Nrf2 Deficiency Impairs Fracture Healing in Mice

Lippross, Sebastian; Beckmann, Rainer; Streubesand, Nadine; Ayub, Ferda; Tohidnezhad, Mersedeh; Campbell, G.; Kan, Yuet Wai; Fischer, Horst; Sönmez, Tolga Taha; Varoga, Deike; Lichte, Philipp; Jahr, Holger; Wruck, Christoph Jan

doi:10.1007/s00223-014-9900-5

Cited by 43 publications

(33 citation statements)

References 28 publications

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“…Induction of cytoprotective enzymes by NRF2 activation subsequently inhibits osteoclastogenesis (Kanzaki et al, 2013, 2014, 2015; Sakai et al, 2013; Gambari et al, 2014; Lee et al, 2014; Lu et al, 2015; Bhattarai et al, 2016). Inversely, augmented osteoclastogenesis and bone destruction was observed with NRF2 deficiency (Rana et al, 2012; Hyeon et al, 2013; Ibanez et al, 2014; Lippross et al, 2014; Sun et al, 2015). Taken together, this shows that NRF2-dependent cytoprotective enzymes play a critical role in the regulation of bone destruction.…”

Section: Mechanisms That Protect Against Oxidative Stressmentioning

confidence: 99%

Pathways that Regulate ROS Scavenging Enzymes, and Their Role in Defense Against Tissue Destruction in Periodontitis

et al. 2017

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Periodontitis, an inflammatory disease that affects the tissues surrounding the teeth, is a common disease worldwide. It is caused by a dysregulation of the host inflammatory response to bacterial infection, which leads to soft and hard tissue destruction. In particular, it is the excessive inflammation in response to bacterial plaque that leads to the release of reactive oxygen species (ROS) from neutrophils, which, then play a critical role in the destruction of periodontal tissue. Generally, ROS produced from immune cells exhibit an anti-bacterial effect and play a role in host defense and immune regulation. Excessive ROS, however, can exert cytotoxic effects, cause oxidative damage to proteins, and DNA, can interfere with cell growth and cell cycle progression, and induce apoptosis of gingival fibroblasts. Collectively, these effects enable ROS to directly induce periodontal tissue damage. Some ROS also act as intracellular signaling molecules during osteoclastogenesis, and can thus also play an indirect role in bone destruction. Cells have several protective mechanisms to manage such oxidative stress, most of which involve production of cytoprotective enzymes that scavenge ROS. These enzymes are transcriptionally regulated via NRF2, Sirtuin, and FOXO. Some reports indicate an association between periodontitis and these cytoprotective enzymes' regulatory axes, with superoxide dismutase (SOD) the most extensively investigated. In this review article, we discuss the role of oxidative stress in the tissue destruction manifest in periodontitis, and the mechanisms that protect against this oxidative stress.

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Section: Mechanisms That Protect Against Oxidative Stressmentioning

confidence: 99%

Pathways that Regulate ROS Scavenging Enzymes, and Their Role in Defense Against Tissue Destruction in Periodontitis

et al. 2017

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“…Reduced Nrf2 activity has been linked to a number of pathological conditions . Furthermore, alterations of the Keap1/Nrf2 pathway have been reported in animal models of bone disease, and lack of Nrf2 exacerbated pathological phenotypes . In fact, unresolved oxidative stress stimulates osteoclast (OC) formation and osteocyte apoptosis, and affects osteoblast (OB) functions …”

Section: Introductionmentioning

confidence: 99%

“…(13)(14)(15)(16)(17)(18) Furthermore, alterations of the Keap1/Nrf2 pathway have been reported in animal models of bone disease, and lack of Nrf2 exacerbated pathological phenotypes. (19)(20)(21)(22) In fact, unresolved oxidative stress stimulates osteoclast (OC) formation and osteocyte apoptosis, and affects osteoblast (OB) functions. (5) In this context, the dipeptidyl peptidase 3 (DPP3) has been recently identified as an upstream activator of the Keap1/Nrf2 antioxidant signaling cascade by binding to Keap1 and favoring Nrf2 function.…”

Section: Introductionmentioning

confidence: 99%

Absence of Dipeptidyl Peptidase 3 Increases Oxidative Stress and Causes Bone Loss

Menale

Robinson

Palagano

et al. 2019

Journal of Bone and Mineral Research

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Controlling oxidative stress through the activation of antioxidant pathways is crucial in bone homeostasis, and impairments of the cellular defense systems involved contribute to the pathogenesis of common skeletal diseases. In this work we focused on the dipeptidyl peptidase 3 (DPP3), a poorly investigated ubiquitous zinc‐dependent exopeptidase activating the Keap1‐Nrf2 antioxidant pathway. We showed Dpp3 expression in bone and, to understand its role in this compartment, we generated a Dpp3 knockout (KO) mouse model and specifically investigated the skeletal phenotype. Adult Dpp3 KO mice showed a mild growth defect, a significant increase in bone marrow cellularity, and bone loss mainly caused by increased osteoclast activity. Overall, in the mouse model, lack of DPP3 resulted in sustained oxidative stress and in alterations of bone microenvironment favoring the osteoclast compared to the osteoblast lineage. Accordingly, in vitro studies revealed that Dpp3 KO osteoclasts had an inherent increased resorptive activity and ROS production, which on the other hand made them prone to apoptosis. Moreover, absence of DPP3 augmented bone loss after estrogen withdrawal in female mice, further supporting its relevance in the framework of bone pathophysiology. Overall, we show a nonredundant role for DPP3 in the maintenance of bone homeostasis and propose that DPP3 might represent a possible new osteoimmunological player and a marker of human bone loss pathology. © 2019 American Society for Bone and Mineral Research.

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“…Fracture nonunion is a major complication of the process of bone tissue repair. Because fracture healing is a complex process, which requires a timely coordination of different growth factors and cell types, several genes have been related with the origin of fracture healing impairment using different genetic strategies . Here, we used a model of fracture healing that follows an endochondral ossification pathway, where chondrogenenic commitment of mesenchymal progenitors is a central key in the regenerative progress , to study the mechanisms controlling BMP2 expression in fracture nonunion.…”

Section: Discussionmentioning

confidence: 99%

Hypoxia and Reactive Oxygen Species Homeostasis in Mesenchymal Progenitor Cells Define a Molecular Mechanism for Fracture Nonunion

et al. 2016

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Fracture nonunion is a major complication of bone fracture regeneration and repair. The molecular mechanisms that result in fracture nonunion appearance are not fully determined. We hypothesized that fracture nonunion results from the failure of hypoxia and hematoma, the primary signals in response to bone injury, to trigger Bmp2 expression by mesenchymal progenitor cells (MSCs). Using a model of nonstabilized fracture healing in transgenic 5 0 Bmp2BAC mice we determined that Bmp2 expression appears in close association with hypoxic tissue and hematoma during the early phases of fracture healing. In addition, BMP2 expression is induced when human periosteum explants are exposed to hypoxia ex vivo. Transient interference of hypoxia signaling in vivo with PX-12, a thioredoxin inhibitor, results in reduced Bmp2 expression, impaired fracture callus formation and atrophic-like nonunion by a HIF-1a independent mechanism. In isolated human periosteum-derived MSCs, BMP2 expression could be induced with the addition of platelets concentrate lysate but not with hypoxia treatment, confirming HIF-1a-independent BMP2 expression. Interestingly, in isolated human periosteum-derived mesenchymal progenitor cells, inhibition of BMP2 expression by PX-12 is accomplished only under hypoxic conditions seemingly through dis-regulation of reactive oxygen species (ROS) levels. In conclusion, we provide evidence of a molecular mechanism of hypoxia-dependent BMP2 expression in MSCs where interference with ROS homeostasis specifies fracture nonunion-like appearance in vivo through inhibition of Bmp2 expression. STEM CELLS 2016;34:2342-2353 SIGNIFICANCE STATEMENTFracture nonunion is a major cause of chronic pain and disability. However, the molecular mechanisms that result in impaired fracture healing are not yet determined. The regenerative capability of bone tissue resides in the mesenchymal progenitor cells (MSCs) that can differentiate into chondrocytes and osteoblasts in response to several stimuli derived of bone injury. Here we demonstrate that fracture-healing initiation is highly dependent on the management by MSCs of hypoxiaderived intracellular oxidative stress. This study identifies a mechanism for fracture nonunion appearance that may allow the prevention and non-surgical treatment of fracture nonunions.

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Nrf2 Deficiency Impairs Fracture Healing in Mice

Cited by 43 publications

References 28 publications

Pathways that Regulate ROS Scavenging Enzymes, and Their Role in Defense Against Tissue Destruction in Periodontitis

Pathways that Regulate ROS Scavenging Enzymes, and Their Role in Defense Against Tissue Destruction in Periodontitis

Absence of Dipeptidyl Peptidase 3 Increases Oxidative Stress and Causes Bone Loss

Hypoxia and Reactive Oxygen Species Homeostasis in Mesenchymal Progenitor Cells Define a Molecular Mechanism for Fracture Nonunion

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