–L5) spine fusion in the rat [ 21 ]. This study was the first to suggest a link between AhR activation and the reduced healing rates seen in smokers after spinal arthrodesis.…”

Section: Introductionmentioning

confidence: 99%

Aryl Hydrocarbon Receptor Antagonists Mitigate the Effects of Dioxin on Critical Cellular Functions in Differentiating Human Osteoblast-Like Cells

Yun

Katchko

Schallmo

et al. 2018

IJMS

Self Cite

View full text Add to dashboard Cite

show abstract

“…The Ahr plays an important role in xenobiotic metabolism, and previous studies have shown that pathway hyper-activation can have deleterious effects on bone biology (Singh et al, 2000, Jamsa et al, 2001, Naruse et al, 2002, Ryan et al, 2007). A proportionately minor constituent of CS, dioxin is a prototypical ligand frequently used to study Ahr involvement in biological activities, due to its extremely high affinity for the receptor and the widely-accepted belief that dioxin acts primarily through this mechanism (Hsu et al, 2015). Dioxin has previously been shown to inhibit some markers of osteoblastic differentiation in established murine cell lines (Singh et al, 2000, Ryan et al, 2007, Carpi et al, 2009).…”

Section: Discussionmentioning

confidence: 99%

“…Our recent work showed that dioxin exposure inhibits spine fusion in the rat (Hsu et al, 2015). With the present study, we sought to elucidate the underlying mechanisms of dioxin-mediated effects on bone regeneration using rat primary BMSC, and to explore the capacity of Ahr antagonists as potential agents to mitigate these effects.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Mechanistic insight into the effects of Aryl Hydrocarbon Receptor activation on osteogenic differentiation

et al. 2017

Self Cite

View full text Add to dashboard Cite

While inhibition of bone healing and increased rates of pseudarthrosis are known adverse outcomes associated with cigarette smoking, the underlying mechanisms by which this occurs are not well understood. Recent work has implicated the Aryl Hydrocarbon Receptor (Ahr) as one mediator of the anti-osteogenic effects of cigarette smoke (CS), which contains numerous toxic ligands for the Ahr. 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD, dioxin) is a high-affinity Ahr ligand frequently used to evaluate Ahr pathway activation. The purpose of this study was to elucidate the downstream mechanisms of dioxin action on bone regeneration and investigate Ahr antagonism as a potential therapeutic approach to mitigate the effects of dioxin on bone. Markers of osteogenic activity and differentiation were assessed in primary rat bone marrow stromal cells (BMSC) after exposure to dioxin, Ahr antagonists, or antagonist + dioxin. Four Ahr antagonists were evaluated: α-Naphthoflavone (ANF), resveratrol (Res), 3,3′-Diindolylmethane (DIM), and luteolin (Lut). Our results demonstrate that dioxin inhibited ALP activity, migratory capacity, and matrix mineralization, whereas co-treatment with each of the antagonists mitigated these effects. Dioxin also inhibited BMSC chemotaxis, while co-treatment with several antagonists partially rescued this effect. RNA and protein expression studies found that dioxin down-regulated numerous pro-osteogenic targets, whereas co-treatment with Ahr antagonists prevented these dioxin-induced expression changes to varying degrees. Our results suggest that dioxin adversely affects bone regeneration in a myriad of ways, many of which appear to be mediated by the Ahr. Our work suggests that the Ahr should be investigated as a therapeutic target to combat the adverse effects of CS on bone healing.

show abstract

Bone and bone marrow disruption by endocrine‐active substances

Agas

Lacava

Sabbieti

2018

Journal Cellular Physiology

View full text Add to dashboard Cite

Bone is a multifaceted dynamic tissue, involved in mobility, mineral metabolism, and mesenchymal or stromal and hematopoietic progenitor or stem cells breading. Recently, an endocrine role has been attributed to bone due to its ability to produce at least two hormones (osteocalcin and fibroblast growth factor 23) and to participate directly or indirectly in leptin, insulin, estrogens, and serotonin signaling; regulation; and action. Also, bearing in mind the enormous amounts of substances secreted by the different bone marrow cell types, it becomes understandable the contribution of bone tissue to systemic homeostasis. Besides, bone is a well-known estrogen-responsive tissue, reacting to environmental influences. Thus, it has been coined as a critical target of environmental xenoestrogens, known as endocrine-disrupting chemicals (EDCs). The exposure to EDCs results to disruption or imbalance of the systemic hormonal regulation of the skeleton including bone modeling and remodeling, local hormones, and cytokine or chemokine release. The present report highlights the harmful EDCs effects on bone tissue and provides up-to-date information of xenoestrogen action on proliferation, maturation, and homing of bone marrow inhabitants.

show abstract

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

Cited by 22 publications

References 51 publications

Aryl Hydrocarbon Receptor Antagonists Mitigate the Effects of Dioxin on Critical Cellular Functions in Differentiating Human Osteoblast-Like Cells

Aryl Hydrocarbon Receptor Antagonists Mitigate the Effects of Dioxin on Critical Cellular Functions in Differentiating Human Osteoblast-Like Cells

Mechanistic insight into the effects of Aryl Hydrocarbon Receptor activation on osteogenic differentiation

Bone and bone marrow disruption by endocrine‐active substances

Contact Info

Product

Resources

About