Oroxylin A reduces osteoclast formation and bone resorption via suppressing RANKL-induced ROS and NFATc1 activation

Xian, Yansi; Su, Yuangang; Liang, Jiamin; Long, Feng; Feng, Xiaoliang; Yu, Xiao; Lian, Haoyu; Xu, Jiake; Zhao, Jinmin; Liu, Qian; Song, Fangming

doi:10.1016/j.bcp.2021.114761

Cited by 62 publications

(40 citation statements)

References 49 publications

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“…Interestingly, pharmacological downregulation of ROS leads to reduced numbers of mature osteoclasts as well as decreased resorbing activity in the remaining OC via RANKL/NFATc1 signaling without cytotoxicity ( 29 , 50 , 51 ). As the intracellular ROS level is reduced by exposure to low doses of X-rays ( 52 ), this reduced level of oxidative stress could be one cause for the reduced resorbing activity of irradiated OC precursors in our study.…”

Section: Discussionmentioning

confidence: 99%

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Modulation of Differentiation and Bone Resorbing Activity of Human (Pre-) Osteoclasts After X-Ray Exposure

et al. 2022

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Low-dose radiotherapy (LD-RT) is a local treatment option for patients with chronic degenerative and inflammatory diseases, in particular musculoskeletal diseases. Despite reported analgesic and anti-inflammatory effects, cellular and molecular mechanisms related to osteoimmunological effects are still elusive. Here we test the hypothesis that X-irradiation inhibits the differentiation of precursor osteoclasts into mature osteoclasts (mOC) and their bone resorbing activity. Circulating monocytes from healthy donors were isolated and irradiated after attachment with single or fractionated X-ray doses, comparable to an LD-RT treatment scheme. Then monocytes underwent ex vivo differentiation into OC during cultivation up to 21 days, under conditions mimicking the physiological microenvironment of OC on bone. After irradiation, apoptotic frequencies were low, but the total number of OC precursors and mOC decreased up to the end of the cultivation period. On top, we observed an impairment of terminal differentiation, i.e. a smaller fraction of mOC, reduced resorbing activity on bone, and release of collagen fragments. We further analyzed the effect of X-irradiation on multinucleation, resulting from the fusion of precursor OC, which occurs late during OC differentiation. At 21 days after exposure, the observation of smaller cellular areas and a reduced number of nuclei per mOC suggest an impaired fusion of OC precursors to form mOC. Before, at 14 days, the nuclear translocation of Nuclear Factor Of Activated T Cells 1 (NFATc1), a master regulator of osteoclast differentiation and fusion, was decreased. In first results, obtained in the frame of a longitudinal LD-RT study, we previously reported a pain-relieving effect in patients. However, in a subgroup of patients suffering from Calcaneodynia or Achillodynia, we did not observe a consistent decrease of established blood markers for resorption and formation of bone, or modified T cell subtypes involved in regulating these processes. To assess the relevance of changes in bone metabolism for other diseases treated with LD-RT will be subject of further studies. Taken together, we observed that in vitro X-irradiation of monocytes results in an inhibition of the differentiation into bone-resorbing OC and a concomitant reduction of resorbing activity. The detected reduced NFATc1 signaling could be one underlying mechanism.

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Section: Discussionmentioning

confidence: 99%

“…On a molecular level, multiple factors tightly regulate OC differentiation. Nuclear factor of activated T cells cytoplasmic-1 (NFATc1) is a master regulator of osteoclast differentiation ( 27 , 29 ), regulating the expression of genes involved in cell fusion and activation of mOC ( 30 , 31 ).…”

Section: Introductionmentioning

confidence: 99%

Modulation of Differentiation and Bone Resorbing Activity of Human (Pre-) Osteoclasts After X-Ray Exposure

et al. 2022

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“…Sun et al developed a few-layered Nb2C (FNC) as an antioxidant to scavenge ROS and inhibit osteoclastogenesis to attenuate osteolysis [ 12 ]. Xian et al found that oroxylin A, a natural flavonoid isolated, prevented osteoclast-mediated osteolysis by suppressing RANKL-induced ROS and NFATc1 activation [ 13 ]. We demonstrated that the inhibition of NOX4, which contributes to the generation of ROS, prevented RANKL-induced osteoclastogenesis and oxidative stress to ameliorate wear particle-induced PPO.…”

Section: Discussionmentioning

confidence: 99%

“…Previous studies have suggested that hyperactive osteoclasts and increased oxidative stress level-induced bone resorption are predominant in the initiation of PPO. Further evidence has unanimously indicated that the inhibition of ROS through various mechanisms can restrain osteoclast differentiation and bone resorption [ 10 – 13 ]. Therefore, regulating unbalanced ROS production could be a strategy to treat PPO.…”

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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“…An in-depth exploration of melatonin towards improving bone health using preclinical and clinical studies has been given elsewhere [ 186 ]. Other natural products such as maackiain, cycloastragenol, gamabufotalin, abrine, hymenialdisine, oroxylin A, demethylbelamcandaquinone B, and pitavastatin have been recently shown to promote bone health by enhancing the differentiation and maturation of endogenous molecules that inhibit bone resorption and/or promote osteoblastogenesis, and some of the compounds such as hymenialdisine, cycloastragenol, 12-deoxyphorbol 13-acetate, aerophobin-1, and pitavastatin have been demonstrated to be bioactive in both in vitro and in vivo experiments [ 187 , 188 , 189 , 190 , 191 , 192 , 193 , 194 , 195 , 196 ]. Nonetheless, further studies towards the enhancement of the protein levels of these endogenous osteoprotective molecules and their receptors hold promise towards finding novel interventions in the prevention, treatment, or management of BDs.…”

Section: Cellular and Molecular Mechanisms Of Bone Health-promoting P...mentioning

confidence: 99%

A Review on the Molecular Mechanisms of Action of Natural Products in Preventing Bone Diseases

Okagu

Ezeorba

Aguchem

et al. 2022

IJMS

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The drugs used for treating bone diseases (BDs), at present, elicit hazardous side effects that include certain types of cancers and strokes, hence the ongoing quest for the discovery of alternatives with little or no side effects. Natural products (NPs), mainly of plant origin, have shown compelling promise in the treatments of BDs, with little or no side effects. However, the paucity in knowledge of the mechanisms behind their activities on bone remodeling has remained a hindrance to NPs’ adoption. This review discusses the pathological development of some BDs, the NP-targeted components, and the actions exerted on bone remodeling signaling pathways (e.g., Receptor Activator of Nuclear Factor κ B-ligand (RANKL)/monocyte/macrophage colony-stimulating factor (M-CSF)/osteoprotegerin (OPG), mitogen-activated protein kinase (MAPK)s/c-Jun N-terminal kinase (JNK)/nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), Kelch-like ECH-associated protein 1 (Keap-1)/nuclear factor erythroid 2–related factor 2 (Nrf2)/Heme Oxygenase-1 (HO-1), Bone Morphogenetic Protein 2 (BMP2)-Wnt/β-catenin, PhosphatidylInositol 3-Kinase (PI3K)/protein kinase B (Akt)/Glycogen Synthase Kinase 3 Beta (GSK3β), and other signaling pathways). Although majority of the studies on the osteoprotective properties of NPs against BDs were conducted ex vivo and mostly on animals, the use of NPs for treating human BDs and the prospects for future development remain promising.

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Oroxylin A reduces osteoclast formation and bone resorption via suppressing RANKL-induced ROS and NFATc1 activation

Cited by 62 publications

References 49 publications

Modulation of Differentiation and Bone Resorbing Activity of Human (Pre-) Osteoclasts After X-Ray Exposure

Modulation of Differentiation and Bone Resorbing Activity of Human (Pre-) Osteoclasts After X-Ray Exposure

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

A Review on the Molecular Mechanisms of Action of Natural Products in Preventing Bone Diseases

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