Mitochondrial serine metabolism fuels epigenetic remodelling in osteoclast differentiation and is the main target of methotrexate
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ABSTRACT:
PROVIDER: PRJNA1015717 | ENA |
REPOSITORIES: ENA
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Project description:Osteoclasts are specialized myeloid cells with crucial roles in skeletal homeostasis and disease. Differentiation of precursor cells to osteoclasts requires extensive metabolic and epigenetic rewiring, but pathways governing these processes are poorly characterized. Here, we found that transdifferentiation into osteoclasts crucially depends on the generation of one carbon units from serine catabolized by SHMT2. Serine mediatedde novopurine synthesis fuels increased mitochondrial ATP production and ultimately SAM generation necessary for epigenetic repression of macrophage lineage genes. Intriguingly, methotrexate restrains osteoclast precursors from engaging in serine mediated one carbon metabolism, unravelling a hitherto unknown therapeutic mechanism of action. Supplementation of purine precursor metabolites which restore mitochondrial ATP generation fully rescues osteoclastogenesis of SHMT2 knockout or methotrexate inhibited cells. Together, we show an essential role of serine catabolism for metabolic epigenetic coupling in osteoclast differentiation and provide a framework how methotrexate prevents osteoclast-mediated joint destruction.
2025-09-01 | GSE243008 | GEO
Project description:SHORT CHAIN FATTY ACIDS MITIGATE OSTEOCLAST-MEDIATED ARTHRITIC BONE REMODELLING
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Project description:Objective: To study the effects of Short Chain Fatty Acids (SCFAs) on arthritic bone remodeling. Methods: We treated a recently described preclinical murine model of psoriatic arthritis (PsA), R26STAT3Cstopfl/fl CD4Cre mice, with SCFA supplemented water. We also performed in vitro osteoclast differentiation assays in the presence of serum-level SCFAs to evaluate the direct impact of these microbial metabolites on maturation and function of osteoclasts. We further characterized the molecular mechanism of SCFAs by bulk transcriptomics analysis. Results: The osteoporosis condition in R26STAT3Cstopfl/fl CD4Cre animals is attributed primarily to an expansion of osteoclast progenitor cells (OCPs), leading to robust osteoclast differentiation. We show that SCFA supplementation can rescue the osteoporosis phenotype in this model of PsA. Our in vitro experiments revealed an inhibitory effect of the SCFAs on osteoclast differentiation, even at very low serum concentrations. This suppression of osteoclast differentiation enabled SCFAs to impede osteoporosis development in R26STAT3Cstopfl/fl CD4Cre mice. Further interrogation revealed that bone marrow derived OCPs from diseased mice expressed a higher level of SCFA receptors than that of control mice and that the progenitor cells in the bone marrow of SCFA-treated mice presented a modified transcriptomic landscape, suggesting a direct impact by SCFAs on osteoclast progenitors. Conclusion: We demonstrated how gut microbiota-derived SCFAs can regulate distal pathology, i.e., osteoporosis, and identified a potential therapeutic option for restoring bone density in rheumatic disease, further highlighting the critical role of the gut-bone axis in these disorders.
2024-01-01 | GSE241033 | GEO
Project description:bulk sequencing outputs of Caco2 cells after exposure to permeability modifying and permeability rescuing agents. To identify the molecular drivers for methotrexate-induced barrier dysfunction, we conducted RNA sequencing on Caco2 spheroids treated with methotrexate and lactoferrin. Given our observation that barrier function was compromised as early as 4-6 hours after exposure to methotrexate, we isolated RNA from spheroids 4-hour post-treatment to capture the transcriptional events responsible for initiating the processes.
2020-01-10 | GSE140066 | GEO
Project description:Caco2 response to methotrexate, lactoferrin, and methotrexate-lactoferrin co-exposure
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Project description:CSF attenuates methotrexate efficacy
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Project description:Treatment and prophylaxis of the central nervous system (CNS) is a critical component of acute lymphoblastic leukemia (ALL) therapy. However, CNS-directed therapies are a significant cause of morbidity and CNS relapse remains a cause of treatment failure. CNS-directed ALL therapies must target leukemia cells within cerebrospinal fluid (CSF), a fluid that is compositionally distinct from plasma and has been shown to impact leukemia biology. Herein, we demonstrate that human CSF attenuates the potency and efficacy of anti-folate drugs including methotrexate, the primary CNS-directed chemotherapeutic for over six decades. Importantly, this effect of CSF on leukemia methotrexate sensitivity was reversible. Additional mechanistic studies support that diminished proliferation and activation of the integrated stress response (ISR) in leukemia cells in CSF contribute to this resistance. Our findings suggest potential strategies to enhance methotrexate efficacy in CNS-directed ALL therapy and highlight the need to critically reassess even established standards of care.
2024-09-23 | GSE274857 | GEO
Project description:This SuperSeries is composed of the following subset Series: GSE9947: Transcriptional analysis of Leishmania infantum methotrexate resistant strains using full-genome DNA microarrays GSE9948: Transcriptional analysis of Leishmania major methotrexate resistant strains using full-genome DNA microarrays Keywords: SuperSeries Refer to individual Series
2010-05-25 | E-GEOD-9949 | biostudies-arrayexpress
Project description:We used microarrays to understand the effect miR-155 has on osteoclast differentiation. RAW264.7 cells were grown in a-MEM supplemented with 10% FBS and antibiotics. mRNA extracted from wild-type RAW264.7 cells and miR-155 mis-expressing cells either before or after 72 hr of stimulation with 20ng/ml RANKL and M-CSF to induce osteoclast differentiation.
2010-07-30 | E-GEOD-16749 | biostudies-arrayexpress