Low‐dose <scp>TNF</scp> augments fracture healing in normal and osteoporotic bone by up‐regulating the innate immune response

Chan, James; Glass, Graeme E.; Ersek, Adel; Freidin, A; Williams, Graham V.; Gowers, Kate H.C.; Santo, Ana I. Espirito; Jeffery, Rosemary; Otto, W; Poulsom, Richard; Feldmann, Marc; Rankin, Sara M.; Horwood, Nicole J.; Nanchahal, Jagdeep

doi:10.15252/emmm.201404487

Cited by 109 publications

(103 citation statements)

References 103 publications

(172 reference statements)

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“…Low and continuous levels of TNF-α were associated with proosteogenic effects, contributing to the formation of bone spurs (enthesis) by upregulating the activity of ALP (Ding et al, 2009; Lencel et al, 2011). However, the involvement of NF-κB signaling during the inflammation and healing processes remains unclear (Chan et al, 2015; Glass et al, 2011). …”

Section: Nf-κb and Bone Remodelingmentioning

confidence: 99%

NF-κB as a Therapeutic Target in Inflammatory-Associated Bone Diseases

Lin

Pajarinen

et al. 2017

Chromatin Proteins and Transcription Factors as Therapeutic Targets

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Inflammation is a defensive mechanism for pathogen clearance and maintaining tissue homeostasis. In the skeletal system, inflammation is closely associated with many bone disorders including fractures, nonunions, periprosthetic osteolysis (bone loss around orthopedic implants), and osteoporosis. Acute inflammation is a critical step for proper bone-healing and bone-remodeling processes. On the other hand, chronic inflammation with excessive proinflammatory cytokines disrupts the balance of skeletal homeostasis involving osteoblastic (bone formation) and osteoclastic (bone resorption) activities. NF-κB is a transcriptional factor that regulates the inflammatory response and bone-remodeling processes in both bone-forming and bone-resorption cells. In vitro and in vivo evidences suggest that NF-κB is an important potential therapeutic target for inflammation-associated bone disorders by modulating inflammation and bone-remodeling process simultaneously. The challenges of NF-κB-targeting therapy in bone disorders include: (1) the complexity of canonical and noncanonical NF-κB pathways; (2) the fundamental roles of NF-κB-mediated signaling for bone regeneration at earlier phases of tissue damage and acute inflammation; and (3) the potential toxic effects on nontargeted cells such as lymphocytes. Recent developments of novel inhibitors with differential approaches to modulate NF-κB activity, and the controlled release (local) or bone-targeting drug delivery (systemic) strategies, have largely increased the translational application of NF-κB therapy in bone disorders. Taken together, temporal modulation of NF-κB pathways with the combination of recent advanced bone-targeting drug delivery techniques is a highly translational strategy to reestablish homeostasis in the skeletal system.

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Section: Nf-κb and Bone Remodelingmentioning

confidence: 99%

NF-κB as a Therapeutic Target in Inflammatory-Associated Bone Diseases

Lin

Pajarinen

et al. 2017

Chromatin Proteins and Transcription Factors as Therapeutic Targets

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“…In addition, expression of Il6 and Il1β , pro-inflammatory cytokines induced downstream of TNF signaling, were significantly higher in WT neonates at 72 h PEC compared to the Ccr2 −/− neonates. It has been previously shown that early induction of Tnf is associated with improved wound healing [27]. The early induction of lung Tnf and the better survival in WT neonates with LRT E. coli compared to Ccr2 −/− neonates, suggests a possible beneficial link between an intact CCL2-CCR2 axis and the induction of lung Tnf expression in the neonate during Ec -LRTI.…”

Section: Resultsmentioning

confidence: 99%

“…It has been reported that the early expression of TNF and IL6 during injury can facilitate wound healing while suppression of these cytokines can impair healing [27,40]. Chan and colleagues, found that early induction of TNF and CCL2 was associated with migration of neutrophils and bone marrow-derived mononuclear cells into areas of bone injury [27]. They noted improved healing of the bone fracture with early administration of recombinant human TNF, whereas inhibition of CCR2 signaling impaired bone healing.…”

Section: Discussionmentioning

confidence: 99%

The innate immune response to lower respiratory tract E. Coli infection and the role of the CCL2-CCR2 axis in neonatal mice

et al. 2017

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Neonates have greater morbidity/mortality from lower respiratory tract infections (LRTI) compared to older children. Lack of conditioning of the pulmonary immune system due to limited environmental exposures and/or infectious challenges likely contributes to the increase susceptibility in the neonate. In this study, we sought to gain insights into the nature and dynamics of the neonatal pulmonary immune response to LRTI using a murine model. Methods Wildtype (WT) and Ccr2−/− C57BL/6 neonatal and juvenile mice received E. coli or PBS by direct pharyngeal aspiration. Flow cytometry was used to measure immune cell dynamics and identify cytokine-producing cells. Real-time PCR and ELISA were used to measure cytokine/chemokine expression. Results Innate immune cell recruitment in response to E. coli-induced LRTI was delayed in the neonatal lung compared to juvenile lung. Lung clearance of bacteria was also significantly delayed in the neonate. Ccr2−/− neonates, which lack an intact CCL2-CCR2 axis, had higher mortality after E. coli challenged than Ccr2+/+ neonates. A greater percentage of CD8+ T cells and monocytes from WT neonates challenged with E. coli produced TNF compared to controls. Conclusion The pulmonary immune response to E. coli-induced LRTI differed significantly between neonatal and juvenile mice. Neonates were more susceptible to increasing doses of E. coli and exhibited greater mortality than juveniles. In the absence of an intact CCL2-CCR2 axis, susceptibility to LRTI-induced mortality was further increased in neonatal mice. Taken together these findings underscore the importance of age-related differences in the innate immune response to LRTI during early stages of postnatal life.

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“…Consistent with this mechanism, there is a rescue of impaired fracture healing in COX‐2 knockout mice by activation of prostaglandin E 2 receptor subtype 4 (Xie et al., ) and interestingly also teriparatide (human PTH1‐34) (Yukata et al., ). TNFα receptor (p55/p75)‐deficient mice and systemic administration of anti‐TNFα impaired fracture healing (Chan et al., ; Gerstenfeld et al., ). In line with this concept, adding low concentrations of TNFα promotes fracture repair by augmenting the recruitment and differentiation of muscle‐derived stromal cells (Chan et al., ; Glass et al., ).…”

Section: Preamblementioning

confidence: 99%

Osteoimmunology: Inflammatory osteolysis and regeneration of the alveolar bone

Gruber

2019

J Clinic Periodontology

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Aim Osteoimmunology covers the cellular and molecular mechanisms responsible for inflammatory osteolysis that culminates in the degradation of alveolar bone. Osteoimmunology also focuses on the interplay of immune cells with bone cells during bone remodelling and regeneration. The aim of this review was to provide insights into how osteoimmunology affects alveolar bone health and disease. Method This review is based on a narrative approach to assemble mouse models that provide insights into the cellular and molecular mechanisms causing inflammatory osteolysis and on the impact of immune cells on alveolar bone regeneration. Results Mouse models have revealed the molecular pathways by which microbial and other factors activate immune cells that initiate an inflammatory response. The inflammation‐induced alveolar bone loss occurs with the concomitant suppression of bone formation. Mouse models also showed that immune cells contribute to the resolution of inflammation and bone regeneration, even though studies with a focus on alveolar socket healing are rare. Conclusions Considering that osteoimmunology is evolutionarily conserved, osteolysis removes the cause of inflammation by provoking tooth loss. The impact of immune cells on bone regeneration is presumably a way to reinitiate the developmental mechanisms of intramembranous and endochondral bone formation.

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

Cited by 109 publications

References 103 publications

NF-κB as a Therapeutic Target in Inflammatory-Associated Bone Diseases

NF-κB as a Therapeutic Target in Inflammatory-Associated Bone Diseases

The innate immune response to lower respiratory tract E. Coli infection and the role of the CCL2-CCR2 axis in neonatal mice

Osteoimmunology: Inflammatory osteolysis and regeneration of the alveolar bone

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