Targeting Caspase-1 in osteoarthritis: multi-omics insights into the effects of VX-765 on human chondrocyte function and phenotype

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F67985904%3A_____%2F25%3A00640392" target="_blank" >RIV/67985904:_____/25:00640392 - isvavai.cz</a>

Nalezeny alternativní kódy

RIV/62157124:16170/25:43882451

Výsledek na webu

<a href="https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2025.1677801/full" target="_blank" >https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2025.1677801/full</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.3389/fimmu.2025.1677801" target="_blank" >10.3389/fimmu.2025.1677801</a>

Jazyk výsledku

angličtina

Název v původním jazyce

Targeting Caspase-1 in osteoarthritis: multi-omics insights into the effects of VX-765 on human chondrocyte function and phenotype

Popis výsledku v původním jazyce

Background Osteoarthritis (OA) progression involves chronic inflammation, chondrocyte senescence, and extracellular matrix (ECM) degradation affecting all synovial joint tissues. To date, no regenerative OA drugs have been approved. Caspase-1, a core effector of the inflammasome, may contribute to OA via both canonical inflammatory and non-canonical functions, but its therapeutic value remains unclear.Methods We combined transcriptomic, proteomic, functional, and Mendelian randomization (MR) approaches. Using GSE168505 data, we analyzed CASP1, CARD gene family members (CARD16/17/18/8), and OA-related genes in OA- versus non-OA chondrocytes. We established an in vitro OA model by treating human chondrocytes with TNF-alpha +/- VX-765 and assessed Caspase-1 activity, cell metabolism, and MMP secretion. We further conducted LC-MS/MS proteomic profiling, molecular docking, and MR analysis to identify molecular mechanisms and causal links.Results CASP1 and inflammatory/ECM-degrading genes (e.g., IL1B, MMP13) were upregulated in OA chondrocytes, whereas SOX9 was downregulated. CASP1 gene expression correlated positive with genes involved in senescence, inflammation, oxidative stress and ECM remodeling. Inhibitor VX-765 significantly inhibited Caspase-1 activity, reduced senescence, and enhanced migration in non-OA- and OA chondrocytes, with donor-dependent effects in OA chondrocytes. It also suppressed MMP13 secretion in OA chondrocytes. Integrated transcriptomic and proteomic analysis showed that VX-765 reprogrammed OA-activated signaling, significantly downregulating pathways related to senescence, inflammation, complement activation, and ECM organization, while upregulating interferon-alpha/gamma responses. Moreover, in silico performed molecular docking analyses suggest that caspase-1 may directly bind MMP13, CTSD, ABL1, MRPS11, POLR21, SMAD2 and SOX9. MR analysis supported a causal link between increased CARD17/18/8 gene expression and reduced OA risk, several CASP1 SNPs (e.g., rs61751523) showed negative OA associations, suggesting a protective role.Conclusions This study demonstrates that Caspase-1 contributes to OA pathogenesis through both canonical and non-canonical mechanisms, and that VX-765 can alleviate chondrocyte dysfunction. The combined evidence supports VX-765 as a potential disease-modifying target for OA therapy. However, further investigation is warranted to clarify Caspase-1's physiological roles, including possible off-target effects of its inhibitors, in cartilage and other joint tissues and the clinical relevance of inter-individual variability, with genomic variants (e.g., rs61751523) as one potential contributor, for therapeutic application.

Název v anglickém jazyce

Targeting Caspase-1 in osteoarthritis: multi-omics insights into the effects of VX-765 on human chondrocyte function and phenotype

Popis výsledku anglicky

Background Osteoarthritis (OA) progression involves chronic inflammation, chondrocyte senescence, and extracellular matrix (ECM) degradation affecting all synovial joint tissues. To date, no regenerative OA drugs have been approved. Caspase-1, a core effector of the inflammasome, may contribute to OA via both canonical inflammatory and non-canonical functions, but its therapeutic value remains unclear.Methods We combined transcriptomic, proteomic, functional, and Mendelian randomization (MR) approaches. Using GSE168505 data, we analyzed CASP1, CARD gene family members (CARD16/17/18/8), and OA-related genes in OA- versus non-OA chondrocytes. We established an in vitro OA model by treating human chondrocytes with TNF-alpha +/- VX-765 and assessed Caspase-1 activity, cell metabolism, and MMP secretion. We further conducted LC-MS/MS proteomic profiling, molecular docking, and MR analysis to identify molecular mechanisms and causal links.Results CASP1 and inflammatory/ECM-degrading genes (e.g., IL1B, MMP13) were upregulated in OA chondrocytes, whereas SOX9 was downregulated. CASP1 gene expression correlated positive with genes involved in senescence, inflammation, oxidative stress and ECM remodeling. Inhibitor VX-765 significantly inhibited Caspase-1 activity, reduced senescence, and enhanced migration in non-OA- and OA chondrocytes, with donor-dependent effects in OA chondrocytes. It also suppressed MMP13 secretion in OA chondrocytes. Integrated transcriptomic and proteomic analysis showed that VX-765 reprogrammed OA-activated signaling, significantly downregulating pathways related to senescence, inflammation, complement activation, and ECM organization, while upregulating interferon-alpha/gamma responses. Moreover, in silico performed molecular docking analyses suggest that caspase-1 may directly bind MMP13, CTSD, ABL1, MRPS11, POLR21, SMAD2 and SOX9. MR analysis supported a causal link between increased CARD17/18/8 gene expression and reduced OA risk, several CASP1 SNPs (e.g., rs61751523) showed negative OA associations, suggesting a protective role.Conclusions This study demonstrates that Caspase-1 contributes to OA pathogenesis through both canonical and non-canonical mechanisms, and that VX-765 can alleviate chondrocyte dysfunction. The combined evidence supports VX-765 as a potential disease-modifying target for OA therapy. However, further investigation is warranted to clarify Caspase-1's physiological roles, including possible off-target effects of its inhibitors, in cartilage and other joint tissues and the clinical relevance of inter-individual variability, with genomic variants (e.g., rs61751523) as one potential contributor, for therapeutic application.

Druh

J_imp - Článek v periodiku v databázi Web of Science

CEP obor

—

OECD FORD obor

30403 - Technologies involving identifying the functioning of DNA, proteins and enzymes and how they influence the onset of disease and maintenance of well-being (gene-based diagnostics and therapeutic interventions [pharmacogenomics, gene-based therapeutics])

Projekt

<a href="/cs/project/LUABA22019" target="_blank" >LUABA22019: Kaspáza-1 a chondrocyty: integrace výzkumu orientovaného na osteoartritidu</a><br>

Návaznosti

I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Rok uplatnění

2025

Kód důvěrnosti údajů

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Název periodika

Frontiers in Immunology

ISSN

1664-3224

e-ISSN

1664-3224

Svazek periodika

16

Číslo periodika v rámci svazku

OCT 3

Stát vydavatele periodika

CH - Švýcarská konfederace

Počet stran výsledku

22

Strana od-do

1677801

Kód UT WoS článku

001595519600001

EID výsledku v databázi Scopus

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