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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

Effects of inhibiting inflammatory cell recruitment on fracture healingTreatment with CCR2 antagonist, INCB3344, led to impaired fracture healing compared to vehicle control as shown by the reduced % callus mineralization at day 28 after operation. Data are presented as mean ± SEM. *P = 0.011 unpaired two-sided t-test. Representative micro-CT images are shown. Scale bar, 2 mm.
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fig04: Effects of inhibiting inflammatory cell recruitment on fracture healingTreatment with CCR2 antagonist, INCB3344, led to impaired fracture healing compared to vehicle control as shown by the reduced % callus mineralization at day 28 after operation. Data are presented as mean ± SEM. *P = 0.011 unpaired two-sided t-test. Representative micro-CT images are shown. Scale bar, 2 mm.

Mentions: Although CCL2 was originally named “monocyte chemoattractant protein-1” (MCP-1), it has also been shown to be important in the recruitment of neutrophils (Matsukawa et al, 1999; Speyer et al, 2004) as well as of monocytes and macrophages (Shi & Pamer, 2011), including at the fracture site (Xing et al, 2010). CCL2 is produced by a number of cell types including neutrophils (Burn et al, 1994; Yoshimura & Takahashi, 2007; Pliyev, 2008; Pelletier et al, 2010) and monocytes (Yoshimura et al, 1989), as well as endothelial cells (Hu et al, 2009), fibroblasts, vascular smooth muscle cells (Xing et al, 2007), and bone marrow cells (Cushing et al, 1990; Moehle et al, 2011). It was detected within the first 24 h following trauma in an in vitro fracture hematoma model (Hoff et al, 2013). Despite reports that mRNA for CCL2 can been detected in neutrophils (Burn et al, 1994; Yamashiro et al, 2000), it is unknown whether human or murine neutrophils express the protein. We found that addition of rhTNF to enriched bone marrow-derived murine neutrophils exposed to fracture supernatant in vitro led to increased levels of CCL2 by ELISA (Fig3C). Notably, we were also able to directly visualize murine neutrophils derived from bone marrow readily expressing CCL2 protein by immunocytochemistry when they were exposed to fracture supernatant and rhTNF but not rhTNF alone (Supplementary Fig S1F). Our findings add to a previous report which demonstrated that TNF upregulated CCL2 mRNA by human neutrophils in vitro when co-stimulated with TLR ligands (Yamashiro et al, 2000). Our finding that both neutrophil depletion and CCR2 antagonism lead to impaired fracture healing supports the crucial role of neutrophil-derived CCL2 in fracture repair (Figs2D, E and 4).


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)

Effects of inhibiting inflammatory cell recruitment on fracture healingTreatment with CCR2 antagonist, INCB3344, led to impaired fracture healing compared to vehicle control as shown by the reduced % callus mineralization at day 28 after operation. Data are presented as mean ± SEM. *P = 0.011 unpaired two-sided t-test. Representative micro-CT images are shown. Scale bar, 2 mm.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4492816&req=5

fig04: Effects of inhibiting inflammatory cell recruitment on fracture healingTreatment with CCR2 antagonist, INCB3344, led to impaired fracture healing compared to vehicle control as shown by the reduced % callus mineralization at day 28 after operation. Data are presented as mean ± SEM. *P = 0.011 unpaired two-sided t-test. Representative micro-CT images are shown. Scale bar, 2 mm.
Mentions: Although CCL2 was originally named “monocyte chemoattractant protein-1” (MCP-1), it has also been shown to be important in the recruitment of neutrophils (Matsukawa et al, 1999; Speyer et al, 2004) as well as of monocytes and macrophages (Shi & Pamer, 2011), including at the fracture site (Xing et al, 2010). CCL2 is produced by a number of cell types including neutrophils (Burn et al, 1994; Yoshimura & Takahashi, 2007; Pliyev, 2008; Pelletier et al, 2010) and monocytes (Yoshimura et al, 1989), as well as endothelial cells (Hu et al, 2009), fibroblasts, vascular smooth muscle cells (Xing et al, 2007), and bone marrow cells (Cushing et al, 1990; Moehle et al, 2011). It was detected within the first 24 h following trauma in an in vitro fracture hematoma model (Hoff et al, 2013). Despite reports that mRNA for CCL2 can been detected in neutrophils (Burn et al, 1994; Yamashiro et al, 2000), it is unknown whether human or murine neutrophils express the protein. We found that addition of rhTNF to enriched bone marrow-derived murine neutrophils exposed to fracture supernatant in vitro led to increased levels of CCL2 by ELISA (Fig3C). Notably, we were also able to directly visualize murine neutrophils derived from bone marrow readily expressing CCL2 protein by immunocytochemistry when they were exposed to fracture supernatant and rhTNF but not rhTNF alone (Supplementary Fig S1F). Our findings add to a previous report which demonstrated that TNF upregulated CCL2 mRNA by human neutrophils in vitro when co-stimulated with TLR ligands (Yamashiro et al, 2000). Our finding that both neutrophil depletion and CCR2 antagonism lead to impaired fracture healing supports the crucial role of neutrophil-derived CCL2 in fracture repair (Figs2D, E and 4).

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