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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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Alendronate treatment or Streptococcus aureus infection increases TNFα expression and inhibits osteoclastogenesis.Osteoclast progenitors were isolated from wild-type mice and cultured in the presence or absence of M-CSF (M) and RANKL (R) with or without 1 or 10 μg/ml alendronate (Ale) (a,b) or Streptococcus aureus lysate (SA) (c,d). Osteoclast formation was evaluated by TRAP staining (a,c), or realtime PCR to analyze expression of Cathepsin K (Ctsk) and NFATc1 (b,d). TNFα expression was also analyzed by realtime PCR(b,d). Scale bar = 100 μm. Data represent mean Ctsk, NFATc1 or TNFα expression relative to β-actin ± SD (n = 3). *P < 0.05; **P < 0.01; ***P < 0.001; NS, not significant. Representative data of at least two independent experiments are shown.
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f3: Alendronate treatment or Streptococcus aureus infection increases TNFα expression and inhibits osteoclastogenesis.Osteoclast progenitors were isolated from wild-type mice and cultured in the presence or absence of M-CSF (M) and RANKL (R) with or without 1 or 10 μg/ml alendronate (Ale) (a,b) or Streptococcus aureus lysate (SA) (c,d). Osteoclast formation was evaluated by TRAP staining (a,c), or realtime PCR to analyze expression of Cathepsin K (Ctsk) and NFATc1 (b,d). TNFα expression was also analyzed by realtime PCR(b,d). Scale bar = 100 μm. Data represent mean Ctsk, NFATc1 or TNFα expression relative to β-actin ± SD (n = 3). *P < 0.05; **P < 0.01; ***P < 0.001; NS, not significant. Representative data of at least two independent experiments are shown.

Mentions: To determine potential effects of anti-resorptive agents on osteoclast progenitors, we isolated M-CSF-dependent bone marrow macrophages (BMMs) as osteoclast progenitors and then cultured with M-CSF (M) and RANKL (R) in the presence or absence of various alendronate concentrations (Fig. 3). Interestingly, TNFα expression in BMMs was significantly downregulated by RANKL along with osteoclast differentiation, as indicated by induction of Cathepsin K (Ctsk) and nuclear factor of activated T cells 1 (NFAtc1), but was significantly stimulated by alendronate in a dose-dependent manner inversely correlated with inhibition of osteoclastogenesis (Fig. 3a and b).


Elevation of pro-inflammatory cytokine levels following anti-resorptive drug treatment is required for osteonecrosis development in infectious osteomyelitis
Alendronate treatment or Streptococcus aureus infection increases TNFα expression and inhibits osteoclastogenesis.Osteoclast progenitors were isolated from wild-type mice and cultured in the presence or absence of M-CSF (M) and RANKL (R) with or without 1 or 10 μg/ml alendronate (Ale) (a,b) or Streptococcus aureus lysate (SA) (c,d). Osteoclast formation was evaluated by TRAP staining (a,c), or realtime PCR to analyze expression of Cathepsin K (Ctsk) and NFATc1 (b,d). TNFα expression was also analyzed by realtime PCR(b,d). Scale bar = 100 μm. Data represent mean Ctsk, NFATc1 or TNFα expression relative to β-actin ± SD (n = 3). *P < 0.05; **P < 0.01; ***P < 0.001; NS, not significant. Representative data of at least two independent experiments are shown.
© Copyright Policy - open-access
Related In: Results  -  Collection

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f3: Alendronate treatment or Streptococcus aureus infection increases TNFα expression and inhibits osteoclastogenesis.Osteoclast progenitors were isolated from wild-type mice and cultured in the presence or absence of M-CSF (M) and RANKL (R) with or without 1 or 10 μg/ml alendronate (Ale) (a,b) or Streptococcus aureus lysate (SA) (c,d). Osteoclast formation was evaluated by TRAP staining (a,c), or realtime PCR to analyze expression of Cathepsin K (Ctsk) and NFATc1 (b,d). TNFα expression was also analyzed by realtime PCR(b,d). Scale bar = 100 μm. Data represent mean Ctsk, NFATc1 or TNFα expression relative to β-actin ± SD (n = 3). *P < 0.05; **P < 0.01; ***P < 0.001; NS, not significant. Representative data of at least two independent experiments are shown.
Mentions: To determine potential effects of anti-resorptive agents on osteoclast progenitors, we isolated M-CSF-dependent bone marrow macrophages (BMMs) as osteoclast progenitors and then cultured with M-CSF (M) and RANKL (R) in the presence or absence of various alendronate concentrations (Fig. 3). Interestingly, TNFα expression in BMMs was significantly downregulated by RANKL along with osteoclast differentiation, as indicated by induction of Cathepsin K (Ctsk) and nuclear factor of activated T cells 1 (NFAtc1), but was significantly stimulated by alendronate in a dose-dependent manner inversely correlated with inhibition of osteoclastogenesis (Fig. 3a and b).

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