Systemic inflammation induced by a thoracic trauma alters the cellular composition of the early fracture callus

Recknagel, Stefan; Bindl, Ronny; Brochhausen, Christoph; Göckelmann, Melanie; Wehner, Tim; Schoengraf, Philipp; Huber‐Lang, Markus; Claes, Lutz; Ignatius, Anita

doi:10.1097/ta.0b013e318278956d

Cited by 62 publications

(75 citation statements)

References 32 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…In the BAL fluid, C5a and IL-6 were significantly enhanced in both genotypes (Table 3). The additional thoracic trauma did not influence the concentration of inflammatory mediators in the fracture hematoma (Table 3) but, according to our previous studies [14,15,19,24], increased the recruitment of neutrophils to the fracture site in WT mice (Fig 2). However, the osteoblast-specific overexpression of C5aR1 did not affect inflammatory parameters in the combined trauma model (Table 3, Fig 2).…”

Section: Resultssupporting

confidence: 65%

“…We evaluated fracture healing in a model of uncomplicated isolated fracture and in a model of impaired healing by combining the fracture with an additional thoracic trauma, which is associated with local and systemic complement activation and severe inflammation [14,15]. We hypothesize that if osteoblasts were important target cells for C5a, fracture healing would be disturbed.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Osteoblast-specific overexpression of complement receptor C5aR1 impairs fracture healing

et al. 2017

Self Cite

View full text Add to dashboard Cite

The anaphylatoxin receptor C5aR1 plays an important role not only in innate immune responses, but also in bone metabolism and fracture healing, being highly expressed on immune and bone cells, including osteoblasts and osteoclasts. C5aR1 induces osteoblast migration, cytokine generation and osteoclastogenesis, however, the exact role of C5aR1-mediated signaling in osteoblasts is not entirely known. Therefore, we hypothesized that osteoblasts are essential target cells for C5a and that fracture healing should be disturbed in mice with an osteoblast-specific C5aR1 overexpression (Col1a1-C5aR1). Osteoblast activity in vitro, bone phenotype and fracture healing after isolated osteotomy and after combined osteotomy with additional thoracic trauma were analyzed. The systemic and local inflammatory reactions were analyzed by determining C5a and IL-6 concentrations in blood, bronchoalveolar lavage fluid and fracture callus and the recruitment of immune cells. In vitro, osteoblast proliferation and differentiation were similar to wildtype cells, and phosphorylation of p38 and expression of IL-6 and RANKL were increased in osteoblasts derived from Col1a1-C5aR1 mice. Bone phenotype and the inflammatory reaction were unaffected in Col1a1-C5aR1 mice. Fracture healing was significantly impaired as demonstrated by significantly reduced bone content, bone mineral density and flexural rigidity, possibly due to significantly increased osteoclast numbers. C5aR1 signaling in osteoblasts might possibly affect RANKL/OPG balance, leading to increased bone resorption. Additional trauma significantly impaired fracture healing, particularly in Col1a1-C5aR1 mice. In conclusion, the data indicate that C5aR1 signaling in osteoblasts plays a detrimental role in bone regeneration after fracture.

show abstract

Section: Resultssupporting

confidence: 65%

Section: Introductionmentioning

confidence: 99%

Osteoblast-specific overexpression of complement receptor C5aR1 impairs fracture healing

et al. 2017

Self Cite

View full text Add to dashboard Cite

show abstract

“…In a rat model it was shown that repair of a stabilized femoral osteotomy in the presence of acute systemic inflammation induced by chest trauma was associated with an increase in granulocytes and a decrease in macrophages during the early soft callus phase of healing [38]. In another study conducted in neutrophil-deficient mice it was concluded that this type of granulocyte was not involved in the disruption of bone repair leading to malunion in the presence of systemic inflammation [27].…”

Section: Introductionmentioning

confidence: 97%

Defective Bone Repair in C57Bl6 Mice With Acute Systemic Inflammation

Behrends

Hui

Gao

et al. 2017

Clinical Orthopaedics &Amp; Related Research

View full text Add to dashboard Cite

Background Bone repair is initiated with a local inflammatory response to injury. The presence of systemic inflammation impairs bone healing and often leads to malunion, although the underlying mechanisms remain poorly defined. Our research objective was to use a mouse model of cortical bone repair to determine the effect of systemic inflammation on cells in the bone healing microenvironment. Question/Purposes (1) Does systemic inflammation, induced by lipopolysaccharide (LPS) administration affect the quantity and quality of regenerating bone in primary bone healing? (2) Does systemic inflammation alter vascularization and the number or activity of inflammatory cells, osteoblasts, and osteoclasts in the bone healing microenvironment? Methods Cortical defects were drilled in the femoral diaphysis of female and male C57BL/6 mice aged 5 to 9 months that were treated with daily systemic injections of LPS or physiologic saline as control for 7 days. Mice were euthanized at 1 week (Control, n = 7; LPS, n = 8), 2 weeks (Control, n = 7; LPS, n = 8), and 6 weeks (Control, n = 9; LPS, n = 8) after surgery. The quantity (bone volume per tissue volume [BV/TV]) and microarchitecture (trabecular separation and thickness, porosity) of bone in the defect were quantified with time using microCT. The presence or activity of vascular endothelial cells (CD34), macrophages (F4/80), osteoblasts (alkaline phosphatase [ALP]), and osteoclasts (tartrate-resistant acid phosphatase [TRAP]) were evaluated using histochemical analyses.The institution of one or more of the authors (JEH, PAM) has received, during the study period, funding from the Fonds de recherche Santé Québec. The remaining authors certify that neither he or she, nor a member of his or her immediate family, has funding or commercial associations (consultancies, stock ownership, equity interest, patent/licensing arrangements, etc) that might pose a conflict of interest in connection with the submitted article. Results Only one of eight defects was bridged completely 6 weeks after surgery in LPS-injected mouse bones compared with seven of nine defects in the control mouse bones (odds ratio [OR], 0.04; 95% CI, 0.003-0.560; p = 0.007). The decrease in cortical bone in LPS-treated mice was reflected in reduced BV/TV (21% ± 4% vs 39% ± 10%; p\0.01), increased trabecular separation (240 ± 36 lm vs 171 ± 29 lm; p \ 0.01), decreased trabecular thickness (81 ± 18 lm vs 110 ± 22 lm; p = 0.02), and porosity (79% ± 4% vs 60% ± 10%; p \ 0.01) at 6 weeks postoperative. Defective healing was accompanied by decreased CD34 (1.1 ± 0.6 vs 3.4 ± 0.9; p\0.01), ALP (1.9 ± 0.9 vs 6.1 ± 3.2; p = 0.03), and TRAP (3.3 ± 4.7 vs 7.2 ± 4.0; p = 0.01) activity, and increased F4/80 (13 ± 2.6 vs 6.8 ± 1.7; p \ 0.01) activity at 2 weeks postoperative. Conclusion The results indicate that LPS-induced systemic inflammation reduced the amount and impaired the quality of bone regenerated in mouse femurs. The effects were associated with impaired revascularization, decreased bone turnover by osteoblasts...

show abstract

“…7 Inflammation is an important regulator of bone regeneration. 8,9 Following fracture injury, there is an initial inflammatory response that has a crucial role in bone healing. 1,10 However, severe or prolonged inflammatory response leads to delayed healing or bone repair failure.…”

mentioning

confidence: 99%

IL-12p40 impairs mesenchymal stem cell-mediated bone regeneration via CD4+ T cells

Wang

et al. 2016

Cell Death Differ

View full text Add to dashboard Cite

Severe or prolonged inflammatory response caused by infection or biomaterials leads to delayed healing or bone repair failure. This study investigated the important roles of the proinflammatory cytokines of the interleukin-12 (IL-12) family, namely, IL-12 and IL-23, in the inflammation-mediated inhibition of bone formation in vivo. IL-12p40 −/− mice lacking IL-12 and IL-23 exhibited enhanced bone formation. IL-12 and IL-23 indirectly inhibited bone marrow mesenchymal stem cell (BMMSC) differentiation by stimulating CD4 + T cells to increase interferon γ (IFN-γ) and IL-17 levels. Mechanistically, IL-17 synergistically enhanced IFN-γ-induced BMMSC apoptosis. Moreover, INF-γ and IL-17 exerted proapoptotic effects by upregulating the expression levels of Fas and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), as well as by activating the caspase cascade in BMMSCs. IL-12p40 depletion in mice could promote ectopic bone formation. Thus, IL-12p40 is an attractive therapeutic target to overcome the inflammation-mediated inhibition of bone formation in vivo.

show abstract

Systemic inflammation induced by a thoracic trauma alters the cellular composition of the early fracture callus

Cited by 62 publications

References 32 publications

Osteoblast-specific overexpression of complement receptor C5aR1 impairs fracture healing

Osteoblast-specific overexpression of complement receptor C5aR1 impairs fracture healing

Defective Bone Repair in C57Bl6 Mice With Acute Systemic Inflammation

IL-12p40 impairs mesenchymal stem cell-mediated bone regeneration via CD4+ T cells

Contact Info

Product

Resources

About