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Elevation of pro-inflammatory cytokine levels following anti-resorptive drug treatment is required for osteonecrosis development in infectious osteomyelitis

View Article: PubMed Central - PubMed

ABSTRACT

Various conditions, including bacterial infection, can promote osteonecrosis. For example, following invasive dental therapy with anti-bone resorptive agents, some patients develop osteonecrosis in the jaw; however, pathological mechanisms underlying these outcomes remain unknown. Here, we show that administration of anti-resorptive agents such as the bisphosphonate alendronate accelerates osteonecrosis promoted by infectious osteomyelitis. Potent suppression of bone turnover by these types of agents is considered critical for osteonecrosis development; however, using mouse models we found that acceleration of bone turnover by teriparatide injection did not prevent osteonecrosis but rather converted osteoclast progenitors to macrophages expressing inflammatory cytokines, which were required for osteonecrosis development. In fact, we demonstrate that TNFα-, IL-1α/β- or IL-6-deficient mice as well as wild-type mice administered a TNFα-inhibitor were significantly resistant to development of osteonecrosis accompanying infectious myelitis, even under bisphosphonate treatment. Our data provide new insight into mechanisms underlying osteonecrosis and suggest new ways to prevent it.

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Blocking TNFα significantly antagonizes osteonecrosis development.Wild-type mice were administered alendronate for two weeks. Then, infectious osteomyelitis was established by Streptococcus aureus infection of left femurs. The TNFα inhibitor etanercept (eta) or ISO type control (ISO) was subcutaneously injected one week before surgery and then subsequently twice a week. Seven days after surgery, cortical bone sections of left femurs were prepared and stained with HE (a), and the proportion of empty versus whole lacunae was calculated (b). Scale bars = 100 (upper) or 10 μm (lower panels). Data shows the mean percentage (%) of empty versus whole lacunae ± SD (n = 4, *P < 0.05). Representative data of at least two independent experiments are shown.
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f5: Blocking TNFα significantly antagonizes osteonecrosis development.Wild-type mice were administered alendronate for two weeks. Then, infectious osteomyelitis was established by Streptococcus aureus infection of left femurs. The TNFα inhibitor etanercept (eta) or ISO type control (ISO) was subcutaneously injected one week before surgery and then subsequently twice a week. Seven days after surgery, cortical bone sections of left femurs were prepared and stained with HE (a), and the proportion of empty versus whole lacunae was calculated (b). Scale bars = 100 (upper) or 10 μm (lower panels). Data shows the mean percentage (%) of empty versus whole lacunae ± SD (n = 4, *P < 0.05). Representative data of at least two independent experiments are shown.

Mentions: To develop potential treatments against osteonecrosis brought on by infectious osteomyelitis and treatment with anti-resorptive agents, we administered etanercept, a TNFα-inhibitor, subcutaneously one week before surgery and subsequently twice a week to alendronate-treated model mice infected in the left femur with SA (Fig. 5). Etanercept treatment significantly blocked osteonecrosis development in the infected femur (Fig. 5).


Elevation of pro-inflammatory cytokine levels following anti-resorptive drug treatment is required for osteonecrosis development in infectious osteomyelitis
Blocking TNFα significantly antagonizes osteonecrosis development.Wild-type mice were administered alendronate for two weeks. Then, infectious osteomyelitis was established by Streptococcus aureus infection of left femurs. The TNFα inhibitor etanercept (eta) or ISO type control (ISO) was subcutaneously injected one week before surgery and then subsequently twice a week. Seven days after surgery, cortical bone sections of left femurs were prepared and stained with HE (a), and the proportion of empty versus whole lacunae was calculated (b). Scale bars = 100 (upper) or 10 μm (lower panels). Data shows the mean percentage (%) of empty versus whole lacunae ± SD (n = 4, *P < 0.05). Representative data of at least two independent experiments are shown.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC5384218&req=5

f5: Blocking TNFα significantly antagonizes osteonecrosis development.Wild-type mice were administered alendronate for two weeks. Then, infectious osteomyelitis was established by Streptococcus aureus infection of left femurs. The TNFα inhibitor etanercept (eta) or ISO type control (ISO) was subcutaneously injected one week before surgery and then subsequently twice a week. Seven days after surgery, cortical bone sections of left femurs were prepared and stained with HE (a), and the proportion of empty versus whole lacunae was calculated (b). Scale bars = 100 (upper) or 10 μm (lower panels). Data shows the mean percentage (%) of empty versus whole lacunae ± SD (n = 4, *P < 0.05). Representative data of at least two independent experiments are shown.
Mentions: To develop potential treatments against osteonecrosis brought on by infectious osteomyelitis and treatment with anti-resorptive agents, we administered etanercept, a TNFα-inhibitor, subcutaneously one week before surgery and subsequently twice a week to alendronate-treated model mice infected in the left femur with SA (Fig. 5). Etanercept treatment significantly blocked osteonecrosis development in the infected femur (Fig. 5).

View Article: PubMed Central - PubMed

ABSTRACT

Various conditions, including bacterial infection, can promote osteonecrosis. For example, following invasive dental therapy with anti-bone resorptive agents, some patients develop osteonecrosis in the jaw; however, pathological mechanisms underlying these outcomes remain unknown. Here, we show that administration of anti-resorptive agents such as the bisphosphonate alendronate accelerates osteonecrosis promoted by infectious osteomyelitis. Potent suppression of bone turnover by these types of agents is considered critical for osteonecrosis development; however, using mouse models we found that acceleration of bone turnover by teriparatide injection did not prevent osteonecrosis but rather converted osteoclast progenitors to macrophages expressing inflammatory cytokines, which were required for osteonecrosis development. In fact, we demonstrate that TNF&alpha;-, IL-1&alpha;/&beta;- or IL-6-deficient mice as well as wild-type mice administered a TNF&alpha;-inhibitor were significantly resistant to development of osteonecrosis accompanying infectious myelitis, even under bisphosphonate treatment. Our data provide new insight into mechanisms underlying osteonecrosis and suggest new ways to prevent it.

No MeSH data available.


Related in: MedlinePlus