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Low-dose TNF augments fracture healing in normal and osteoporotic bone by up-regulating the innate immune response.

Chan JK, Glass GE, Ersek A, Freidin A, Williams GA, Gowers K, Espirito Santo AI, Jeffery R, Otto WR, Poulsom R, Feldmann M, Rankin SM, Horwood NJ, Nanchahal J - EMBO Mol Med (2015)

Bottom Line: Fragility, or osteoporotic, fractures represent a major medical problem as they are associated with permanent disability and premature death.Using a murine model of fragility fractures, we found that local rhTNF treatment improved fracture healing during the early phase of repair.If translated clinically, this promotion of fracture healing would reduce the morbidity and mortality associated with delayed patient mobilization.

View Article: PubMed Central - PubMed

Affiliation: Kennedy Institute of Rheumatology, University of Oxford, Oxford, UK.

No MeSH data available.


Related in: MedlinePlus

Role of TNF in fracture healing in vivoAddition of rhTNF at the fracture site on days 0 and 1 led to augmented healing, indicated by increased % callus mineralization, at day 28 after operation in a dose-dependent manner. Data are presented as mean ± SEM. Treatment with 1 ng TNF versus PBS control, ****P < 0.0001 by one-way ANOVA with Dunnett's multiple comparisons test.Addition of rhTNF at the fracture site must be given within the first 24 h to augment healing, indicated by % callus mineralization. Data are presented as mean ± SEM. 1 ng TNF versus PBS control treatment on days 0 and 1, ***P = 0.0009 by one-way ANOVA with Dunnett's multiple comparisons test.Treatment with systemic anti-TNF or local rmIL-10 led to impaired fracture repair at day 28, indicated by % callus mineralization. Data are presented as mean ± SEM. Treatment with PBS control versus anti-TNF, *P = 0.037, PBS control versus rmIL-10, *P = 0.037, by unpaired two-sided t-tests.Representative micro-CT images at the fracture site showing (from left to right): lateral view of tibia, cross-section, and cross and longitudinal sections with color overlay and 3D reconstruction. In the color overlays, the shade of blue corresponds to percentage mineralization: light blue denotes soft immature callus, whereas dark blue denotes hard mineralized callus. Scale bar, 2 mm.Representative ISH image (light field) showing TNF expression at the murine fracture site at 24 h after fracture. Scale bar, 250 μm. Red box indicates region of interest.High-power micrographs of region of interest from (E): at 24 h after fracture, mTNF expression (white signal on dark field, above) co-localized with polymorphonuclear cells found on the adjacent H&E section (below). Scale bar, 25 μm. Neutrophils were identified by their polymorphonuclear morphology as well as positive dark brown staining with anti-neutrophil elastase.High-power micrographs: at 7 days, TNF expression (white signal on dark field, above) co-localized with F4/80-positive cells (stained dark brown) extravasating from a blood vessel on the adjacent H&E section (below). Scale bar, 25 μm.
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fig01: Role of TNF in fracture healing in vivoAddition of rhTNF at the fracture site on days 0 and 1 led to augmented healing, indicated by increased % callus mineralization, at day 28 after operation in a dose-dependent manner. Data are presented as mean ± SEM. Treatment with 1 ng TNF versus PBS control, ****P < 0.0001 by one-way ANOVA with Dunnett's multiple comparisons test.Addition of rhTNF at the fracture site must be given within the first 24 h to augment healing, indicated by % callus mineralization. Data are presented as mean ± SEM. 1 ng TNF versus PBS control treatment on days 0 and 1, ***P = 0.0009 by one-way ANOVA with Dunnett's multiple comparisons test.Treatment with systemic anti-TNF or local rmIL-10 led to impaired fracture repair at day 28, indicated by % callus mineralization. Data are presented as mean ± SEM. Treatment with PBS control versus anti-TNF, *P = 0.037, PBS control versus rmIL-10, *P = 0.037, by unpaired two-sided t-tests.Representative micro-CT images at the fracture site showing (from left to right): lateral view of tibia, cross-section, and cross and longitudinal sections with color overlay and 3D reconstruction. In the color overlays, the shade of blue corresponds to percentage mineralization: light blue denotes soft immature callus, whereas dark blue denotes hard mineralized callus. Scale bar, 2 mm.Representative ISH image (light field) showing TNF expression at the murine fracture site at 24 h after fracture. Scale bar, 250 μm. Red box indicates region of interest.High-power micrographs of region of interest from (E): at 24 h after fracture, mTNF expression (white signal on dark field, above) co-localized with polymorphonuclear cells found on the adjacent H&E section (below). Scale bar, 25 μm. Neutrophils were identified by their polymorphonuclear morphology as well as positive dark brown staining with anti-neutrophil elastase.High-power micrographs: at 7 days, TNF expression (white signal on dark field, above) co-localized with F4/80-positive cells (stained dark brown) extravasating from a blood vessel on the adjacent H&E section (below). Scale bar, 25 μm.

Mentions: We previously reported that 1 ng rhTNF injected at the fracture site on days 0 and 1 improved fracture repair (Glass et al, 2011). To identify the optimal dose in vivo, we injected increasing amounts of rhTNF at the fracture site on days 0 and 1 (i.e. immediately and at 24 h) following osteotomy and found that rhTNF was effective in augmenting fracture healing, as indicated by increased relative % callus mineralization, by day 28 after injury only at 1 ng (Fig1A). As shown by the micro-CT reconstructions, treatment with 1 ng of rhTNF led to improved healing and earlier remodeling as evidenced by a more compact and mineralized fracture callus (Fig1D).


Low-dose TNF augments fracture healing in normal and osteoporotic bone by up-regulating the innate immune response.

Chan JK, Glass GE, Ersek A, Freidin A, Williams GA, Gowers K, Espirito Santo AI, Jeffery R, Otto WR, Poulsom R, Feldmann M, Rankin SM, Horwood NJ, Nanchahal J - EMBO Mol Med (2015)

Role of TNF in fracture healing in vivoAddition of rhTNF at the fracture site on days 0 and 1 led to augmented healing, indicated by increased % callus mineralization, at day 28 after operation in a dose-dependent manner. Data are presented as mean ± SEM. Treatment with 1 ng TNF versus PBS control, ****P < 0.0001 by one-way ANOVA with Dunnett's multiple comparisons test.Addition of rhTNF at the fracture site must be given within the first 24 h to augment healing, indicated by % callus mineralization. Data are presented as mean ± SEM. 1 ng TNF versus PBS control treatment on days 0 and 1, ***P = 0.0009 by one-way ANOVA with Dunnett's multiple comparisons test.Treatment with systemic anti-TNF or local rmIL-10 led to impaired fracture repair at day 28, indicated by % callus mineralization. Data are presented as mean ± SEM. Treatment with PBS control versus anti-TNF, *P = 0.037, PBS control versus rmIL-10, *P = 0.037, by unpaired two-sided t-tests.Representative micro-CT images at the fracture site showing (from left to right): lateral view of tibia, cross-section, and cross and longitudinal sections with color overlay and 3D reconstruction. In the color overlays, the shade of blue corresponds to percentage mineralization: light blue denotes soft immature callus, whereas dark blue denotes hard mineralized callus. Scale bar, 2 mm.Representative ISH image (light field) showing TNF expression at the murine fracture site at 24 h after fracture. Scale bar, 250 μm. Red box indicates region of interest.High-power micrographs of region of interest from (E): at 24 h after fracture, mTNF expression (white signal on dark field, above) co-localized with polymorphonuclear cells found on the adjacent H&E section (below). Scale bar, 25 μm. Neutrophils were identified by their polymorphonuclear morphology as well as positive dark brown staining with anti-neutrophil elastase.High-power micrographs: at 7 days, TNF expression (white signal on dark field, above) co-localized with F4/80-positive cells (stained dark brown) extravasating from a blood vessel on the adjacent H&E section (below). Scale bar, 25 μm.
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fig01: Role of TNF in fracture healing in vivoAddition of rhTNF at the fracture site on days 0 and 1 led to augmented healing, indicated by increased % callus mineralization, at day 28 after operation in a dose-dependent manner. Data are presented as mean ± SEM. Treatment with 1 ng TNF versus PBS control, ****P < 0.0001 by one-way ANOVA with Dunnett's multiple comparisons test.Addition of rhTNF at the fracture site must be given within the first 24 h to augment healing, indicated by % callus mineralization. Data are presented as mean ± SEM. 1 ng TNF versus PBS control treatment on days 0 and 1, ***P = 0.0009 by one-way ANOVA with Dunnett's multiple comparisons test.Treatment with systemic anti-TNF or local rmIL-10 led to impaired fracture repair at day 28, indicated by % callus mineralization. Data are presented as mean ± SEM. Treatment with PBS control versus anti-TNF, *P = 0.037, PBS control versus rmIL-10, *P = 0.037, by unpaired two-sided t-tests.Representative micro-CT images at the fracture site showing (from left to right): lateral view of tibia, cross-section, and cross and longitudinal sections with color overlay and 3D reconstruction. In the color overlays, the shade of blue corresponds to percentage mineralization: light blue denotes soft immature callus, whereas dark blue denotes hard mineralized callus. Scale bar, 2 mm.Representative ISH image (light field) showing TNF expression at the murine fracture site at 24 h after fracture. Scale bar, 250 μm. Red box indicates region of interest.High-power micrographs of region of interest from (E): at 24 h after fracture, mTNF expression (white signal on dark field, above) co-localized with polymorphonuclear cells found on the adjacent H&E section (below). Scale bar, 25 μm. Neutrophils were identified by their polymorphonuclear morphology as well as positive dark brown staining with anti-neutrophil elastase.High-power micrographs: at 7 days, TNF expression (white signal on dark field, above) co-localized with F4/80-positive cells (stained dark brown) extravasating from a blood vessel on the adjacent H&E section (below). Scale bar, 25 μm.
Mentions: We previously reported that 1 ng rhTNF injected at the fracture site on days 0 and 1 improved fracture repair (Glass et al, 2011). To identify the optimal dose in vivo, we injected increasing amounts of rhTNF at the fracture site on days 0 and 1 (i.e. immediately and at 24 h) following osteotomy and found that rhTNF was effective in augmenting fracture healing, as indicated by increased relative % callus mineralization, by day 28 after injury only at 1 ng (Fig1A). As shown by the micro-CT reconstructions, treatment with 1 ng of rhTNF led to improved healing and earlier remodeling as evidenced by a more compact and mineralized fracture callus (Fig1D).

Bottom Line: Fragility, or osteoporotic, fractures represent a major medical problem as they are associated with permanent disability and premature death.Using a murine model of fragility fractures, we found that local rhTNF treatment improved fracture healing during the early phase of repair.If translated clinically, this promotion of fracture healing would reduce the morbidity and mortality associated with delayed patient mobilization.

View Article: PubMed Central - PubMed

Affiliation: Kennedy Institute of Rheumatology, University of Oxford, Oxford, UK.

No MeSH data available.


Related in: MedlinePlus