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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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Related in: MedlinePlus

A schematic model for osteonecrosis development by osteomyelitis in the presence of administration of anti-resorptive agents.(upper) In the normal state, osteoclast progenitors differentiate into osteoclasts by RANKL exposure. (middle) Treatment with anti-resorptive agents converts osteoclast progenitors to inflammatory cytokine-expressing macrophages. (lower) Bacterial infection further promotes inflammatory cytokine expression, which in turn promotes osteocyte apoptosis, leading to osteonecrosis.
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f6: A schematic model for osteonecrosis development by osteomyelitis in the presence of administration of anti-resorptive agents.(upper) In the normal state, osteoclast progenitors differentiate into osteoclasts by RANKL exposure. (middle) Treatment with anti-resorptive agents converts osteoclast progenitors to inflammatory cytokine-expressing macrophages. (lower) Bacterial infection further promotes inflammatory cytokine expression, which in turn promotes osteocyte apoptosis, leading to osteonecrosis.

Mentions: Treatment with anti-resorptive agents may promote ARONJ, and there is debate over whether these types of drugs should be withdrawn to prevent ARONJ prior to invasive oral treatment, despite fracture risk. In this study we show that alendronate treatment significantly exacerbates infectious osteomyelitis-induced osteonecrosis development. We found that osteonecrosis development was not blocked by teriparatide, which promotes bone turnover, suggesting that low bone turnover does not underlie osteonecrosis. Instead, we show that osteonecrosis development in infectious osteomyelitis mice administered alendronate was significantly blocked by gene targeting of either TNFα-, IL-6 or IL-1α/β, or by treatment with a TNFα inhibitor. Moreover we observed that osteoclast progenitors were converted to inflammatory cytokine-expressing cells following alendronate treatment, even in the presence of RANKL. Thus, pro-inflammatory cytokines may represent therapeutic targets to prevent osteonecrosis induced by infectious osteomyelitis in patients treated with anti-resorptive therapy (Fig. 6).


Elevation of pro-inflammatory cytokine levels following anti-resorptive drug treatment is required for osteonecrosis development in infectious osteomyelitis
A schematic model for osteonecrosis development by osteomyelitis in the presence of administration of anti-resorptive agents.(upper) In the normal state, osteoclast progenitors differentiate into osteoclasts by RANKL exposure. (middle) Treatment with anti-resorptive agents converts osteoclast progenitors to inflammatory cytokine-expressing macrophages. (lower) Bacterial infection further promotes inflammatory cytokine expression, which in turn promotes osteocyte apoptosis, leading to osteonecrosis.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f6: A schematic model for osteonecrosis development by osteomyelitis in the presence of administration of anti-resorptive agents.(upper) In the normal state, osteoclast progenitors differentiate into osteoclasts by RANKL exposure. (middle) Treatment with anti-resorptive agents converts osteoclast progenitors to inflammatory cytokine-expressing macrophages. (lower) Bacterial infection further promotes inflammatory cytokine expression, which in turn promotes osteocyte apoptosis, leading to osteonecrosis.
Mentions: Treatment with anti-resorptive agents may promote ARONJ, and there is debate over whether these types of drugs should be withdrawn to prevent ARONJ prior to invasive oral treatment, despite fracture risk. In this study we show that alendronate treatment significantly exacerbates infectious osteomyelitis-induced osteonecrosis development. We found that osteonecrosis development was not blocked by teriparatide, which promotes bone turnover, suggesting that low bone turnover does not underlie osteonecrosis. Instead, we show that osteonecrosis development in infectious osteomyelitis mice administered alendronate was significantly blocked by gene targeting of either TNFα-, IL-6 or IL-1α/β, or by treatment with a TNFα inhibitor. Moreover we observed that osteoclast progenitors were converted to inflammatory cytokine-expressing cells following alendronate treatment, even in the presence of RANKL. Thus, pro-inflammatory cytokines may represent therapeutic targets to prevent osteonecrosis induced by infectious osteomyelitis in patients treated with anti-resorptive therapy (Fig. 6).

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.

No MeSH data available.


Related in: MedlinePlus