Delayed Bone Regeneration Is Linked to Chronic Inflammation in Murine Muscular Dystrophy

Abou-Khalil, Rana; Yang, Frank; Mortreux, Marie; Lieu, Shirley; Yu, Yan-yiu; Wurmser, Maud; Pereira, Cláudia; Relaix, Frédéric; Miclau, Theodore; Marcucio, Ralph; Colnot, Céline

doi:10.1002/jbmr.2038

Cited by 48 publications

(56 citation statements)

References 58 publications

(88 reference statements)

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“…First, the results are not directly applicable to humans as a murine model was used. However, the immune response to LPS-induced systemic inflammation in mice has been well characterized in rodents [1,12,23,27,49], and shown to be (n = 7) (n = 8) (n = 7) (n = 8) (n = 9) (n = 8) comparable to that seen in humans [8]. LPS introduced into the intraperitoneal cavity enters the systemic circulation via the portal vein and activates the immune system [5], which was confirmed by monitoring serum TNFa in our study.…”

Section: Discussionmentioning

confidence: 99%

“…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]. Others have investigated bone repair in a mouse model of chronic inflammation and reported reduced vascularization, increased numbers of macrophages, and impaired remodeling of the callus [1]. These studies begin to address the mechanisms underlying impaired bone healing in the presence of systemic inflammation.…”

Section: Introductionmentioning

confidence: 99%

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Defective Bone Repair in C57Bl6 Mice With Acute Systemic Inflammation

Behrends

Hui

Gao

et al. 2017

Clinical Orthopaedics &Amp; Related Research

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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...

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

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“…The normal physiological inflammatory reaction is one of the body's principal defense reactions, which is beneficial to fracture healing (3,4). However, chronic inflammation caused by infection or other factors, is detrimental to fracture healing (5,6). Various inflammatory factors, including tumor necrosis factor (TNF)-α, interleukin (IL)-1β and IL-6, are able to stimulate osteoclast differentiation from monocyte-macrophages (7,8).…”

Section: Introductionmentioning

confidence: 99%

Triptolide inhibits the function of TNF-α in osteoblast differentiation by inhibiting the NF-κB signaling pathway

Liu

Wang

et al. 2017

Experimental and Therapeutic Medicine

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Abstract. Chronic inflammation often delays fracture healing or leads to bone nonunion. Effectively suppressing pathological inflammation is crucial for fracture healing or bone remodeling. Triptolide, which is a diterpenoid epoxide, is the major active component of the Thunder God Vine, Tripterygium wilfordii. The aim of the present study was to investigate the role of triptolide in osteoblast differentiation and explore the molecular mechanisms of triptolide in fracture healing. Alkaline phosphatase (ALP) activity was used to evaluate osteoblast differentiation. ALP activity was measured via histochemical staining and western blotting was used to determine the expression of factors associated with inflammation. C2C12 cells were initially treated with 200 ng/ml bone morphogenetic protein (BMP)-2 alone for 3 days, which caused a significant increase in ALP activity (P<0.01). However, treatment with tumor necrosis factor (TNF)-α significantly decreased the ALP activity (P<0.05). Notably, treatment with the chronic inflammatory cytokine TNF-α significantly decreased the effect of BMP-2 in C2C12 cells compared with BMP-2 treatment alone (P<0.01). C2C12 cells were treated with increasing concentrations of BMP-2 or TNF-α for 3 days. The results demonstrated that TNF-α treatment significantly inhibited BMP-2-induced osteoblast differentiation in a dose-dependent manner (P<0.01). The role of triptolide in BMP-2-induced osteoblast differentiation was also examined. Cells were treated with BMP-2, BMP-2 + TNF-α alone, or BMP2 + TNF-α with increasing concentrations of triptolide (4, 8 or 16 ng/ml). After 3 days, the results of ALP activity revealed that triptolide significantly reversed the TNF-α-associated inhibition of osteoblast differentiation (P<0.01). Western blotting analysis demonstrated that triptolide markedly inhibited the phosphorylation of nuclear factor-κB, therefore suppressing the effects of TNF-α. In summary, triptolide is able to reverse the TNF-α-associated suppression of osteoblast differentiation, suggesting that triptolide treatment may have a positive effect on bone remodeling and fracture repairing.

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“…(20) Histological, immunohistochemistry, and quantitative PCR assessments of the callus tissue were performed as described. (9,10,22) (Details are available in the Supporting Information-Methods and Supporting Tables 1 and 2. )…”

Section: Analysis Of Fracture Callus Formationmentioning

confidence: 99%

Loss of Gi G-Protein-Coupled Receptor Signaling in Osteoblasts Accelerates Bone Fracture Healing

Wang

Hsiao

Lieu

et al. 2015

Journal of Bone and Mineral Research

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G-protein-coupled receptors (GPCRs) are key regulators of skeletal homeostasis and are likely important in fracture healing. Because GPCRs can activate multiple signaling pathways simultaneously, we used targeted disruption of G i -GPCR or activation of G s -GPCR pathways to test how each pathway functions in the skeleton. We previously demonstrated that blockade of G i signaling by pertussis toxin (PTX) transgene expression in maturing osteoblastic cells enhanced cortical and trabecular bone formation and prevented agerelated bone loss in female mice. In addition, activation of G s signaling by expressing the G s -coupled engineered receptor Rs1 in maturing osteoblastic cells induced massive trabecular bone formation but cortical bone loss. Here, we test our hypothesis that the G i and G s pathways also have distinct functions in fracture repair. We applied closed, nonstabilized tibial fractures to mice in which endogenous G i signaling was inhibited by PTX, or to mice with activated G s signaling mediated by Rs1. Blockade of endogenous G i resulted in a smaller callus but increased bone formation in both young and old mice. PTX treatment decreased expression of Dkk1 and increased Lef1 mRNAs during fracture healing, suggesting a role for endogenous G i signaling in maintaining Dkk1 expression and suppressing Wnt signaling. In contrast, adult mice with activated G s signaling showed a slight increase in the initial callus size with increased callus bone formation. These results show that G i blockade and G s activation of the same osteoblastic lineage cell can induce different biological responses during fracture healing. Our findings also show that manipulating the GPCR/cAMP signaling pathway by selective timing of G s and G i -GPCR activation may be important for optimizing fracture repair.

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Delayed Bone Regeneration Is Linked to Chronic Inflammation in Murine Muscular Dystrophy

Cited by 48 publications

References 58 publications

Defective Bone Repair in C57Bl6 Mice With Acute Systemic Inflammation

Defective Bone Repair in C57Bl6 Mice With Acute Systemic Inflammation

Triptolide inhibits the function of TNF-α in osteoblast differentiation by inhibiting the NF-κB signaling pathway

Loss of Gi G-Protein-Coupled Receptor Signaling in Osteoblasts Accelerates Bone Fracture Healing

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