Zoledronic acid regulates the synthesis and secretion of IL-1β through Histone methylation in macrophages

Yang, Xiaojie; Xu, Xing; Wang, Qing; Wang, Guangfei; Ai, Xuemin; Wang, Xu; Pan, Jinsong

doi:10.1038/s41420-020-0273-4

Cited by 16 publications

(9 citation statements)

References 39 publications

(46 reference statements)

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“…Zoledronic acid triggers M1-like macrophage polarization and increases the mRNA and protein levels of IL-1β by activating the NLRP3 inflammasome and cleaving pro-caspase-1 in LPS-primed THP-1 cells; these effects can be reversed by silencing of ASC ( 131 ). Zoledronic acid also induces caspase-1-dependent and GSDMD-mediated pyroptosis and secretion of IL-1β in RAW264.7 cells, by mediating methylation of histone H3 (H3k27me3) ( 193 ). Furthermore, increased numbers of Th17 cells and IL-17 levels were found to be correlated with elevation of the M1/M2 macrophage ratio in human and murine BRONJ lesions ( 302 ).…”

Section: Inflammasomes In Inflammatory Osteolysis Of the Alveolar Bone And Jawsmentioning

confidence: 99%

Inflammasomes in Alveolar Bone Loss

Ling

Jiang

2021

Front. Immunol.

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Bone remodeling is tightly controlled by osteoclast-mediated bone resorption and osteoblast-mediated bone formation. Fine tuning of the osteoclast–osteoblast balance results in strict synchronization of bone resorption and formation, which maintains structural integrity and bone tissue homeostasis; in contrast, dysregulated bone remodeling may cause pathological osteolysis, in which inflammation plays a vital role in promoting bone destruction. The alveolar bone presents high turnover rate, complex associations with the tooth and periodontium, and susceptibility to oral pathogenic insults and mechanical stress, which enhance its complexity in host defense and bone remodeling. Alveolar bone loss is also involved in systemic bone destruction and is affected by medication or systemic pathological factors. Therefore, it is essential to investigate the osteoimmunological mechanisms involved in the dysregulation of alveolar bone remodeling. The inflammasome is a supramolecular protein complex assembled in response to pattern recognition receptors and damage-associated molecular patterns, leading to the maturation and secretion of pro-inflammatory cytokines and activation of inflammatory responses. Pyroptosis downstream of inflammasome activation also facilitates the clearance of intracellular pathogens and irritants. However, inadequate or excessive activity of the inflammasome may allow for persistent infection and infection spreading or uncontrolled destruction of the alveolar bone, as commonly observed in periodontitis, periapical periodontitis, peri-implantitis, orthodontic tooth movement, medication-related osteonecrosis of the jaw, nonsterile or sterile osteomyelitis of the jaw, and osteoporosis. In this review, we present a framework for understanding the role and mechanism of canonical and noncanonical inflammasomes in the pathogenesis and development of etiologically diverse diseases associated with alveolar bone loss. Inappropriate inflammasome activation may drive alveolar osteolysis by regulating cellular players, including osteoclasts, osteoblasts, osteocytes, periodontal ligament cells, macrophages, monocytes, neutrophils, and adaptive immune cells, such as T helper 17 cells, causing increased osteoclast activity, decreased osteoblast activity, and enhanced periodontium inflammation by creating a pro-inflammatory milieu in a context- and cell type-dependent manner. We also discuss promising therapeutic strategies targeting inappropriate inflammasome activity in the treatment of alveolar bone loss. Novel strategies for inhibiting inflammasome signaling may facilitate the development of versatile drugs that carefully balance the beneficial contributions of inflammasomes to host defense.

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Section: Inflammasomes In Inflammatory Osteolysis Of the Alveolar Bone And Jawsmentioning

confidence: 99%

Inflammasomes in Alveolar Bone Loss

Ling

Jiang

2021

Front. Immunol.

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“…Moreover, the capacity of PC1 to prevent BTZ-induced increase of some proinflammatory cytokines, such as IL-1β, suggests that PK system might epigenetically regulate inflammatory processes involved in pain maintenance. In this regard, previous studies showed the KDM6A’s ability to regulate H3k27me3 demethylation at the IL-1β gene promoter [ 42 ].…”

Section: Discussionmentioning

confidence: 99%

Interplay between Prokineticins and Histone Demethylase KDM6A in a Murine Model of Bortezomib-Induced Neuropathy

Rullo

Franchi

Amodeo

et al. 2021

IJMS

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Chemotherapy-induced neuropathy (CIN) is a major adverse effect associated with many chemotherapeutics, including bortezomib (BTZ). Several mechanisms are involved in CIN, and recently a role has been proposed for prokineticins (PKs), a chemokine family that induces proinflammatory/pro-algogen mediator release and drives the epigenetic control of genes involved in cellular differentiation. The present study evaluated the relationships between epigenetic mechanisms and PKs in a mice model of BTZ-induced painful neuropathy. To this end, spinal cord alterations of histone demethylase KDM6A, nuclear receptors PPARα/PPARγ, PK2, and pro-inflammatory cytokines IL-6 and IL-1β were assessed in neuropathic mice treated with the PK receptors (PKRs) antagonist PC1. BTZ treatment promoted a precocious upregulation of KDM6A, PPARs, and IL-6, and a delayed increase of PK2 and IL-1β. PC1 counteracted allodynia and prevented the increase of PK2 and of IL-1β in BTZ neuropathic mice. The blockade of PKRs signaling also opposed to KDM6A increase and induced an upregulation of PPAR gene transcription. These data showed the involvement of epigenetic modulatory enzymes in spinal tissue phenomena associated with BTZ painful neuropathy and underline a role of PKs in sustaining the increase of proinflammatory cytokines and in exerting an inhibitory control on the expression of PPARs through the regulation of KDM6A gene expression in the spinal cord.

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“…Recent studies have revealed an essential role of macrophages in the development of BRONJ ( Zhu et al, 2019 ; Yang et al, 2020 ; Zhao et al, 2020 ). We previously showed that macrophages orchestrate inflammation trends by shifting their phenotypes in microenvironment, in which efferocytosis is necessary for its anti-inflammatory response ( Zhu et al, 2019 ).…”

Section: Discussionmentioning

confidence: 99%

Geranylgeraniol Restores Zoledronic Acid-Induced Efferocytosis Inhibition in Bisphosphonate-Related Osteonecrosis of the Jaw

Chen

Zhu

et al. 2021

Front. Cell Dev. Biol.

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Bisphosphonate-related osteonecrosis of the jaw (BRONJ) is a severe side effect of long-term administration of bisphosphonates such as zoledronic acid (ZA), but its pathogenesis remains unclear. Impairment of the clearance of apoptotic cells (termed “efferocytosis”) by ZA may be associated with the pathogenesis of BRONJ. The aim of this study was to investigate whether ZA might inhibit macrophage efferocytosis and promote osteocytic apoptosis, and the underlying mechanisms responsible for the disturbing balance between clean and generation of osteocytic apoptosis. We found that ZA significantly promoted the apoptosis of osteocyte and pre-osteoblast via BRONJ mouse models and in vitro MC3T3-E1 but also inhibited the efferocytosis of macrophage on apoptotic cells. Moreover, supplement with geranylgeraniol (GGOH), a substrate analog for geranylgeranylation of Rac1, could restore Rac1 homeostasis and rescue macrophage efferocytosis. GGOH partially inhibits MC3T3-E1 apoptosis induced by ZA via downregulation of Rac1/JNK pathway. We also examined the Rac1 distribution and activation conditions in bone marrow-derived macrophages (BMDMs) and MC3T3-E1 under ZA treatment, and we found that ZA impaired Rac1 migration to BMDM membrane, leading to round appearance with less pseudopodia and efferocytosis inhibition. Moreover, ZA simultaneously activated Rac1, causing overexpression of P-JNK and cleaved caspase 3 in MC3T3-E1. Finally, the systemic administration of GGOH decreased the osteocytic apoptosis and improved the bone healing of the extraction sockets in BRONJ mouse models. Taken together, our findings provided a new insight and experimental basis for the application of GGOH in the treatment of BRONJ.

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Zoledronic acid regulates the synthesis and secretion of IL-1β through Histone methylation in macrophages

Cited by 16 publications

References 39 publications

Inflammasomes in Alveolar Bone Loss

Inflammasomes in Alveolar Bone Loss

Interplay between Prokineticins and Histone Demethylase KDM6A in a Murine Model of Bortezomib-Induced Neuropathy

Geranylgeraniol Restores Zoledronic Acid-Induced Efferocytosis Inhibition in Bisphosphonate-Related Osteonecrosis of the Jaw

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