NADPH oxidases in bone and cartilage homeostasis and disease: A promising therapeutic target

Wegner, Adam M.; Haudenschild, Dominik R.

doi:10.1002/jor.24693

Cited by 17 publications

(17 citation statements)

References 98 publications

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“…Indeed, POLDIP2 was expressed in femoral bone in vivo and its levels were enhanced in aged mice compared to young adult mice [ 8 ]. Downregulation of POLDIP2 via shPOLDIP2 markedly inhibited lipopolysaccharide-induced increases in the expression of Nox4 [ 28 ], which was upregulated in differentiated osteoclasts compared to osteoclast precursors, indicating its role in the physiology and pathobiology of bone and joints [ 29 ]. We found here that TRAP, NFATC, CTSK, MMP9, c-Fos, and Acp5 expression was significantly downregulated in bone tissues of OVX rats following ectopic expression of POLDIP2.…”

Section: Discussionmentioning

confidence: 99%

ZEB1 regulates bone metabolism in osteoporotic rats through inducing POLDIP2 transcription

2022

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Background Osteoporosis (OP) is a common metabolic bone disease mainly involving bone remodeling and blood vessels. The current study aimed to explore the role of zinc finger E-box binding homeobox 1 (ZEB1) in OP. Methods First, gene expression microarrays for OP were downloaded from the Gene Expression Omnibus database and analyzed to screen for potential targets. Subsequently, a rat OP model was constructed using ovariectomy (OVX), and osteoblastic and osteoclastic differentiation and alterations in osteoporotic symptoms were observed upon intraperitoneal injection of oe-ZEB1 lentiviral vectors. DNA polymerase delta interacting protein 2 (POLDIP2) was predicted to be a downstream target of ZEB1, which was validated by ChIP-qPCR and dual-luciferase experiments. RAW264.7 cells were subjected to lentiviral vector infection of oe-ZEB1 and/or sh-POLDIP2, followed by RANKL treatment to induce osteoclast differentiation. Results ZEB1 was poorly expressed in blood samples of postmenopausal patients with OP and in bone tissues of OVX-treated rats. Overexpression of ZEB1 or POLDIP2 in OVX rats promoted osteoblastogenesis and inhibited osteoclast differentiation. In RANKL-treated RAW264.7 cells, the transcription factor ZEB1 enhanced the expression of POLDIP2, and silencing of POLDIP2 attenuated the inhibitory effect of oe-ZEB1 on the differentiation of macrophages RAW264.7 to osteoclasts. Conclusions ZEB1 promotes osteoblastogenesis and represses osteoclast differentiation, ultimately reducing the occurrence of postmenopausal OP by elevating the expression of POLDIP2.

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Section: Discussionmentioning

confidence: 99%

ZEB1 regulates bone metabolism in osteoporotic rats through inducing POLDIP2 transcription

2022

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“…regulator of bone homeostasis (Sun et al, 2015;Wegner and Haudenschild, 2020). Nuclear respiratory factor 1 (Nrf1) is also a transcription factor, of the same family, and known to regulate the antioxidant response elements-driven target genes (Xing et al, 2007).…”

Section: Oxidative Stress In Bone Homeostasismentioning

confidence: 99%

“…There are three identified Nox isoforms involved in osteoclast differentiation and function, Nox1, Nox2, and Nox4. Nox isoforms expression is controlled by several mechanisms such as the transcription factor nuclear factor-erythroid 2-related factor (Nrf2), key to antioxidant cellular responses, and regulator of bone homeostasis ( Sun et al, 2015 ; Wegner and Haudenschild, 2020 ). Nuclear respiratory factor 1 (Nrf1) is also a transcription factor, of the same family, and known to regulate the antioxidant response elements-driven target genes ( Xing et al, 2007 ).…”

Section: Oxidative Stress In Bone Homeostasismentioning

confidence: 99%

In Sickness and in Health: The Oxygen Reactive Species and the Bone

Reis

Ramos

2021

Front. Bioeng. Biotechnol.

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Oxidative stress plays a central role in physiological and pathological bone conditions. Its role in signalment and control of bone cell population differentiation, activity, and fate is increasingly recognized. The possibilities of its use and manipulation with therapeutic goals are virtually unending. However, how redox balance interplays with the response to mechanical stimuli is yet to be fully understood. The present work summarizes current knowledge on these aspects, in an integrative and broad introductory perspective.

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“…Nicotinamide adenine dinucleotide phosphate oxidase 4 (NOX4), one of the members of the nicotinamide adenine dinucleotide phosphate oxidase family, is induced during differentiation in many cells. Accumulating evidence indicates that NOX4 is involved in the production of ROS [ 11 , 14 – 16 ]. More importantly, NOX4 is constitutively active and produces H 2 O 2 without cytosolic activator proteins, while H 2 O 2 has been confirmed to contribute to the development of aseptic loosening [ 17 , 18 ].…”

Section: Introductionmentioning

confidence: 99%

NOX4 blockade suppresses titanium nanoparticle-induced bone destruction via activation of the Nrf2 signaling pathway

et al. 2022

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Periprosthetic osteolysis (PPO) triggered by wear particles is the most severe complication of total joint replacement (TJR) surgeries, representing the major cause of implant failure, which is public health concern worldwide. Previous studies have confirmed the specialized role of osteoclast-induced progressive bone destruction in the progression of PPO. Additionally, the reactive oxygen species (ROS) induced by wear particles can promote excessive osteoclastogenesis and bone resorption. Nicotinamide adenine dinucleotide phosphate oxidase 4 (NOX4), a cellular enzyme, is considered to be responsible for the production of ROS and the formation of mature osteoclasts. However, NOX4 involvement in PPO has not yet been elucidated. Therefore, we investigated the mechanism by which NOX4 regulates osteoclast differentiation and the therapeutic effects on titanium nanoparticle-induced bone destruction. We found that NOX4 blockade suppressed osteoclastogenesis and enhanced the scavenging of intracellular ROS. Our rescue experiment revealed that nuclear factor-erythroid 2-related factor 2 (Nrf2) silencing reversed the effects of NOX4 blockade on ROS production and osteoclast differentiation. In addition, we found increased expression levels of NOX4 in PPO tissues, while NOX4 inhibition in vivo exerted protective effects on titanium nanoparticle-induced osteolysis through antiosteoclastic and antioxidant effects. Collectively, these findings suggested that NOX4 blockade suppresses titanium nanoparticle-induced bone destruction via activation of the Nrf2 signaling pathway and that NOX4 blockade may be an attractive therapeutic approach for preventing PPO. Graphical Abstract

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NADPH oxidases in bone and cartilage homeostasis and disease: A promising therapeutic target

Cited by 17 publications

References 98 publications

ZEB1 regulates bone metabolism in osteoporotic rats through inducing POLDIP2 transcription

ZEB1 regulates bone metabolism in osteoporotic rats through inducing POLDIP2 transcription

In Sickness and in Health: The Oxygen Reactive Species and the Bone

NOX4 blockade suppresses titanium nanoparticle-induced bone destruction via activation of the Nrf2 signaling pathway

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