Galectin-8 induces functional disease markers in human osteoarthritis and cooperates with galectins-1 and -3.
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PROVIDER: PRJNA545084 | ENA |
REPOSITORIES: ENA
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Project description:The reading of glycan-encoded signals by tissue lectins is considered a major route of the flow of biological information in many (patho)physiological processes. The arising challenge for current research is to proceed from work on a distinct protein to family-wide testing of lectin function. Having previously identified homodimeric galectin-1 and chimera-type galectin-3 as molecular switches in osteoarthritis progression, we here provide proof-of-principle evidence for an intra-network cooperation of galectins with three types of modular architecture. We show that the presence of tandem-repeat-type galectin-8 significantly correlated with cartilage degeneration and that it is secreted by osteoarthritic chondrocytes. Glycan-inhibitable surface binding of galectin-8 to these cells increased gene transcription and the secretion of functional disease markers. The natural variant galectin-8 (F19Y) was less active than the prevalent form. Genome-wide array analysis revealed induction of a pro-degradative/inflammatory gene signature, largely under control of NF-κB signaling. This signature overlapped with respective gene-expression patterns elicited by galectins-1 and -3, but also presented supplementary features. Functional assays with mixtures of galectins that mimic the pathophysiological status unveiled cooperation between the three galectins. Our findings shape the novel concept to consider individual galectins as part of a so far not realized teamwork in osteoarthritis pathogenesis, with relevance beyond this disease.
2021-02-17 | GSE131822 | GEO
Project description:Inflammatory chemo- and cytokines and matrix-degrading proteases underlie the progression of osteoarthritis (OA). Aiming to define upstream regulators for these disease markers, we pursued initial evidence for an upregulation of members of the adhesion/growth-regulatory galectin family. Immunohistochemical localization of galectin-3 (Gal-3) in sections of human cartilage with increasing levels of degeneration revealed a linear correlation reaching a chondrocyte positivity of 60%. Presence in situ was cytoplasmic, in OA chondrocyte cultures the lectin was secreted and binding of Gal-3 yielded lactose-inhibitable surface staining. Exposure of cells to the lectin led to enhanced gene expression and secretion of functional disease markers. Genome-wide transcriptomic analysis broadened this insight to reveal a pro-degradative/inflammatory gene signature under the control of NF-κB. Fittingly, targeting this route of activation by inhibitors impaired the unfavourable response to Gal-3 binding, as also seen by shortening the lectin’s collagen-like repeat region. Gal-3’s activation profile overlaps with that of homodimeric galectin-1 (Gal-1) and also has distinctive (supplementing) features. Tested at subsaturating concentrations in a mixture, we found cooperation between the two galectins, apparently able to team up as driving forces in OA pathogenesis. In summary, our results suggest that a network of endogenous lectins acts as upstream master regulator in OA.
2017-02-09 | GSE85254 | GEO
Project description:Osteoarthritis is a degenerative joint disease that ranks among the leading causes of pain, adult disability, shortening of working life, and socioeconomic costs worldwide. The mechanisms underlying osteoarthritis pathogenesis are yet to be fully elucidated, thus limiting current disease management and treatment. Galectin-1 is an endogenous carbohydrate-binding protein central to adhesion via glycan-bridging, glycoconjugate-mediated signaling, cell proliferation, differentiation, apoptosis, cancers, and host-pathogen interactions. The chondrocyte glycophenotype, which can act as a system of counter-receptors for galectin binding, is compromised in osteoarthritis. We here investigated Galectin-1 and associated gene network's role in human osteoarthritis pathogenesis. Immunohistochemical analysis showed that Galectin-1 associates with osteoarthritic cartilage and subchondral bone histopathology and severity (p<0.0001, n=29 patients). Glycan-dependent Galectin-1 binding to osteoarthritic chondrocytes' cell surface led to marked upregulation of matrix metalloproteinases and activation of NF-κB. Biochemical, molecular and genome-wide analyses showed that Galectin-1 strongly activates a large inflammatory gene network (p<10-16). Bioinformatic analyses of gene promoters up-regulated by Galectin-1 unveiled an overwhelming NF-κB signaling signature. Inhibition of any of several components of the NF-κB pathway using dedicated inhibitors led to dose-dependent impairment of Galectin-1-mediated transcriptional activation. This study identifies for the first time Galectin-1 as an activator of clinically relevant inflammatory-response genes co-regulated by NF-κB. Since inflammation is critical to cartilage degeneration in osteoarthritis, this report is also first to put glycobiology at the center-stage of osteoarthritic cartilage degeneration. Finally, this is the first report to uncover a Galectin-1 gene signature and associated gene network in any biological setting or species. For microarray experiments, osteoarthritic chondrocytes were isolated from five male patients (47-78 years). Following starvation, cells were incubated in the presence of 50 µg/ml recombinant Galectin-1 for 24 h. For each donor population, untreated cells were included as control. In total, 10 samples were analyzed.
2016-03-01 | E-GEOD-68760 | biostudies-arrayexpress
Project description:Osteoarthritis is a degenerative joint disease that ranks among the leading causes of pain, adult disability, shortening of working life, and socioeconomic costs worldwide. The mechanisms underlying osteoarthritis pathogenesis are yet to be fully elucidated, thus limiting current disease management and treatment. Galectin-1 is an endogenous carbohydrate-binding protein central to adhesion via glycan-bridging, glycoconjugate-mediated signaling, cell proliferation, differentiation, apoptosis, cancers, and host-pathogen interactions. The chondrocyte glycophenotype, which can act as a system of counter-receptors for galectin binding, is compromised in osteoarthritis. We here investigated Galectin-1 and associated gene network's role in human osteoarthritis pathogenesis. Immunohistochemical analysis showed that Galectin-1 associates with osteoarthritic cartilage and subchondral bone histopathology and severity (p<0.0001, n=29 patients). Glycan-dependent Galectin-1 binding to osteoarthritic chondrocytes' cell surface led to marked upregulation of matrix metalloproteinases and activation of NF-κB. Biochemical, molecular and genome-wide analyses showed that Galectin-1 strongly activates a large inflammatory gene network (p<10-16). Bioinformatic analyses of gene promoters up-regulated by Galectin-1 unveiled an overwhelming NF-κB signaling signature. Inhibition of any of several components of the NF-κB pathway using dedicated inhibitors led to dose-dependent impairment of Galectin-1-mediated transcriptional activation. This study identifies for the first time Galectin-1 as an activator of clinically relevant inflammatory-response genes co-regulated by NF-κB. Since inflammation is critical to cartilage degeneration in osteoarthritis, this report is also first to put glycobiology at the center-stage of osteoarthritic cartilage degeneration. Finally, this is the first report to uncover a Galectin-1 gene signature and associated gene network in any biological setting or species.
2016-03-01 | GSE68760 | GEO
Project description:The reading of glycan-encoded signals by tissue lectins is considered a major route of the flow of biological information in many (patho)physiological processes. The arising challenge for current research is to proceed from work on a distinct protein to family-wide testing of lectin function. Having previously identified homodimeric galectin-1 and chimera-type galectin-3 as molecular switches in osteoarthritis progression, we here provide proof-of-principle evidence for an intra-network cooperation of galectins with three types of modular architecture. We show that the presence of tandem-repeat-type galectin-8 significantly correlated with cartilage degeneration and that it is secreted by osteoarthritic chondrocytes. Glycan-inhibitable surface binding of galectin-8 to these cells increased gene transcription and the secretion of functional disease markers. The natural variant galectin-8 (F19Y) was less active than the prevalent form. Genome-wide array analysis revealed induction of a pro-degradative/inflammatory gene signature, largely under control of NF-κB signaling. This signature overlapped with respective gene-expression patterns elicited by galectins-1 and -3, but also presented supplementary features. Functional assays with mixtures of galectins that mimic the pathophysiological status unveiled cooperation between the three galectins. Our findings shape the novel concept to consider individual galectins as part of a so far not realized teamwork in osteoarthritis pathogenesis, with relevance beyond this disease.
| S-EPMC6182346 | biostudies-literature
Project description:The severity of osteoarthritis is linked to elevated levels of galectins. Here, the aim of the study was to evaluate the role of Galectin-4 in osteoarthritic cartilage.
2022-02-23 | GSE183531 | GEO
Project description:Human monocyte derived dendritic cells matured via galectin-1 or LPS. Experiment Overall Design: 4 conditions with 3 replicates of each include control or intreated immature MDDCS, galectin-1 treated MDDCs, LPS treated MDDCs, and vehicle control MDDCs. (each replicate is from a distinct DONOR). Dendritic cells (DCs) are potent mediators of the immune response, and can be activated by exogenous pathogen components. Galectin-1 is a member of the conserved beta-galactoside-binding lectin family that binds galactoside residues on cell surface glycoconjugates. Galectin-1 is known to play a role in immune regulation via action on multiple immune cells. However, its effects on human DCs are unknown. In this study, we show that galectin-1 induces a phenotypic and functional maturation in human monocyte-derived DCs (MDDCs) similar to but distinct from the activity of the exogenous pathogen stimuli, LPS. Immature human MDDCs exposed to galectin-1 up-regulated cell surface markers characteristic of DC maturation (CD40, CD83, CD86, and HLA-DR), secreted high levels of IL-6 and TNF-alpha, stimulated T cell proliferation, and showed reduced endocytic capacity, similar to LPS-matured MDDCs. However, unlike LPS-matured DCs, galectin-1-treated MDDCs did not produce the Th1-polarizing cytokine IL-12. Microarray analysis revealed that in addition to modulating many of the same DC maturation genes as LPS, galectin-1 also uniquely up-regulated a significant subset of genes related to cell migration through the extracellular matrix (ECM). Indeed, compared with LPS, galectin-1-treated human MDDCs exhibited significantly better chemotactic migration through Matrigel, an in vitro ECM model. Our findings show that galectin-1 is a novel endogenous activator of human MDDCs that up-regulates a significant subset of genes distinct from those regulated by a model exogenous stimulus (LPS). One unique effect of galectin-1 is to increase DC migration through the ECM, suggesting that galectin-1 may be an important component in initiating an immune response.
2007-10-26 | E-GEOD-4984 | biostudies-arrayexpress
Project description:RIP1 perturbation induces chondrocyte necroptosis and promotes osteoarthritis pathogenesis
| PRJNA693686 | ENA
Project description:Mice overexpressing galectin-8 (gal-8 Tg), a secreted mammalian lectin, exhibit enhanced bone turnover and reduced bone mass, similar to cases of post-menopausal osteoporosis. Gal-8 knockout (KO) mice have increased bone mass accrual at young age, but exhibit accelerated bone loss during adulthood. These phenotypes can be attributed to gal-8-mediated increase in RANKL expression that promotes osteoclastogenesis, combined with direct inhibition of osteoblasts differentiation, evident by reduced BMP signaling, SMAD phosphorylation, and reduced expression of osteoblasts differentiation markers OSX, OCN, RUNX2, DMP-1 and ALP. Gal-8 mRNA positively correlates with the mRNA levels of osteoclastogenic markers RANKL, TRAP and CTSK in human femurs. Collectively, these findings identify gal-8 as a new physiological player in the regulation of bone mass.
2017-11-08 | GSE106631 | GEO
Project description:Ablation of the Mammalian Lectin Galectin-8 Induces Bone Defects in Mice
| PRJNA417476 | ENA