Ntu 2: Acteoside Suppresses RANKL-Mediated Osteoclastogenesis Los Ntawm Inhibiting C-Fos Induction Thiab NF- KB Pathway Thiab Attenuating ROS Production
Mar 05, 2022
Hu rau: Audrey Hu Whatsapp / hp: 0086 13880143964 Email:audrey.hu@wecistanche.com
Seung-Youp Lee1,2., Keun-Soo Lee3.¤, Sea Hyun Yi2., Sung-Ho Kook, Jeong-Chae Lee22,3*
Pls nyem qhov no rov qab mus rau Ntu 1
ActeosideInhibits Pob Txha Resorption los ntawm Macrophages Acteoside kuj tiv thaiv RANKL-mediated pob txha resorption nyob rau hauv ib koob tshuaj, raws li ntsuas los ntawm ib tug nyob rau hauv vitro qauv system (Fig. 3A). Pob txha resorption tau cuam tshuam loj heev thaum BMMs tau tsim nrog 1 mM acteoside (Fig. 3B). Kev kho 10 mM acteoside yuav luag tag nrho txo qis RANKL-vim qhov tsim los ntawm BMMs. Ib yam li ntawd, acteoside txo cov pob txha resorption hauv RANKL-stimulated RAW264.7 hlwb (Figs. S2A thiab B). Lub peev xwm ntawm acteoside los inhibit pob txha resorption nyob ntawm lub sijhawm ntawm kev kho mob txheeb ze rau RANKL stimulation. Acteoside (10 mM) ntxiv 4 hnub tom qab RANKL stimulation tsis txo qhov tsim nyob rau hauv BMMs, whereas nws suppressed tus naj npawb ntawm osteoclasts tsim (Fig. 3C). Cov txiaj ntsig sib txawv no yog ib feem ntawm qhov chaw uas twb muaj lawm tom qab 4 hnub ntawm RANKL stimulation tsim (Fig. 3D).
ActeosideDown-Regulates Early RANKL Signaling Pathways
RANKL induces qhov ua rau ntawm 3 paub zoo MAPKs thiab NF-kB nyob rau hauv osteoclast precursors, thiab qhov no yuav tsum tau rau thaum ntxov osteoclast sib txawv. Kom nkag siab txog cov mechanisms uas ua tauacteosideinhibits osteoclastogenesis, peb tshawb xyuas cov nyhuv ntawmacteosidentawm MAPKs thiab NF-kB ua kom nyob rau hauv macrophages. BMMs thiab RAW264.7 hlwb raug pretreated nrog 10 mM acteoside rau 2 h thiab ces stimulated nrog 100 ng / ml RANKL rau 30 min. MAPK phosphorylation tau tshuaj xyuas los ntawm Western blotting thiab immunometric tsom xam. RANKL induced phosphorylation ntawm p38, ERK, thiab JNK hauv BMMs (Fig. 4A) thiab RAW264.7 hlwb (Fig. 4B). Acteoside tiv thaiv cov RANKL-induced nce hauv p-p38, p-ERK, thiab p-JNK. Qhov txiaj ntsig no tau txais kev txhawb nqa los ntawm kev tshuaj ntsuam immunometric, uas qhov kev kho ua ntej nrog 10 mM acteoside cuam tshuam cov qib ntawm phosphorylated MAPKs hauv cov macrophages (Fig. 4C). RANKL kev kho mob tau nce DNA-binding ntawm NF-kB, whereas acteoside inhibited RANKL-induced activation ntawm NF-kB-DNA binding (Fig. 5A). Qhov kev tiv thaiv no yog qhov tseem ceeb hauv BMMs dua li hauv RAW264.7 hlwb. Acteoside kuj txo qis RANKL-stimulated p65 thiab IkBa phosphorylation hauv BMMs thiab RAW264.7 hlwb (Fig. 5B thiab C). Ntxiv 10 mM acteoside yuav luag tag nrho inhibited degradation thiab ua kom IkBa hauv BMMs (Fig. 5B). Txhawm rau kom paub meej ntxiv tias NF-kB ua kom muaj kev koom tes hauv kev ua ntawm acteoside, kB txhawb nqa-luciferase tsim tau hloov pauv mus rau RAW264.7 hlwb. Cov hlwb incubated nrog 100 ng/ml RANKL muaj 3-fold ntau dua kB txhawb kev ua haujlwm, uas tau txo qis los ntawm 10 mM acteoside (Fig. 5D).
ActeosideTxhawb nqa kev tsim cov Cytokines Inflammatory Cytokines thiab Kev Tshaj Tawm ntawm TNF-a, c-Fos, thiab NFATc1 hauv RANKL-Stimulated Macrophages TNF-a, IL-1b, thiab IL-6 yog qhov tseem ceeb hauv kev tsim osteoclast thiab muaj nuj nqi, uas yog kho los ntawm NF-kB signaling hauv RANKL-stimulated macrophages. RANKL txhawb kev tsim cov cytokines, thiab qhov kev tsim tawm no tau txo qis los ntawm 10 mM acteoside pretreatment hauv BMMs (Fig. 6A). Ib yam li ntawd, acteoside attenuated RANKL-induced zus tau tej cov cytokines, tshwj tsis yog IL-6, hauv RAW264.7 macrophages (Fig. S3). Txhawm rau nkag siab txog cov txheej txheem molecular ntawm acteoside kev txiav txim hauv osteoclastogenesis, peb tau soj ntsuam ntxiv cov txiaj ntsig ntawm acteoside ntawm TNF-a, c-Fos, thiab NFATc1 qhia. RANKL nce- tswj mRNA kev qhia ntawm cov xwm txheej no hauv BMMs thiab RAW264.7 hlwb (Fig. 6B thiab C). Pretreatment nrog 10 mM acteoside cuam tshuam qhov RANKL-vim qhia ntawm cov xwm txheej no hauv ob qho tib si.
BMMs thiab RAW264.7 hlwb. Acteoside pretreatment kuj txo qis cov protein ntau ntawm c-Fos thiab NFATc1 hauv RANKL- stimulated BMMs (Fig. 6D). Cov txiaj ntsig no qhia tias acteoside down-regulates RANKL inducing mediators of osteoclast formation at the gene and protein levels.
CISTANCHE EXTRACT: ACTEOSIDE
Acteoside Diminishes Intracellular ROS Generation nyob rau hauv BMMs nyob rau hauv ib tug Dose-Dependent
Txij li thaum nws paub tias intracellular ROS ntau lawm muaj feem cuam tshuam nrog RANKL-stimulated osteoclastogenesis, peb tau tshawb xyuas seb acteoside inhibits ROS ntau lawm thaum RANKL-mediated osteoclast sib txawv siv cell-permeable, oxidation-sensitive dye, DCFH-DA. Flow cytometry tsom xam pom tias lub ntsiab lus fluorescence teeb liab tshwj xeeb rau DCF hauv BMMs tau pom meej txoj cai hloov tom qab stimulation nrog RANKL, piv rau cov tsis kho cov hlwb (Fig. 7A). Qhov kev hloov pauv no zoo ib yam li cov ntaub ntawv uas RAW264.7 macrophages tau pom tom qab RANKL stimulation (cov ntaub ntawv tsis qhia). Kev kho BMMs nrog acteoside txo cov teeb liab siv ntawm DCF nyob rau hauv koob tshuaj. Pretreatment nrog 10 mM acteoside yuav luag tag nrho txo cov theem ntawm intracellular ROS uas tsim thaum lub sij hawm osteoclast sib txawv rau cov qib tsis kho (Fig. 7B).
Oral Acteoside Administration Inhibits Hloov ntawm Osteoporotic Biochemical Markers thiab pob txha poob hauv Ovariectomized nas
Txhawm rau tshawb nrhiav cov txiaj ntsig ntawm acteoside ntawm cov pob txha poob, peb tau npaj cov qauv tsiaj osteoporotic los ntawm ovariectomy. Tsis muaj qhov sib txawv ntawm lub cev hnyav ntawm OVX thiab Sham nas thaum lub sijhawm sim (cov ntaub ntawv tsis qhia). OVX pab pawg muaj cov ntshav qab zib ntau dua ntawm IL-1b thiab IL-6 ntau dua li pawg Sham (Fig. 8). Ovariectomy-induced nce nyob rau hauv cov inflammatory cytokines tau attenuated los ntawm qhov ncauj acteoside tswj (AC pawg). Cov qib ntshav ntawm cov pob txha hloov pauv xws li ALP, calcium, TRAP5b, thiab OC tau nce ntau hauv OVX pawg. Ntawm cov cim osteoporotic no, qhov nce qib ntawm calcium, TRAP5b, thiab OC hauv OVX nas tau pom meej inhibited los ntawm kev kho mob acteoside, thaum qib ntshav ntawm ALP tsis hloov los ntawm kev kho mob. Qhov nruab nrab qhov siab tshaj plaws pob txha load rau nruab nrab ntawm txoj cai femoral ncej yog qhov qis dua hauv OVX pawg dua li hauv pawg Sham (Fig. 9A). Kev kho mob Acteoside tsa qhov siab tshaj plaws pob txha rov qab mus rau ntawm pawg Sham. Thaum cov pob txha cortical ntawm lub femur raug muab tshem tawm thiab pom los ntawm optic microscopy, cov yam ntxwv osteoporotic qhia hauv OVX pawg tau yuav luag tag nrho hauv AC nas (Fig. 9B). Txhawm rau txheeb xyuas cov txiaj ntsig ntawm acteoside ntawm OVX-induced osteoporosis qauv, BMD thiab cov pob txha morphologic tsis nyob rau hauv trabecular ntawm lub teeb proximal femur tau soj ntsuam los ntawm micro-CT. Raws li pom nyob rau hauv daim duab 9C, ib qho kev hloov ntawm femoral trabecular architecture tau pom nyob rau hauv OVX nas, qhov kev hloov no tau ploj zuj zus los ntawm kev kho mob nrog acteoside. Cov txiaj ntsig tau los ntawm micro-CT tsom xam pom tias BMD, qhov ntsuas ntawm cov pob txha muaj zog, tau txo qis hauv OVX nas (Daim duab 9D). Piv nrog rau pawg Sham, OVX nas kuj pom cov kev hloov pauv tseem ceeb hauv BV / TV, Tb. Sp, and Tb. N, tab sis tsis nyob hauv Tb.Th. Kev kho qhov ncauj ntawm qhov ncauj ntawm OVX nas tau tiv thaiv kev hloov pauv hauv BMD nrog rau BV / TV thiab Tb.N.
Acteoside tsis cuam tshuam rau Osteoblastogenesis hauv pob txha hlwb
Lub luag haujlwm ntawm acteoside ntawm kev sib txawv osteoblastic tau tshawb xyuas ntxiv siv cov pob txha hlwb. Raws li pom nyob rau hauv daim duab 10A, DAG kev kho mob tau nce tus naj npawb ntawm alizarin liab-stained hlwb thiab qhov no tsis tau hloov los ntawm 10 mM acteoside pretreatment. Tus nqi ntawm cov dye tam sim no qhia tau hais tias ua ke acteoside thiabKev kho DAG tsis hloov cov mineralization (Fig. 10B). Ib yam li ntawd, DAG-induced nce hauv intracellular calcium cov ntsiab lus (Fig. 10C) thiab mRNA theem (Fig. 10D) ntawm cov pob txha tshwj xeeb cov cim, xws li Runx2, osterix, BSP, thiab OC, tsis cuam tshuam los ntawm pretreatment nrog acteoside.
Cov nyhuv ntawm cistanche acteoside
Kev sib tham
Kev kho pob txha yog nruj tswj hwm los ntawm qhov sib npaug ntawm cov pob txha tsim los ntawm osteoblasts thiab pob txha resorption los ntawm osteoclasts. Ntev ntev thiab ntau cov pob txha resorption ua rau qhov tsis txaus ntawm cov pob txha hloov pauv, ua rau cov pob txha resorptive kab mob. Txhawm rau tshawb nrhiav cov teebmeem ntawm acteoside ntawm osteoclastogenesis, peb siv ob lub macrophages, thawj kab lis kev cai BMMs thiab RAW264.7 hlwb.
Cov hlwb no tau txhawb nqa nrog RANKL kom sib txawv rau hauv osteoclasts nyob rau hauv lub xub ntiag thiab tsis muaj acteoside. Peb tau pom thawj zaug uas acteoside inhibits osteoclast sib txawv thiab tsim. Acteoside nws tus kheej ntawm qhov kev tshuaj ntsuam xyuas tsis ua rau txo qis ntawm kev muaj peev xwm ntawm thawj kab lis kev cai macrophages hauv ob qho tib si ntawm kev loj hlob thiab kev sib txawv.
Kev kho mob Acteoside kuj txo qis cov haujlwm resorption ntawm cov laus osteoclasts. Cov txiaj ntsig no qhia tias acteoside suppresses osteoclastic tsim los ntawm macrophages thiab osteoclast resorption kev ua haujlwm. Cov txiaj ntsig los ntawm peb cov kab lis kev cai, uas tsis suav nrog osteoblasts lossis stromal hlwb, kuj qhia tias acteoside tiv thaiv kev tsim osteoclast los ntawm kev ua ncaj qha rau osteoclast precursors.
RANKL qhib MAPKs suav nrog p38, ERK, thiab JNK. Peb cov kinases no koom nrog kev sib txawv ntawm cov osteoclastic thaum ntxov thiab yog li lawv cov inhibition pharmacologically los yog nrog ib tug tseem ceeb-negative JNK transfection suppresses RANKL-induced osteoclas-togenesis [29]. Peb cov txiaj ntsig tau tshaj tawm tias acteoside pretreatment inhibited tag nrho cov kinases, qhia txog qhov tsis tshwj xeeb ntawm kev cai ntawm MAPKs. Qhov txiaj ntsig no txawv ib feem ntawm tsab ntawv tshaj tawm dhau los uas EGCG, qhov tseem ceeb tiv thaiv kab mob hauv cov tee ntsuab, tshwj xeeb ua rau JNK ua kom tsis muaj kev cuam tshuam rau ERK lossis p38 ua rau hauv RANKL-stimulated BMMs [7]. Paeonol, ib qho tshuaj tiv thaiv kab mob tau muab los ntawm Suav tshuaj ntsuab, kuj tau tshaj tawm tias inhibit ERK thiab p38, tab sis tsis yog JNK, phosphorylation hauv RANKL-stimulated RAW264.7 hlwb [30]. Nyob rau hauv sib piv, silibinin, ib tug tshiab inhibitor nyob rau hauv cov pob txha, attenuated RANKL-induced activation ntawm p38, ERK, thiab JNK [31]. Cov kev tshawb pom no qhia tias qhov cuam tshuam ntawm cov tshuaj tiv thaiv resorptive ntawm MAPK ua kom los ntawm RANKL nyob ntawm qhov sib xyaw, txawm tias tag nrho peb MAPKs koom nrog hauv osteoclastogenesis thaum ntxov.
Xav txog qhov kev soj ntsuam uas acteoside attenuated p-JNK
qib hauv RANKL-stimulated BMMs, txawm tias ntawm 1 mM, qhov thaiv ntawm JNK ntau dua li ntawm p38 MAPK lossis ERK tau tshwm sim ntau qhov xwm txheej hauv acteoside-mediated anti-osteoclastogenesis hauv cov hlwb. Txawm hais tias acteoside ntawm tib qhov concentration tsis txo tus naj npawb ntawm osteoclasts hauv BMMs, muaj qhov txo qis hauv qhov tsim los ntawm kev kho acteoside. Peb kuj pom tias pretreatment nrog SP600125, ib tug pharmacological inhibitor tshwj xeeb rau JNK, dramatically tiv thaiv cov tsim ntawm osteoclasts (cov ntaub ntawv tsis qhia). Sib sau ua ke, cov kev tshawb pom no qhia tias JNK-mediated signaling yog ze ze rau cov acteoside- mediated suppression ntawm osteoclastogenesis stimulated los ntawm RANKL.
NF-kB signaling tswj cov xwm txheej ntawm tes, suav nrog apoptosis, cell-cycle progression, cell adhesion, cytokine production, and survival in macrophages [32]. NF-kB signaling tseem yuav tsum tau rau kev txhim kho osteoclast, uas tau pom los ntawm cov tsos mob ntawm osteopetrosis hauv NF-kB-knockout nas [33,34]. Yog li ntawd, inhibiting NF-kB yog npaj los ua lub hom phiaj zoo rau cov tshuaj tiv thaiv resorptive kom txo qis kev ua haujlwm ntawm osteoclast thiab kho pob txha. Kev hloov pauv tom qab kev hloov pauv ntawm NF-kB subfamily proteins yog qhov tseem ceeb hauv kev ua haujlwm ntawm NF-kB. Tshwj xeeb tshaj yog, phosphorylation ntawm p65 subunit thiab IkB kinase yog ib qho tseem ceeb rau NF-kB kom induce osteoclastogenesis [7]. Peb qhov kev tshawb pom tam sim no tau pom tias RANKL stimulation tau nce DNA kev ua haujlwm ntawm NF-kB thiab phosphorylation ntawm p65 subunit thiab IkBa hauv BMMs thiab RAW264.7 hlwb. Pretreatment nrog acteoside inhibited cov RANKL-induced tsub kom, ua rau down-regulated NF-kB kev ua si. Yog li ntawd, cov txiaj ntsig no qhia tias, ntxiv rau MAPKs, NF-kB signaling yog lub hom phiaj tseem ceeb ntawm acteoside hauv inhibiting osteoclast sib txawv thiab tsim los ntawm RANKL-stimulated macrophages.
Ntxiv nrog rau NF-kB signaling, txoj kev c-Fos/c-Jun/NFATc1 plays lub luag haujlwm tseem ceeb hauv kev txhim kho osteoclast, yog li qhov tsis muaj cov protein no tuaj yeem ntes osteoclastogenesis [35,36]. Hauv txoj kev tshawb no, peb pom tias acteoside tiv thaiv RANKL-induced c- Fos thiab NFATc1 qhia ntawm mRNA thiab protein ntau. JNK yog ib qho kinase ntawm c-Jun, uas yuav tsum tau rau NFATc1 qhia thiab osteoclastogenesis teb rau RANKL [29].
Thaiv txoj kev JNK / c-Jun nrog cov khib nyiab inhibitor txo qis RANKL-induced osteoclast tsim thiab c-Fos thiab NFATc1 qhia [7]. Peb cov txiaj ntsig thiab kev tshawb pom yav dhau los qhia tias inhibiting JNK-mediated signaling los ntawm acteoside yog ze rau kev tiv thaiv RANKL-mediated c-Fos thiab NFATc1.qhia, uas suppresses osteoclast sib txawv hauv macrophages. Qhov sib txawv ntawm cov teebmeem ntawm acteoside ntawm BMMs thiab RAW264.7 hlwb tsawg kawg yog ib feem vim qhov sib txawv ntawm qhov rhiab heev rau JNK inhibition.
TNF-a tuaj yeem ua rau osteoclastogenesis ywj siab ntawm RANKL- RANK signaling [37]. IL-1 yog ib tug muaj zog nruab nrab ntawm cov pob txha pathological puas vim los ntawm estrogen deficiency lossis o [7]. Kev cuam tshuam rau hom I IL-1 receptor lossis IL-1 kev taw qhia tuaj yeem thim rov qab pob txha los ntawm ovariectomy [38] lossis mob caj dab rheumatoid [39]. Txoj kev tshawb no tau pom tias muaj peev xwm ntawm acteoside los txo qhov tsim cov cytokines xws li TNF-a, IL{10}}b, thiab IL-6 hauv macrophages. Acteoside xav tias inhibit inflammatory cytokine ntau lawm los ntawm suppressing p38 kinase thiab ERK signaling, vim activating ERK1/2, p38 MAPK, los yog ob qho tib si yuav tsum tau rau lipopolysaccharide-induced zus tau tej cov cytokines nyob rau hauv macrophages [40,41]. Luteolin, ib qho tshuaj tiv thaiv kab mob, kuj tau tshaj tawm los txwv kev tsim cov tshuaj kho mob inflammatory los ntawm inhibiting p38 MAPK activation [42]. Hauv txoj kev tshawb no, peb kuj pom tias acteoside txo qis cov pob txha poob hauv cov nas ovariectomized, raws li pov thawj los ntawm qhov rov qab siab tshaj plaws pob txha quab yuam ntawm lub midshaft ntawm txoj cai femur thiab ploj ntawm cov pob txha cortical osteoporotic. Kev tswj hwm qhov ncauj ntawm qhov ncauj txo qis- tswj cov ovariectomized-induced in-creases hauv cov ntshav IL-1b thiab IL{25}} qib, tab sis tsis yog ALP. Kev nce qib ntawm calcium, TRAP thiab OC hauv OVX kuj tseem cuam tshuam los ntawm kev kho qhov ncauj nrog acteoside, qhia tias acteoside txo qis kev hloov pauv ntawm biomarkers tshwj xeeb rau cov pob txha tsim thiab resorption. Raws li cov txha caj qaum yog tus cwj pwm txo qis thiab cov pob txha tsis zoo, ovx-inducation hloov pauv tau los ntawm kev ua yeeb yam ntawm qhov ncauj. Cov kev tshawb pom no qhia tias acteoside tuaj yeem siv los ua tus neeg sawv cev tiv thaiv kab mob los kho pob txha los ntawm kev thim rov qab osteoclast ua kom tsis muaj zog. Txawm li cas los xij, osteoblasts yog lub luag haujlwm tseem ceeb rau kev tsim cov pob txha tshiab. Yog li tus neeg sawv cev tuaj yeem ua kom osteoblast proliferation lossis sib txawv yog xav tau los txhim kho pob txha tsim [30]. Hauv qhov sib piv, peb pom tias acteoside tsis cuam tshuam rau kev sib txawv ntawm osteoblast lossis mineralization hauv DAG-kho cov pob txha hlwb. Ua ke, peb cov txiaj ntsig tau qhia tias acteoside muaj cov nyhuv anti-resorption tab sis tsis cuam tshuam ncaj qha rau pob txha tsim. Cov ncauj lus kom ntxaws ntxiv txheeb xyuas cov pob txha tshwj xeeb hauv vivo thiab hauv vitro yog xav tau los qhia meej seb puas muaj txiaj ntsig zoo li cas osteoblastogenesis.
Txoj kev tshawb no qhia txog qhov inhibitory nyhuv ntawm acteoside ntawm osteoclast sib txawv thiab pob txha resorption los ntawm suppressing MAPKs thiab ntau yam transcriptional yam xws li NF-kB, c-Fos, thiab NFATc1. Cov ntaub ntawv qhia ob txoj kev ua tau los ntawm qhov uas acteoside muaj cov txiaj ntsig no.
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