TMBIM6 deficiency leads to bone loss by accelerating osteoclastogenesis

Yi, Sun‐Ju; Jang, You-Jee; Lee, S.; Cho, Sung‐Jin; Kang, Ki‐Woon; Park, Jaeil; Chae, Han-Jung; Kim, Hyung‐Ryong; Kim, Kyunghwan

doi:10.1016/j.redox.2023.102804

Cited by 4 publications

(3 citation statements)

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“…The gene Eyes absent homolog 4 ( EYA4 ) plays a putative tumor-promoting role in nervous system tumors ( Chong et al, 2023 ) and was found to promote cell proliferation in GBM ( Li et al, 2018b ). Transmembrane BAX inhibitor motif containing 6 ( TMBIM6 ) is elevated in GBM but may be downregulated in other tumor entities; it may be associated with tumor growth and dependent signaling ( Yi et al, 2023 ). Knockdown of the Poly(U) binding splicing factor 60 ( PUF60 ) reduced GBM tumorigenicity and proliferation ( Wang et al, 2022 ).…”

Section: Resultsmentioning

confidence: 99%

Molecular landscapes of glioblastoma cell lines revealed a group of patients that do not benefit from WWOX tumor suppressor expression

Kałuzińska-Kołat,

Kołat,

Kośla

et al. 2023

Front. Neurosci.

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IntroductionGlioblastoma (GBM) is notorious for its clinical and molecular heterogeneity, contributing to therapeutic failure and a grim prognosis. WWOX is one of the tumor suppressor genes important in nervous tissue or related pathologies, which was scarcely investigated in GBM for reliable associations with prognosis or disease progression despite known alterations. Recently, we observed a phenotypic heterogeneity between GBM cell lines (U87MG, T98G, U251MG, DBTRG-05MG), among which the anti-GBM activity of WWOX was generally corresponding, but colony growth and formation were inconsistent in DBTRG-05MG. This prompted us to investigate the molecular landscapes of these cell lines, intending to translate them into the clinical context.MethodsU87MG/T98G/U251MG/DBTRG-05MG were subjected to high-throughput sequencing, and obtained data were explored via weighted gene co-expression network analysis, differential expression analysis, functional annotation, and network building. Following the identification of the most relevant DBTRG-distinguishing driver genes, data from GBM patients were employed for, e.g., differential expression analysis, survival analysis, and principal component analysis.ResultsAlthough most driver genes were unique for each cell line, some were inversely regulated in DBTRG-05MG. Alongside driver genes, the differentially-expressed genes were used to build a WWOX-related network depicting protein–protein interactions in U87MG/T98G/U251MG/DBTRG-05MG. This network revealed processes distinctly regulated in DBTRG-05MG, e.g., microglia proliferation or neurofibrillary tangle assembly. POLE4 and HSF2BP were selected as DBTRG-discriminating driver genes based on the gene significance, module membership, and fold-change. Alongside WWOX, POLE4 and HSF2BP expression was used to stratify patients into cell lines-resembling groups that differed in, e.g., prognosis and treatment response. Some differences from a WWOX-related network were certified in patients, revealing genes that clarify clinical outcomes. Presumably, WWOX overexpression in DBTRG-05MG resulted in expression profile change resembling that of patients with inferior prognosis and drug response. Among these patients, WWOX may be inaccessible for its partners and does not manifest its anti-cancer activity, which was proposed in the literature but not regarding glioblastoma or concerning POLE4 and HSF2BP.ConclusionCell lines data enabled the identification of patients among which, despite high expression of WWOX tumor suppressor, no advantageous outcomes were noted due to the cancer-promoting profile ensured by other genes.

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Section: Resultsmentioning

confidence: 99%

Molecular landscapes of glioblastoma cell lines revealed a group of patients that do not benefit from WWOX tumor suppressor expression

Kałuzińska-Kołat,

Kołat,

Kośla

et al. 2023

Front. Neurosci.

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“…8 ROS, which function as intracellular second messengers, play a significant role in stimulating osteoclast differentiation and maturation by activating nuclear factor-κB (NF-κB) and mitogen-activated protein kinase (MAPK) signaling pathways, ultimately contributing to periprosthetic osteolysis. 9 Furthermore, UHMWPE debris contributes to aseptic loosening by modulating the receptor activator of NF-κB ligand (RANKL) and macrophage colony-stimulating factor (M-CSF), which are pivotal factors in osteoclastogenesis. 10,11 Recent studies effectively indicate that excessive levels of ROS promote osteoclast formation and impede the differentiation of bone marrow mesenchymal stem cells (BMSCs) into osteoblasts.…”

Section: •−mentioning

confidence: 99%

“…It has been demonstrated that the periprosthetic microenvironment comprises significantly elevated levels of reactive oxygen species (ROS) owing to the oxidative stress response of the surrounding cells to accumulated UHMWPE particles. , This wear debris initiates a foreign body reaction and activates the innate immune response, which in turn recruits and activates macrophages to generate ROS, including superoxide (O 2 •– ), hydroxyl radicals ( • OH), and hydroperoxide (H 2 O 2 ) . ROS, which function as intracellular second messengers, play a significant role in stimulating osteoclast differentiation and maturation by activating nuclear factor-κB (NF-κB) and mitogen-activated protein kinase (MAPK) signaling pathways, ultimately contributing to periprosthetic osteolysis . Furthermore, UHMWPE debris contributes to aseptic loosening by modulating the receptor activator of NF-κB ligand (RANKL) and macrophage colony-stimulating factor (M-CSF), which are pivotal factors in osteoclastogenesis. , Recent studies effectively indicate that excessive levels of ROS promote osteoclast formation and impede the differentiation of bone marrow mesenchymal stem cells (BMSCs) into osteoblasts. , This disrupts the balance between bone resorption and bone formation, aggravating the oxidative stress microenvironment and accelerating periprosthetic osteolysis.…”

Section: Introductionmentioning

confidence: 99%

Engineered Niobium Carbide MXenzyme-Integrated Self-Adaptive Coatings Inhibiting Periprosthetic Osteolysis by Orchestrating Osteogenesis–Osteoclastogenesis Balance

Li,

Lu,

Chai

et al. 2024

ACS Appl. Mater. Interfaces

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Periprosthetic osteolysis induced by the ultrahighmolecular-weight polyethylene (UHMWPE) wear particles is a major complication associated with the sustained service of artificial joint prostheses and often necessitates revision surgery. Therefore, a smart implant with direct prevention and repair abilities is urgently developed to avoid painful revision surgery. Herein, we fabricate a phosphatidylserine-and polyethylenimine-engineered niobium carbide (Nb 2 C) MXenzyme-coated micro/nanostructured titanium implant (PPN@MNTi) that inhibits UHMWPE particleinduced periprosthetic osteolysis. The specific mechanism by which PPN@MNTi operates involves the bioresponsive release of nanosheets from the MNTi substrate within an osteolysis microenvironment, initiated by the cleavage of a thioketal−dopamine molecule sensitive to reactive oxygen species (ROS). Subsequently, functionalized Nb 2 C MXenzyme could target macrophages and escape from lysosomes, effectively scavenging intracellular ROS through its antioxidant nanozyme-mimicking activities. This further achieves the suppression of osteoclastogenesis by inhibiting NF-κB/MAPK and autophagy signaling pathways. Simultaneously, based on the synergistic effect of MXenzymeintegrated coatings and micro/nanostructured topography, the designed implant promotes the osteogenic differentiation of bone mesenchymal stem cells to regulate bone homeostasis, further achieving advanced osseointegration and alleviable periprosthetic osteolysis in vivo. This study provides a precise prevention and repair strategy of periprosthetic osteolysis, offering a paradigm for the development of smart orthopedic implants.

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