High mobility group box 1 protein regulates osteoclastogenesis through direct actions on osteocytes and osteoclasts in vitro

Davis, Hannah M.; Valdez, Sinai; Gomez, Leland; Malicky, Peter; White, Fletcher A.; Subler, Mark A.; Windle, Jolene J.; Bidwell, Joseph P.; Bruzzaniti, Angela; Plotkin, Lilian I.

doi:10.1002/jcb.28932

Cited by 16 publications

(15 citation statements)

References 43 publications

(96 reference statements)

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“…This is in consistent with the findings that HMGB1, released during osteocyte apoptosis, directly triggers osteoclastogenesis via activation of RAGE, and consequently increases pro-osteoclastogenic cytokine release (e.g., RANKL) from apoptotic osteocytes 93 . Until recently, it has been demonstrated that while the differentiation and formation of osteoclasts were not inhibited by Cx43 def CM with immunodepletion of HMGB1, it yet was suppressed by Cx43 def CM treated with an HMGB1 neutralizing antibody and then followed by immunodepletion of HMGB1, which indicates that the direct role of HMGB1, but not its indirect role, enhances apoptotic osteocytes-triggered osteoclastogenesis 157 . Similarly, Cx43 def osteocytic cells are found to undergo accelerated apoptosis and ensuing increased release of HMGB1, which directly stimulates pro-osteoclastogenic signal release from Cx43 def osteocytes 41 .…”

Section: The Role Of Apoptotic Osteocytes In Osteoclastogenesis-triggmentioning

confidence: 98%

Osteocyte apoptosis: the roles and key molecular mechanisms in resorption-related bone diseases

Wang

2020

Cell Death Dis

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Vital osteocytes have been well known to function as an important orchestrator in the preservation of robustness and fidelity of the bone remodeling process. Nevertheless, some key pathological factors, such as sex steroid deficiency and excess glucocorticoids, and so on, are implicated in inducing a bulk of apoptotic osteocytes, subsequently resulting in resorption-related bone loss. As much, osteocyte apoptosis, under homeostatic conditions, is in an optimal state of balance tightly controlled by pro- and anti-apoptotic mechanism pathways. Importantly, there exist many essential signaling proteins in the process of osteocyte apoptosis, which has a crucial role in maintaining a homeostatic environment. While increasing in vitro and in vivo studies have established, in part, key signaling pathways and cross-talk mechanism on osteocyte apoptosis, intrinsic and complex mechanism underlying osteocyte apoptosis occurs in various states of pathologies remains ill-defined. In this review, we discuss not only essential pro- and anti-apoptotic signaling pathways and key biomarkers involved in these key mechanisms under different pathological agents, but also the pivotal role of apoptotic osteocytes in osteoclastogenesis-triggered bone loss, hopefully shedding new light on the attractive and proper actions of pharmacotherapeutics of targeting apoptosis and ensuing resorption-related bone diseases such as osteoporosis and fragility fractures.

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Section: The Role Of Apoptotic Osteocytes In Osteoclastogenesis-triggmentioning

confidence: 98%

Osteocyte apoptosis: the roles and key molecular mechanisms in resorption-related bone diseases

Wang

2020

Cell Death Dis

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“…Furthermore, the activation of TLR4 up‐regulates RANKL expression in fibroblasts 29,30 . TLR4 is also expressed in osteoclasts, 31 and HMGB1 might directly promote osteoclast formation by binding to TLR4 on osteoclasts 19 . Indeed, a direct effect of HMGB1 on osteoclast formation has been shown in an in vitro study 20 .…”

Section: Discussionmentioning

confidence: 97%

“…29,30 TLR4 is also expressed in osteoclasts, 31 and HMGB1 might directly promote osteoclast formation by binding to TLR4 on osteoclasts. 19 Indeed, a direct effect of HMGB1 on osteoclast formation has been shown in an in vitro study. 20 Moreover, Davis et al demonstrated that HMGB1 promotes osteoclastogenesis by increasing the secretion of pro-osteoclastogenic cytokines from osteocytes through TLR4 activation.…”

Section: Rankl Expression Was Significantly Increased In Periodontalmentioning

confidence: 98%

“…In damaged cells, HMGB1 is released to the extracellular area and mediates various functions by binding to Toll‐like receptor (TLR)2, TLR4, and receptors for advanced glycation end products 17,18 . Several studies have demonstrated that HMGB1 promotes osteoclast differentiation 19‐22 . Indeed, a previous study demonstrated that bone resorption was accelerated when HMGB1 was administered into the mouse skull in vivo 20 .…”

Section: Introductionmentioning

confidence: 99%

“…17,18 Several studies have demonstrated that HMGB1 promotes osteoclast differentiation. [19][20][21][22] Indeed, a previous study demonstrated that bone resorption was accelerated when HMGB1 was administered into the mouse skull in vivo. 20 Furthermore, administration of anti-HMGB1-neutralizing antibodies attenuated periodontal inflammation and bone resorption in a murine periodontitis model.…”

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confidence: 99%

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High‐mobility group box 1 released by traumatic occlusion accelerates bone resorption in the root furcation area in mice

Oyama

Ukai

Yamashita

et al. 2020

J of Periodontal Research

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Background and objective Traumatic occlusion can cause bone resorption without bacterial infection. Although bone resorption in periodontitis has been relatively well studied, little is known about bone resorption by traumatic occlusion. High‐mobility group box 1 (HMGB1) is released from damaged tissue and has been recently shown to promote bone resorption in a murine periodontitis model and may also promote bone resorption by traumatic occlusion. The present study aimed to examine whether HMGB1 accelerates bone resorption by traumatic occlusion in mice. Materials and methods Occlusal trauma was induced in the lower left first molar of mice by bonding a wire to the upper left first molar, and bone resorption and osteoclast formation were evaluated histochemically. The expression of HMGB1, Toll‐like receptor 4 (TLR4; the receptor for HMGB1), and receptor activator of NFκB ligand (RANKL; an essential osteoclast differentiation factor) was evaluated immunohistologically. In addition, mice were administrated with an anti‐HMGB1‐neutralizing antibody to analyze the role of HMGB1. Results Bone resorption and osteoclast formation gradually increased until day 5 at the furcation area after the application of traumatic occlusion. Expression of HMGB1 was observed at the furcation area on day 1, but was attenuated by day 3. Expression of RANKL gradually increased until day 3, but was attenuated by day 5. Administration of anti‐HMGB1 antibody significantly reduced the number of osteoclasts and the expression of RANKL and TLR4 at the furcation area. Conclusion Release of HMGB1 in the root furcation area accelerated bone resorption by up‐regulating RANKL and TLR4 expression in mice with traumatic occlusion.

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Inhibition of Connexin 36 attenuates HMGB1‐mediated depressive‐like behaviors induced by chronic unpredictable mild stress

Jiang

Zeng

et al. 2022

Brain and Behavior

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Background: High mobility group box 1 (HMGB1) released by neurons and microglia was demonstrated to be an important mediator in depressive-like behaviors induced by chronic unpredictable mild stress (CUMS), which could lead to the imbalance of two different metabolic approaches in kynurenine pathway (KP), thus enhancing glutamate transmission and exacerbating depressive-like behaviors. Evidence showed that HMGB1 signaling might be regulated by Connexin (Cx) 36 in inflammatory diseases of central nervous system (CNS). Our study aimed to further explore the role of Cx36 in depressive-like behaviors and its relationship with HMGB1.Methods: After 4-week chronic stress, behavioral tests were conducted to evaluate depressive-like behaviors, including sucrose preference test (SPT), tail suspension test (TST), forced swimming test (FST), and open field test (OFT). Western blot analysis and immunofluorescence staining were used to observe the expression and location of Cx36. Enzyme-linked immunosorbent assay (ELISA) was adopted to detect the concentrations of inflammatory cytokines. And the excitability and inward currents of hippocampal neurons were recorded by whole-cell patch clamping. Results:The expression of Cx36 was significantly increased in hippocampal neurons of mice exposed to CUMS, while treatment with glycyrrhizinic acid (GZA) or quinine could both down-regulate Cx36 and alleviate depressive-like behaviors. The proinflammatory cytokines like HMGB1, tumor necrosis factor alpha (TNF-α), and interleukin-1β (IL-1β) were all elevated by CUMS, and application of GZA and quinine could decrease them. In addition, the enhanced excitability and inward currents of hippocampal neurons induced by lipopolysaccharide (LPS) could be reduced by either GZA or quinine.Conclusions: Inhibition of Cx36 in hippocampal neurons might attenuates HMGB1mediated depressive-like behaviors induced by CUMS through down-regulation of the proinflammatory cytokines and reduction of the excitability and intracellular ion overload.

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High mobility group box 1 protein regulates osteoclastogenesis through direct actions on osteocytes and osteoclasts in vitro

Cited by 16 publications

References 43 publications

Osteocyte apoptosis: the roles and key molecular mechanisms in resorption-related bone diseases

Osteocyte apoptosis: the roles and key molecular mechanisms in resorption-related bone diseases

High‐mobility group box 1 released by traumatic occlusion accelerates bone resorption in the root furcation area in mice

Inhibition of Connexin 36 attenuates HMGB1‐mediated depressive‐like behaviors induced by chronic unpredictable mild stress

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