Autophagy inhibitors 3-MA and LY294002 repress osteoclastogenesis and titanium particle-stimulated osteolysis

Chen, Weishen; Xian, Guoyan; Gu, Minghui; Pan, Baiqi; Wu, Xiaoyu; Ye, Yongyu; Zheng, Lirong; Zhang, Ziji; Sheng, Puyi

doi:10.1039/d1bm00691f

Cited by 18 publications

(11 citation statements)

References 47 publications

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“…To test if other autophagy inhibitors support this proposed mechanism, four different inhibitors were investigated for their effects on OC formation; 3-methoxyamphetamine (3MA, class I PI3K inhibitor) and SAR405, both of which are VPS34 inhibitors and prevent the nucleation process upstream of autophagy as well as BafA1 and CQ, both lysosomal inhibitors, that disrupt the completion process of autophagy 47,48 . All these four reagents were able to significantly inhibit OC formation consistent with previous published findings for 3MA 49 , CQ 8 , and BafA1 50 (Supplementary Fig. 6e, f).…”

Section: Eliglustat Is An Autophagy Inhibitor That Prevents Autolysos...supporting

confidence: 90%

Modulating glycosphingolipid metabolism and autophagy improves outcomes in pre-clinical models of myeloma bone disease

Leng

Zhang

et al. 2022

Nat Commun

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Patients with multiple myeloma, an incurable malignancy of plasma cells, frequently develop osteolytic bone lesions that severely impact quality of life and clinical outcomes. Eliglustat, a U.S. Food and Drug Administration-approved glucosylceramide synthase inhibitor, reduced osteoclast-driven bone loss in preclinical in vivo models of myeloma. In combination with zoledronic acid, a bisphosphonate that treats myeloma bone disease, eliglustat provided further protection from bone loss. Autophagic degradation of TRAF3, a key step for osteoclast differentiation, was inhibited by eliglustat as evidenced by TRAF3 lysosomal and cytoplasmic accumulation. Eliglustat blocked autophagy by altering glycosphingolipid composition whilst restoration of missing glycosphingolipids rescued autophagy markers and TRAF3 degradation thus restoring osteoclastogenesis in bone marrow cells from myeloma patients. This work delineates both the mechanism by which glucosylceramide synthase inhibition prevents autophagic degradation of TRAF3 to reduce osteoclastogenesis as well as highlighting the clinical translational potential of eliglustat for the treatment of myeloma bone disease.

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Section: Eliglustat Is An Autophagy Inhibitor That Prevents Autolysos...supporting

confidence: 90%

Modulating glycosphingolipid metabolism and autophagy improves outcomes in pre-clinical models of myeloma bone disease

Leng

Zhang

et al. 2022

Nat Commun

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“…The average diameter of the Ti particles is 3.2 ± 2.7 μm. The Ti particle storage solution is washed with 70% ethanol and autoclaved to remove endotoxins, according to the previously published methods ( Yang et al, 2018 ; Xian et al, 2020 ; Chen et al, 2021 ). After sterility is ensured, the Limulus assistant kit (Xiamen Houshiji, Fujian, China) is used to determine the endotoxin, and endotoxins <0.01 Eu can be used for experiments in vivo and in vitro .…”

Section: Methodsmentioning

confidence: 99%

“…The cells were seeded into a 12-well plate at a density of 2 × 10 4 cells per milliliter and incubated at 37°C with 5% CO 2 . According to a previous article ( Chen et al, 2021 ), the induction medium (30 ng/ml RANKL, α-MEM) was changed once a day after the cells adhered for 24 h. OCs in the fusion phase began to appear on the third to fourth days. On the fifth day, OCs were identified by TRAP staining, and cells with more than three nuclei were defined as TRAP-positive cells.…”

Section: Methodsmentioning

confidence: 99%

“…The autophagy process regulates the survival and mineralization of osteoblasts (OBs) and the bone resorption function of OCs ( Wang et al, 2015 ; Wang et al, 2017 ; Camuzard et al, 2019 ). Our previous study revealed that autophagy regulation by macrophages is closely related to the progress of inflammatory osteolysis in APL ( Xian et al, 2020 ; Chen et al, 2021 ). The present study suggests that BECN1 contributes to receptor activator of nuclear factor-kappa B ligand (RANKL)-induced OC differentiation as a molecular link that mediates mitochondrial reactive oxygen species (mROS) and nuclear factor of activated T-cell cytoplasmic 1 (NFATc-1) expression.…”

Section: Introductionmentioning

confidence: 99%

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SPHK Inhibitors and Zoledronic Acid Suppress Osteoclastogenesis and Wear Particle-Induced Osteolysis

Pan

Chen

et al. 2022

Front. Pharmacol.

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Background: Inflammatory osteolysis induced by wear particles is the major cause of prosthetic loosening after artificial joint replacement, and its prevention and treatment are difficult worldwide. Our previous study confirmed that sphingosine kinases (SPHKs) are important mediators regulating the wear particle-induced macrophage inflammatory response. However, it is unclear whether SPHKs can modulate chronic inflammation and alleviate osteolysis. Zoledronic acid (ZA), an imidazole-containing bisphosphonate, directly affects osteoclasts and prevents bone mineral-related diseases. However, the effects of SPHK inhibitors and ZA used to treat periprosthetic osteolysis are unknown.Methods: We applied tartrate-resistant acid phosphatase (TRAP) staining to evaluate bone destruction in the interface membranes of patients with aseptic loosening and a control group. A murine calvarial osteolysis model was used to examine the preventative effect of SPHK inhibitors and ZA on osteolysis. Micro-CT scanning, immunohistochemistry (IHC), and histomorphometric analysis were conducted to determine the variations in inflammatory osteolysis. The effects of different drug concentrations on cell viability were evaluated using the Cell Counting Kit-8 (CCK-8) assay. Real-time quantitative polymerase chain reaction (RT-qPCR) analysis was performed to confirm the reduced expression of osteoclast-specific genes after drug and titanium treatment. The osteoclast formation and functions of the drugs were analyzed using TRAP staining in vivo and in vitro. The effect of SPHKs/S1P-TRAF2-BECN1 signaling pathways was verified via RT-qPCR and tissue IHC.Results: In this study, we found that SPHK inhibitors (ABC294640 and FTY720) combined with ZA decreased the degree of inflammatory osteolysis in vivo. However, ABC294640 and ZA suppressed osteoclast differentiation and osteoclast-specific genes in vitro. SPHKs regulate the inflammatory osteolysis induced by wear particles by increasing the expression of SPHKs/S1P-TRAF2-BECN1.Conclusion: Our study revealed that wear particles could induce inflammatory osteolysis by upregulating SPHKs/S1P-TRAF2-BECN1 and SPHK inhibitors/ZA inhibit osteoclastogenesis in vitro and prevent inflammatory osteolysis in vivo, suggesting that SPHK inhibitors and ZA can be a new perspective and scientific basis for the prevention and treatment of prosthesis loosening.

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“…In this series of biological activities, the release of receptor activator of nuclear kappa-B ligand (RANKL) and its binding to receptor RANK are central events, which directly promote osteoclastogenesis and subsequent osteolysis (Zhai et al, 2014;Zhao et al, 2016;Ping et al, 2017). After being stimulated by wear particles, cells in PM can undergo multiple modes of regulated cell death (RCD), including autophagy (Chen et al, 2021), apoptosis (Deng et al, 2017b), pyroptosis (Zhang et al, 2022) and even ferroptosis . Among them, autophagy is a wellstudied RCD mode, which plays a pivotal role in PPO.…”

Section: Introductionmentioning

confidence: 99%

The dual role of autophagy in periprosthetic osteolysis

Yin

Gong²,

Wang³

et al. 2023

Front. Cell Dev. Biol.

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Periprosthetic osteolysis (PPO) induced by wear particles is an important cause of aseptic loosening after artificial joint replacement, among which the imbalance of osteogenesis and osteoclastic processes occupies a central position. The cells involved in PPO mainly include osteoclasts (macrophages), osteoblasts, osteocytes, and fibroblasts. RANKL/RANK/OGP axis is a typical way for osteolysis. Autophagy, a mode of regulatory cell death and maintenance of cellular homeostasis, has a dual role in PPO. Although autophagy is activated in various periprosthetic cells and regulates the release of inflammatory cytokines, osteoclast activation, and osteoblast differentiation, its beneficial or detrimental role remains controversy. In particular, differences in the temporal control and intensity of autophagy may have different effects. This article focuses on the role of autophagy in PPO, and expects the regulation of autophagy to become a powerful target for clinical treatment of PPO.

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Autophagy inhibitors 3-MA and LY294002 repress osteoclastogenesis and titanium particle-stimulated osteolysis

Abstract: Aseptic loosening caused by peri-implant osteolysis (PIO) is a common complication after joint replacement, and there is still no better treatment than revision surgery. The wear particle-induced inflammation response, especially...

Cited by 18 publications

References 47 publications

Modulating glycosphingolipid metabolism and autophagy improves outcomes in pre-clinical models of myeloma bone disease

Modulating glycosphingolipid metabolism and autophagy improves outcomes in pre-clinical models of myeloma bone disease

SPHK Inhibitors and Zoledronic Acid Suppress Osteoclastogenesis and Wear Particle-Induced Osteolysis

The dual role of autophagy in periprosthetic osteolysis

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