Deletion of Nrf2 reduces skeletal mechanical properties and decreases load-driven bone formation

Sun, Yongxin; Li, Lei; Corry, Kylie A.; Zhang, Pei; Yang, Yang; Himes, Evan R.; Mihuti, Cristina Layla; Nelson, Cecilia; Dai, Guoli; Li, Jiliang

doi:10.1016/j.bone.2014.12.066

Cited by 62 publications

(71 citation statements)

References 43 publications

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“…Our recent study has demonstrated that antioxidant factors may play a positive role in bone formation 1 . However, it is not clear if and how antioxidants affect skeletal development and bone homeostasis.…”

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confidence: 99%

Moderate Nrf2 Activation by Genetic Disruption of Keap1 Has Sex-Specific Effects on Bone Mass in Mice

Yin

Corry

Loughran

et al. 2020

Sci Rep

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Keap1 is a negative controller of the transcription factor Nrf2 for its activity. The Keap1/Nrf2 signaling pathway has been considered as a master regulator of cytoprotective genes, and exists in many cell types including osteoblasts and osteoclasts. Our previous study shows Nrf2 deletion decreases bone formation. Recent studies show hyperactivation of Nrf2 causes osteopenia in Keap1 −/− mice, and Keap1 −/− osteoblasts have significantly less proliferative potential than Keap1 +/− osteoblasts. We aimed to examine if moderate Nrf2 activation by disruption of Keap1 impacts bone metabolism. We examined bone phenotype of Keap1 heterozygotic mice (Ht) in comparison with Keap1 wild type (WT) mice. Deletion or knockdown of Keap1 enhanced the gene expression of Nrf2, ALP and wnt5a in cultured primary osteoblasts compared to WT control. In male mice, compared with their age-matched littermate WT controls, Keap1 Ht mice showed significant increase in bone formation rate (+30.7%, P = 0.0029), but did not change the ultimate force (P < 0.01). The osteoclast cell numbers (−32.45%, p = 0.01) and surface (−32.58%, P = 0.03) were significantly reduced by Keap1 deficiency in male mice. Compared to male WT mice, serum bone resorption marker in male Keap1 Ht mice was significantly decreased. Our data suggest that moderate Nrf2 activation by disruption of Keap1 improved bone mass by regulating bone remodeling in male mice.

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confidence: 99%

Moderate Nrf2 Activation by Genetic Disruption of Keap1 Has Sex-Specific Effects on Bone Mass in Mice

Yin

Corry

Loughran

et al. 2020

Sci Rep

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“…Similarly, the bone microenvironment seems to be normal under normal conditions, whereas after inflammatory insult, spontaneous bone fractures occur in Nrf2 −/− mice (12). In addition, other studies have reported that enhanced bone formation occurs in 9‐wk‐old Nrf2 −/− mice (22), but enhanced bone loss was observed in 16‐wk‐old Nrf2 −/− mice (43). Similar discrepancies are observed in Keap1 −/− cells and animals.…”

Section: Discussionmentioning

confidence: 99%

Effects of deficiency of Kelch‐like ECH‐associated protein 1 on skeletal organization: a mechanism for diminished nuclear factor of activated T cells cytoplasmic 1 during osteoclastogenesis

et al. 2017

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Kelch-like ECH-associated protein 1 (Keap1) binds to nuclear factor E2 p45-related factor 2 (Nrf2), a transcription factor for antioxidant enzymes, to suppress Nrf2 activation. The role of oxidative stress in many diseases supports the possibility that processes that are associated with Nrf2 activation might offer therapeutic potential. Nrf2 deficiency induces osteoclastogenesis, which is responsible for bone loss, by activating receptor activator of NF-κB ligand (RANKL)-mediated signaling; however, the effects of Keap1 deficiency remain unclear. By using Keap1-deficient newborn mice, we observed that talus and calcaneus bone formation was partially retarded and that osteoclast number was reduced without severe gross abnormalities. In addition, Keap1-deficient macrophages were unable to differentiate into osteoclasts attenuation of RANKL-mediated signaling and expression of nuclear factor of activated T cells cytoplasmic 1 (NFATc1), a key transcription factor that is involved in osteoclastogenesis. Furthermore, Keap1 deficiency up-regulated the expression of , a negative regulator of NFATc1. RANKL-induced mitochondrial gene expression is required for down-regulation of IFN regulatory factor 8 (IRF-8), a negative transcriptional regulator of NFATc1. Our results indicate that Keap1 deficiency down-regulated peroxisome proliferator-activated receptor-γ coactivator 1β and mitochondrial gene expression and up-regulated expression. These results suggest that the Keap1/Nrf2 axis plays a critical role in NFATc1 expression and osteoclastogenic progression.-Sakai, E., Morita, M., Ohuchi, M., Kido, M. A., Fukuma, Y., Nishishita, K., Okamoto, K., Itoh, K., Yamamoto, M., Tsukuba, T. Effects of deficiency of Kelch-like ECH-associated protein 1 on skeletal organization: a mechanism for diminished nuclear factor of activated T cells cytoplasmic 1 during osteoclastogenesis.

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“…In fact, as far as we investigated, in many aspects Dpp3 gene inactivation led to a phenotype closely resembling the condition displayed in Nrf2 KO and in Ho-1 KO mouse. (20,63,64) Moreover, because Nrf2 is known to take also part in other important cellular processes, such as proteostasis maintenance and endoplasmic reticulum stress quenching, (65,66) absence of DPP3 might also have a detrimental effect in those Nrf2-related contexts, which have not been addressed here.…”

Section: Discussionmentioning

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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Deletion of Nrf2 reduces skeletal mechanical properties and decreases load-driven bone formation

Cited by 62 publications

References 43 publications

Moderate Nrf2 Activation by Genetic Disruption of Keap1 Has Sex-Specific Effects on Bone Mass in Mice

Moderate Nrf2 Activation by Genetic Disruption of Keap1 Has Sex-Specific Effects on Bone Mass in Mice

Effects of deficiency of Kelch‐like ECH‐associated protein 1 on skeletal organization: a mechanism for diminished nuclear factor of activated T cells cytoplasmic 1 during osteoclastogenesis

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

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