Elevated osteoclast(OC)activity is a major contributor to inflammatory bone loss(IBL)during chronic inflammatory diseases.However,the specific OC precursors(OCPs)responding to inflammatory cues and the underlying mech...Elevated osteoclast(OC)activity is a major contributor to inflammatory bone loss(IBL)during chronic inflammatory diseases.However,the specific OC precursors(OCPs)responding to inflammatory cues and the underlying mechanisms leading to IBL are poorly understood.We identified two distinct OCP subsets:Ly6C^(hi)CD11b^(hi) inflammatory OCPs(iOCPs)induced during chronic inflammation,and homeostatic Ly6C^(hi)CD11b^(lo)OCPs(hOCPs)which remained unchanged.Functional and proteomic characterization revealed that while iOCPs were rare and displayed low osteoclastogenic potential under normal conditions,they expanded during chronic inflammation and generated OCs with enhanced activity.In contrast,hOCPs were abundant and manifested high osteoclastogenic potential under normal conditions but generated OCs with low activity and were unresponsive to the inflammatory environment.Osteoclasts derived from iOCPs expressed higher levels of resorptive and metabolic proteins than those generated from hOCPs,highlighting that different osteoclast populations are formed by distinct precursors.We further identified the TNF-αand S100A8/A9 proteins as key regulators that control the iOCP response during chronic inflammation.Furthermore,we demonstrated that the response of iOCPs but not that of hOCPs was abrogated in tnf-α^(-/-)mice,in correlation with attenuated IBL.Our findings suggest a central role for iOCPs in IBL induction.iOCPs can serve as potential biomarkers for IBL detection and possibly as new therapeutic targets to combat IBL in a wide range of inflammatory conditions.展开更多
Tumor progression and metastasis are the major causes of death among cancer associated mortality.Metastatic cells acquire features of migration and invasion and usually undergo epithelia-mesenchymal transition(EMT).Ac...Tumor progression and metastasis are the major causes of death among cancer associated mortality.Metastatic cells acquire features of migration and invasion and usually undergo epithelia-mesenchymal transition(EMT).Acquirement of these various hallmarks rely on different cellular pathways,including TGF-βand Wnt signaling.Recently,we reported that WW domain-containing oxidoreductase(WWOX)acts as a tumor suppressor and has anti-metastatic activities involving regulation of several key microRNAs(miRNAs)in triple-negative breast cancer(TNBC).Here,we report that WWOX restoration in highly metastatic MDA-MB435S cancer cells alters mRNA expression profiles;further,WWOX interacts with various proteins to exert its tumor suppressor function.Careful alignment and analysis of gene and miRNA expression in these cells revealed profound changes in cellular pathways mediating adhesion,invasion and motility.We further demonstrate that WWOX,through regulation of miR-146a levels,regulates SMAD3,which is a member of the TGF-βsignaling pathway.Moreover,proteomic analysis of WWOX partners revealed regulation of the Wnt-signaling activation through physical interaction with Disheveled.Altogether,these findings underscore a significant role for WWOX in antagonizing metastasis,further highlighting its role and therapeutic potential in suppressing tumor progression.展开更多
基金the support of the Society of Research Associates of the Lautenberg Center and the Harold B.Abramson Chair in Immunologythe grant support provided by the Israel Science Foundation(ISF)+6 种基金the Israeli Ministry of Healththe German-Israeli Project Cooperation of the German Research Foundation(DFG)the Postdoctoral Fellowships program of the German Cancer Research Center(DKFZ)the Israel Cancer Research Fund(ICRF)The Israel Ministry of Science and Technology,the Gross Foundationthe Bruce and Baila Waldholtz fundsthe Joseph and Matilda Melnick Funds。
文摘Elevated osteoclast(OC)activity is a major contributor to inflammatory bone loss(IBL)during chronic inflammatory diseases.However,the specific OC precursors(OCPs)responding to inflammatory cues and the underlying mechanisms leading to IBL are poorly understood.We identified two distinct OCP subsets:Ly6C^(hi)CD11b^(hi) inflammatory OCPs(iOCPs)induced during chronic inflammation,and homeostatic Ly6C^(hi)CD11b^(lo)OCPs(hOCPs)which remained unchanged.Functional and proteomic characterization revealed that while iOCPs were rare and displayed low osteoclastogenic potential under normal conditions,they expanded during chronic inflammation and generated OCs with enhanced activity.In contrast,hOCPs were abundant and manifested high osteoclastogenic potential under normal conditions but generated OCs with low activity and were unresponsive to the inflammatory environment.Osteoclasts derived from iOCPs expressed higher levels of resorptive and metabolic proteins than those generated from hOCPs,highlighting that different osteoclast populations are formed by distinct precursors.We further identified the TNF-αand S100A8/A9 proteins as key regulators that control the iOCP response during chronic inflammation.Furthermore,we demonstrated that the response of iOCPs but not that of hOCPs was abrogated in tnf-α^(-/-)mice,in correlation with attenuated IBL.Our findings suggest a central role for iOCPs in IBL induction.iOCPs can serve as potential biomarkers for IBL detection and possibly as new therapeutic targets to combat IBL in a wide range of inflammatory conditions.
基金supported by the Israel science foundation grant(ISF grant agreement No.15/1574)ICRF-City of Hope-Harvey L.Miller Family Foundation and European Research Council(ERC)-Consolidator Grant under the European Union’s Horizon 2020 research and innovation program(grant agreement No.682118).
文摘Tumor progression and metastasis are the major causes of death among cancer associated mortality.Metastatic cells acquire features of migration and invasion and usually undergo epithelia-mesenchymal transition(EMT).Acquirement of these various hallmarks rely on different cellular pathways,including TGF-βand Wnt signaling.Recently,we reported that WW domain-containing oxidoreductase(WWOX)acts as a tumor suppressor and has anti-metastatic activities involving regulation of several key microRNAs(miRNAs)in triple-negative breast cancer(TNBC).Here,we report that WWOX restoration in highly metastatic MDA-MB435S cancer cells alters mRNA expression profiles;further,WWOX interacts with various proteins to exert its tumor suppressor function.Careful alignment and analysis of gene and miRNA expression in these cells revealed profound changes in cellular pathways mediating adhesion,invasion and motility.We further demonstrate that WWOX,through regulation of miR-146a levels,regulates SMAD3,which is a member of the TGF-βsignaling pathway.Moreover,proteomic analysis of WWOX partners revealed regulation of the Wnt-signaling activation through physical interaction with Disheveled.Altogether,these findings underscore a significant role for WWOX in antagonizing metastasis,further highlighting its role and therapeutic potential in suppressing tumor progression.