Advanced glycation end products induced IL-6 and VEGF-A production and apoptosis in osteocyte-like MLO-Y4 cells by activating RAGE and ERK1/2, P38 and STAT3 signalling pathways

Chen, Helin; Liu, Wenjia; Wu, Xiangnan; Gou, Min; Shen, Jiefei; Wang, Hang

doi:10.1016/j.intimp.2017.09.004

Cited by 33 publications

(37 citation statements)

References 35 publications

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“…Involve in gap junction; maintain intercellular communication and mechanical response 42,43,158 Beclin-1 Inhibit the oxidative stress; protect the survival of osteocytes [21][22][23]27 LC3 Inhibit the oxidative stress; protect the survival of osteocytes [21][22][23]28 PTH Reverse the osteocyte apoptosis; promote gap junction-mediated intercellular coupling; stimulate Ca +2 influx [133][134][135]137 VEGF Couple angiogenesis and osteogenesis; preserve osteocytic vitality 140,141 β1-integrin Regulate stretch-induced ERK activation; preserve osteocytic vitality 93 Caveolin-1 Involve in mechanotransduction in osteocytes 55…”

Section: Cx43mentioning

confidence: 99%

“…Based on these findings, it is tempting to speculate that apoptosis of osteocytes functions as a gatekeeper of the regulatory inflammatory responses in pathological bone diseases. Until recently, it was found that receptor for advanced glycation end products (RAGE) has an essential role in upregulating the expression level of IL-6 and VEGF-A in MLO-Y4 cells, as well as in advanced glycation end products (AGEs)induced osteocyte apoptosis 93,94 . Specifically, it is indicated that AGEs activate the downstream signals pathways (e.g., ERK1/2, p38, and STAT3) via RAGE, thus allowing both upregulating the production of IL-6 and VEGF-A in osteocytes in a dose-and time-dependent way and inducing osteocytic apoptosis 93 (Fig.…”

Section: Tnf-α and Inflammationmentioning

confidence: 99%

“…Typically, RAGE is upregulated in states of chronic inflammation, such as rheumatoid arthritis, aging-and diabetes-related osteoporosis 94 . Once AGEs bind to RAGE, the upregulation of nuclear factor kappa-B (NF-κB) is exacerbated, which in turn increases the production of AGEs, IL-6, and VEGF-A from apoptotic osteocytes in an amplifying loop mechanism, consequently promoting osteocyte apoptosis 93 . In addition, it also was suggested that not only osteocytic apoptosis but also its dysfunction both could be induced by AGEs.…”

Section: Tnf-α and Inflammationmentioning

confidence: 99%

“…As described above, RAGE is expressed in many cell types including osteoblasts, osteoclasts, and osteocytes. Normally, it is, under physiological conditions, expressed in the human body at a low level, and has a crucial role in regulating bone metabolism 93,94 . Importantly, RAGE signaling is suggested to be mainly correlated with age-and inflammation-related bone diseases (Fig.…”

Section: Ages-rage/hmgb1-rage Pathwaysmentioning

confidence: 99%

“…Instead, the diabetes-related bone loss may be rescued by irbesartan (an angiotensin II receptor antagonist) via blocking the AGEs/RAGE-mediated oxidative stress pathway 105 . Increasing evidence indicates that AGEs are crucial regulators of the pathogenesis and development of resorption-related bone diseases 93,94,106 . This is in line with the notion that Tanaka et al 107 reported that AGEs could enhance the production of osteocytic DNA fragments correlated with apoptosis.…”

Section: Ages-rage/hmgb1-rage Pathwaysmentioning

confidence: 99%

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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: Cx43mentioning

confidence: 99%

Section: Tnf-α and Inflammationmentioning

confidence: 99%

Section: Tnf-α and Inflammationmentioning

confidence: 99%

Section: Ages-rage/hmgb1-rage Pathwaysmentioning

confidence: 99%

Section: Ages-rage/hmgb1-rage Pathwaysmentioning

confidence: 99%

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

Wang

2020

Cell Death Dis

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

Davis

Valdez

Gomez

et al. 2019

J of Cellular Biochemistry

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Old age and Cx43 deletion in osteocytes are associated with increased osteocyte apoptosis and osteoclastogenesis. We previously demonstrated that apoptotic osteocytes release elevated concentrations of the proinflammatory cytokine, high mobility group box 1 protein (HMGB1) and apoptotic osteocyte conditioned media (CM) promotes osteoclast differentiation. Further, prevention of osteocyte apoptosis blocks osteoclast differentiation and attenuates the extracellular release of HMGB1 and RANKL. Moreover, sequestration of HMGB1, in turn, reduces RANKL production/release by MLO‐Y4 osteocytic cells silenced for Cx43 (Cx43def), highlighting the possibility that HMGB1 promotes apoptotic osteocyte‐induced osteoclastogenesis. However, the role of HMGB1 signaling in osteocytes has not been well studied. Further, the mechanisms underlying its release and the receptor(s) responsible for its actions is not clear. We now report that a neutralizing HMGB1 antibody reduces osteoclast formation in RANKL/M‐CSF treated bone marrow cells. In bone marrow macrophages (BMMs), toll‐like receptor 4 (TLR4) inhibition with LPS‐RS, but not receptor for advanced glycation end products (RAGE) inhibition with Azeliragon attenuated osteoclast differentiation. Further, inhibition of RAGE but not of TLR4 in osteoclast precursors reduced osteoclast number, suggesting that HGMB1 produced by osteoclasts directly affects differentiation by activating TLR4 in BMMs and RAGE in preosteoclasts. Our findings also suggest that increased osteoclastogenesis induced by apoptotic osteocytes CM is not mediated through HMGB1/RAGE activation and that direct HMGB1 actions in osteocytes stimulate pro‐osteoclastogenic signal release from Cx43def osteocytes. Based on these findings, we propose that HMGB1 exerts dual effects on osteoclasts, directly by inducing differentiation through TLR4 and RAGE activation and indirectly by increasing pro‐osteoclastogenic cytokine secretion from osteocytes.

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AGEs induce epithelial to mesenchymal transformation of human peritoneal mesothelial cells via upregulation of STAT3

2019

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Advanced glycation end products induced IL-6 and VEGF-A production and apoptosis in osteocyte-like MLO-Y4 cells by activating RAGE and ERK1/2, P38 and STAT3 signalling pathways

Cited by 33 publications

References 35 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 protein regulates osteoclastogenesis through direct actions on osteocytes and osteoclasts in vitro

AGEs induce epithelial to mesenchymal transformation of human peritoneal mesothelial cells via upregulation of STAT3

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