IndraLab
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"OSM can form a
complex with either LIFR/gp130 or OSMR/gp130 , and therefore the effects of OSM and activation of
downstream signaling pathways such as STAT3, ERK, AKT, and Src signaling in breast
cancer cells may be mediated through either LIFR or OSMR, but previous studies have
not determined which receptor is responsible."
sparser
"The JAK/STAT signaling pathway is involved in a variety of biological processes, including hematopoiesis, tissue repair, inflammation, differentiation, and apoptosis. xref In addition, the JAK/STAT transduction pathway has been widely studied in osteogenic differentiation of cells. xref , xref A previous study showed that Mφ‐derived OSM can bind to OSMR and promote osteogenic differentiation of cells in muscle tissue, thereby enhancing heterotopic ossification; moreover, silencing the OSMR gene can significantly reduce the incidence of heterotopic ossification. xref Another study reported that the combination of Mφ‐derived OSM and GP130/OSMR receptor complex during osteogenic differentiation of MSCs can activate JAK1/2 and mediate STAT3 phosphorylation to promote osteogenic differentiation, and the addition of JAK1/2 specific inhibitors can weaken osteogenic differentiation and inhibit the development of NHO in mice. xref In addition, Zhang et al. xref pointed out that blocking the JAK signaling pathway can effectively attenuate leptin‐induced osteogenic differentiation of MSCs."
sparser
"Supported by LUMINEX-ELISA and RNA-Seq analyses of PCCs, PSCs, and MØ isolated from PSC–PCC and PSC–MØ–PCC co-cultures, they found that MØ-derived Oncostatin M (OSM) activated the OSM receptor (OSMR) on PSCs and stimulated expression of inflammation-related secreted ligands, which in turn induced a protumor environment to activate proliferative and migratory signaling pathways in PCCs, implying therapeutic potential by targeting the MØs–PSC–PCC interaction through OSM–OSMR complex."
sparser
"Work in human fibroblast or epithelial cells show that OSM ligand binding to OSMR induces receptor degradation and then increases the level of receptor synthesis. xref In hepatocytes and hepatoma cells, OSM induces hypoxia-inducible factor 1α gene transcription via a Janus kinase/signal transducer. xref Considered in the context of the literature that indicates that OSM helps regulate erythropoiesis, the fact that we observed increased abundance of OSMR fragments in patients with poor EPO response might be expected."
sparser
"Our results support the relationship of the OSM-OSMR axis (Additional file xref : Fig. S7B) in promoting an osteolytic microenvironment as the tumor-associated MSC-2 population as well as the tumor cells themselves gain expression of OSMR, thereby favoring aberrant osteoclast formation and differentiation."
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"Upon brain infiltration, macrophages release several cytokines and ligands such as oncostatin M, which binds to the oncostatin M receptor and leukemia inhibitory factor receptor that signals through the signal transducer and activator of transcript 3 pathway to induce the MES-like transcriptional program in glioma cells [22]."
| PMC
sparser
"Although our findings are consistent with previous studies highlighting the importance of OSM–OSMR signaling in cervical cancer [ xref , xref , xref ], the functions of other cytokines from various immune cells in cervical cancer need to be further investigated through more single-cell-based sequencing data in the future."
sparser
"Intriguingly, the transcriptomic response of in silico target genes of Osmr was significantly associated with age‐related stress response genes (Figure xref ), supporting the hypothesis that activated OSM–OSMR axis recapitulates an age‐related transcriptomic response to injury and induces aberrant ECM remodeling in aged cartilage."
sparser
"Correlating the downstream effects of OSM–OSMR axis with transcriptomic signature of phenotypes in people with KOA, we discovered that activation of the OSM–OSMR axis recapitulated an inflammatory phenotype of KOA and identified high‐value targets for drug development and repurposing."
sparser
"Thus, proteomic analysis and GSEA confirmed the role of the OSM–OSMR axis in HAEC susceptibility identified by WES, likely through an impaired immune system response and an unbalance of the gut homeostasis, which has already been suggested to underlie the acute inflammation in HAEC."
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"Typically, OSM binding to the OSMR:gp130 complex causes the phosphorylation and activation of both STAT1 and STAT3 via JAK1/2 (23, 24) which in turns leads the transcription of a large range of genes that include suppressor of cytokine signaling (SOCS)-3. A negative feed-back loop is triggered by SOCS3, which binds to both gp130 and activated JAKs, suppressing this signaling cascade and STAT1 and STAT3 activation (25, 26)."
sparser
"Using network‐based cytokine inference integrated with network propagation that simulates synovium‐cartilage cross talk, the current study identified the OSM–OSMR axis as a predicted driver of the aberrant ECM remodeling that we found to be unique to the aged knee joint after injury."
sparser
"For example, Oncostatin M and its receptor (OSM-OSMR) have been reported to drive intestinal inflammation, serving as both biomarkers and therapeutic targets for IBD. xref ICAM1 (also known as LFA1) has also been identified as potential targets for IBD treatment, although results from clinical studies with anti-sense oligonucleotides are inconclusive. xref "
sparser
"Taken together, the increases in OSM expression within the TME, increases in OSMR expression in cancer and stromal cells, and the consequences of OSMR signaling (stem-like/mesenchymal cancer cell reprogramming, iCAF reprogramming, and immune suppression) make targeting the OSM-OSMR axis particularly attractive ( xref )."
sparser
"Taken together, our data supports the future assessment of strategies that target OSM-OSMR signaling, including MAPK signaling, in PDAC as a means of preventing the reprogramming of cancer cells, fibroblasts, and immune cells to variants that support tumor survival and their potential for metastatic dissemination."
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"This patent allows for the design of a variety of inhibitors that would inhibit OSM production or OSMRβ signaling at the cellular level such as enzyme inducers, an enzyme or receptor inhibitor, a ligand for a receptor, a compound that is toxic for cells, or an antisense RNA.Utilizing a separate approach, Boise State University has submitted a patent (US9550828B2) (253) developing small molecule inhibitors against the Site III region of OSM, preventing OSM binding to OSMRβ."
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"The predicted 3D structure of the OSM-OSMR complex and the identified "hot spots" constituting the core of the binding interface provide helpful information in understanding the OSM-OSMR interactions, and the detected sites serve as promising targets in designing small molecules to block the interactions."
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"It is of paramount importance to understand the details of the OSM and OSMR complex formation as well as the potential binding site between the protein–protein interface.In this work, molecular simulation approaches aimed at filling the aforementioned gap were performed to accelerate the discovery of small molecules targeting OSM–OSMR."
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"Starting from the crystal structure of OSM (Deller et al., 2000) and the model of the OSMR [a protein-binding region was built using the leukemia inhibitory factor receptor (LIFR) crystal structure (Huyton et al., 2007) as a template], the near-native conformation of the OSM–OSMR complex was obtained through protein–protein docking."
sparser
"In addition, the OSM-OSMR feed forward loop, whereby OSMR activation results in increased OSMR protein production, is strongly implicated in the persistent signaling noted in other metastatic and drug tolerant cancers, such as glioblastoma, TNBC, small-cell lung cancer, ovarian cancer, and squamous cell carcinomas ( xref , xref , xref , xref , xref )."
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"The decomposed energy terms of the total binding free energy (G ) indicated that electrostatic interaction energy (E , −338.29 ± 44.73 kcal/mol), van der Waals interaction energy (E , −82.02 ± 7.17 kcal/mol), and non-polar solvent energy (G , −11.74 ± 1.08 kcal/mol) play important roles in the formation of the protein–protein complex, whereas polar solvent energies (G , 383.11 ± 43.06 kcal/mol) were unfavored for the interaction.In addition, per-residue energy decomposition analysis was performed to identify the important residues for the OSM–OSMR complex formation."
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"Through FTMap (Kozakov et al., 2011) analysis of the MD simulation-derived structure of the OSM–OSMR complex, 10 potential druggable binding sites were detected from fragment-based searching of the global protein surface (Figure 3D), indicating that the conformation of the residues in the recognition interface is very flexible."
sparser
"Furthermore, a recent study performing whole exome sequencing of patients with bladder squamous cell carcinoma, also displayed significantly higher expression of OSM, OSMRβ, and IL-31, suggesting both OSM-OSMR and IL-31-OSMR signaling may impact bladder cancer progression ( xref )."
sparser
"Our data suggest that OSM–OSMR interactions may also be responsible for inducing TGM2 in other cell types, such as breast cancer cells, in which OSM promotes cell motility and metastatic behaviour and TGM2 has been associated with migration, invasion and metastasis xref – xref ."
sparser
"A role for the OSM-OSMR axis in the pathogenesis of IBD was first discovered by a disease-susceptibility single-nucleotide polymorphism within the OSMR locus on chromosome 5. xref More recently, the landmark study by West, Hegazy, et al xref showed that OSM, out of 64 candidate cytokines, was the most highly and consistently expressed cytokine in the inflamed mucosa of patients with IBD."
sparser
"This upregulation of mucosal OSM was associated with an overexpression of OSMR, whereas LIFR and IL6ST (encoding for gp130) showed no or limited differences, respectively. xref In light of these results, those authors further investigated the functional role of the OSM-OSMR axis in IBD and suggested that OSM may act as an inflammatory amplifier and driver of disease chronicity."
sparser
"To investigate the role of the OSMR SNP rs34675408 in HAEC susceptibility, we then evaluated the effect of OSM-OSMR activation in an HAEC patient homozygous for the T allele (LY3828) and in an HAEC patient homozygous for the HAEC associated G allele (LY4759) by pERK immunofluorescence analysis."
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"Supported by LUMINEX-ELISA and RNA-Seq analyses of PCCs, PSCs, and MØ isolated from PSC–PCC and PSC–MØ–PCC co-cultures, they found that MØ-derived Oncostatin M (OSM) activated the OSM receptor (OSMR) on PSCs and stimulated expression of inflammation-related secreted ligands, which in turn induced a protumor environment to activate proliferative and migratory signaling pathways in PCCs, implying therapeutic potential by targeting the MØs–PSC–PCC interaction through OSM–OSMR complex."
sparser
"Likewise, our findings further validate the OSM-OSMR interaction as a valuable therapeutic target in TNBC, since knockout of OSMR increased TLR3 and IFN-β production and treatment of tumors with an OSM-neutralizing antibody reduced proliferation and angiogenesis, and inhibited tumor growth (Fig. xref B–E, F–J)."
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"Oncostatin M (OSM) is a member of the interleukin-6 (IL-6) family of cytokines and can bind two different receptors, Leukemia inhibitory factor receptor (LIFR) and Oncostatin M receptor (OSMR), through a complex containing the common glycoprotein 130 (gp130) subunit.OSMR binding recruits Janus kinases JAK1 and JAK2, leading to the activation of signal transducers and the activation of transcription factors known as STATs through multiple docking sites."
sparser
"Starting from the crystal structure of OSM (Deller et al., xref ) and the model of the OSMR [a protein-binding region was built using the leukemia inhibitory factor receptor (LIFR) crystal structure (Huyton et al., xref ) as a template], the near-native conformation of the OSM–OSMR complex was obtained through protein–protein docking."
sparser
"Finally, the “hotspots” were mapped to the seven binding sites located at the OSM–OSMR interface detected using FTMap (Kozakov et al., xref ), and three of them were suggested as important target sites for future designs of small molecular modulators in the OSM–OSMR interaction."
sparser
"The predicted 3D structure of the OSM–OSMR complex and the identified “hot spots” constituting the core of the binding interface provide helpful information in understanding the OSM–OSMR interactions, and the detected sites serve as promising targets in designing small molecules to block the interactions."
sparser
"Moreover, using the crystal structure of the LIF–LIFR complex (PDB code 2Q7N), CAS analysis was performed on residues (Pro51, Phe52, Pro53, Leu56, Pro106, Leu109, Phe156, Gln157, Ile234, Val258, Asn261, Ser262, Ile267, Ile310, and Leu313) corresponding to the residues (Arg39, Asp41, Val42, Leu45, Arg100, Leu103, Phe160, Gln161, Phe205, Asn208, Lys209, Tyr214, Asp262, and Leu265) located at same position in the OSM–OSMR interface."
sparser
"Through FTMap (Kozakov et al., xref ) analysis of the MD simulation-derived structure of the OSM–OSMR complex, 10 potential druggable binding sites were detected from fragment-based searching of the global protein surface ( xref ), indicating that the conformation of the residues in the recognition interface is very flexible."
sparser
"Herein, to find the “hot spots” located at the OSM–OSMR interface, the computational alanine scanning (CAS) mutagenesis calculation was conducted on the residues with an absolute energy contribution of more than 1 kcal/mol identified by the per-residue energy decomposition analysis (Yang et al., xref ; Du et al., xref )."
sparser
"Moreover, the 18 residues (Cys179, Leu181, Phe205, Ile206, Asn208, Lys209, Gly210, Tyr214, Glu216, Gln219, Gly220, Asn221, Val222, Ser223, Asp262, Ala264, Leu265, and Trp267) characterized in the OSMR were informative in experimentally verifying these residues, which may play an important role in OSM and OSMR interaction (Huang et al., xref )."