Elevation of the unfolded protein response increases RANKL expression

Iyer, Srividhya; Melendez‐Suchi, Christian; Han, Li; Baldini, Giulia; Almeida, Maria; Jilka, Robert L.

doi:10.1096/fba.2019-00032

Cited by 8 publications

(5 citation statements)

References 75 publications

(118 reference statements)

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“…DNA damage and ER stress stimulate the production of the proresorptive cytokine receptor activator of NF‐κB ligand (RANKL) 31–33 . Stimulation of RANKL by these cellular stressors is thought to contribute to the increase in bone resorption and thereby contribute to bone loss in pathological conditions associated with elevated DNA damage 33 and ER stress 31 .…”

Section: Resultsmentioning

confidence: 99%

“…DNA damage and ER stress stimulate the production of the proresorptive cytokine receptor activator of NF‐κB ligand (RANKL). 31 , 32 , 33 Stimulation of RANKL by these cellular stressors is thought to contribute to the increase in bone resorption and thereby contribute to bone loss in pathological conditions associated with elevated DNA damage 33 and ER stress. 31 We have previously shown that CMA deficiency causes an increase in Rankl ( Tnfsf11) mRNA levels in vitro and in vivo 15 ; however, whether CMA influences DNA‐damage‐ or ER stress‐ induced elevation of RANKL is unknown.…”

Section: Resultsmentioning

confidence: 99%

“… 31 , 32 , 33 Stimulation of RANKL by these cellular stressors is thought to contribute to the increase in bone resorption and thereby contribute to bone loss in pathological conditions associated with elevated DNA damage 33 and ER stress. 31 We have previously shown that CMA deficiency causes an increase in Rankl ( Tnfsf11) mRNA levels in vitro and in vivo 15 ; however, whether CMA influences DNA‐damage‐ or ER stress‐ induced elevation of RANKL is unknown. To test this, we exposed UAMS‐32 cells to genotoxic stress induced by etoposide or ER stress induced by tunicamycin.…”

Section: Resultsmentioning

confidence: 99%

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Loss of chaperone‐mediated autophagy does not alter age‐related bone loss in male mice

Hendrixson,

James,

Akel

et al. 2024

FASEB BioAdvances

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Chaperone‐mediated autophagy (CMA) is a lysosome‐dependent degradation pathway that eliminates proteins that are damaged, partially unfolded, or targeted for selective proteome remodeling. CMA contributes to several cellular processes, including stress response and proteostasis. Age‐associated increase in cellular stressors and decrease in CMA contribute to pathologies associated with aging in various tissues. CMA contributes to bone homeostasis in young mice. An age‐associated reduction in CMA was reported in osteoblast lineage cells; however, whether declining CMA contributes to skeletal aging is unknown. Herein we show that cellular stressors stimulate CMA in UAMS‐32 osteoblastic cells. Moreover, the knockdown of an essential component of the CMA pathway, LAMP2A, sensitizes osteoblasts to cell death caused by DNA damage, ER stress, and oxidative stress. As elevations in these stressors are thought to contribute to age‐related bone loss, we hypothesized that declining CMA contributes to the age‐associated decline in bone formation by sensitizing osteoblast lineage cells to elevated stressors. To test this, we aged male CMA‐deficient mice and controls up to 24 months of age and examined age‐associated changes in bone mass and architecture. We showed that lack of CMA did not alter age‐associated decline in bone mineral density as measured by dual x‐ray absorptiometry (DXA). Moreover, microCT analysis performed at 24 months of age showed that vertebral cancellous bone volume, cortical thickness, and porosity of CMA‐deficient and control mice were similar. Taken together, these results suggest that reduction of CMA does not contribute to age‐related bone loss.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

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Loss of chaperone‐mediated autophagy does not alter age‐related bone loss in male mice

Hendrixson,

James,

Akel

et al. 2024

FASEB BioAdvances

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“…The UPR increased the expression of RANKL in osteoblasts and osteocytes, thus indirectly promoting osteoclast formation and bone resorption [125]. The IRE1-XBP1 signaling pathway activated parathyroid hormone receptor-1 (PTH1R) transcription in osteoblasts, and PTH (parathyroid hormone)/PTH-related peptide promoted RANKL expression in osteoblasts via PTH1R, thereby promoting osteoclast differentiation [15].…”

Section: Upr and The Expression Of Rankl In Osteoblastsmentioning

confidence: 99%

ER Stress, the Unfolded Protein Response and Osteoclastogenesis: A Review

2023

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Endoplasmic reticulum (ER) stress and its adaptive mechanism, the unfolded protein response (UPR), are triggered by the accumulation of unfolded and misfolded proteins. During osteoclastogenesis, a large number of active proteins are synthesized. When an imbalance in the protein folding process occurs, it causes osteoclasts to trigger the UPR. This close association has led to the role of the UPR in osteoclastogenesis being increasingly explored. In recent years, several studies have reported the role of ER stress and UPR in osteoclastogenesis and bone resorption. Here, we reviewed the relevant literature and discussed the UPR signaling cascade response, osteoclastogenesis-related signaling pathways, and the role of UPR in osteoclastogenesis and bone resorption in detail. It was found that the UPR signal (PERK, CHOP, and IRE1-XBP1) promoted the expression of the receptor activator of the nuclear factor-kappa B ligand (RANKL) in osteoblasts and indirectly enhanced osteoclastogenesis. IRE1 promoted osteoclastogenesis via promoting NF-κB, MAPK signaling, or the release of pro-inflammatory factors (IL-6, IL-1β, and TNFα). CREBH promoted osteoclast differentiation by promoting NFATc1 expression. The PERK signaling pathway also promoted osteoclastogenesis through NF-κB and MAPK signaling pathways, autophagy, and RANKL secretion from osteoblasts. However, salubrinal (an inhibitor of eIF2α dephosphorylation that upregulated p-eIF2α expression) directly inhibited osteoclastogenesis by suppressing NFATc1 expression and indirectly promoted osteoclastogenesis by promoting RANKL secretion from osteoblasts. Therefore, the specific effects and mechanisms of p-PERK and its downstream signaling on osteoclastogenesis still need further experiments to confirm. In addition, the exact role of ATF6 and BiP in osteoclastogenesis also required further exploration. In conclusion, our detailed and systematic review provides some references for the next step to fully elucidate the relationship between UPR and osteoclastogenesis, intending to provide new insights for the treatment of diseases caused by osteoclast over-differentiation, such as osteoporosis.

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“…Besides, the calcium signaling also control the growth and differentiation of BMSCs, and related downstream signaling pathways can be activated through the release of Ca 2+ from endoplasmic reticulum to elicit its regulatory effects on BMSCs differentiation [ 31 ]. During the ER stress, the efflux of Ca 2+ from endoplasmic reticulum would function as an important regulative signaling on the cellular behaviors, and the UPR induced by ER stress also could promote the RANKL expression in primary osteoblastic progenitors [ 32 ]. All the previous reports suggest some potential correlations among the ER stress, osteoblastogenesis and osteoclastogenesis.…”

Section: Introductionmentioning

confidence: 99%