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[(simple)-386.6(subcutaneous)-389.5(injection)-387.9(for)-383.3(13)-384.2(days)]TJ 6.7246 0 0 5.9768 235.6724 411.9306 Tm (44)Tj 8.9663 0 0 8.9663 245.8771 407.9621 Tm [(or)-382.8(preintegra-)]TJ -20.5052 -1.2203 TD [(tion)-339(into)-339(scaffolds.)]TJ 6.7246 0 0 5.9768 135.5527 400.9889 Tm (45)Tj 8.9663 0 0 8.9663 145.3039 397.0204 Tm [(The)-335.1(latter)-339.7(has)-333(the)-338.9(advantage)-332.9(in)-335.7(aspects)]TJ -9.2884 -1.2266 TD [(of)-332(cost-effectiveness)-350(and)-328.4(clinician-friendliness.)]TJ 1.1128 -1.2203 TD [(However,)-470.1(to)-464.8(exert)-464.7(their)-469.6(optimal)-464(osteoinductive)-477.7(efcacy,)]TJ -1.1128 -1.2203 TD [(BMPs)-358.6(need)-353.9(to)-357.3(be)-352.1(gradually)-361.4(delivered)-355.6(to)-357.3(the)-357.8(target)-353.2(site,)-355.9(at)-354.1(a)]TJ T* [(low)-381(level)-380.7(and)-379(in)-380(a)-378.9(sustained)-380.5(manner,)-380.4(instead)-377.8(of)-382.6(in)-380(a)-378.9(single)]TJ 0 -1.2266 TD [(high-dose)-540.7(burst.)]TJ 6.7246 0 0 5.9768 128.296 346.2235 Tm (1)Tj 8.9663 0 0 8.9663 136.4598 342.1983 Tm [(Therefore,)-538.4(many)-542.3(efforts)-537.2(have)-541(been)-538.7(per-)]TJ -8.302 -1.2203 TD [(formed)-567.1(to)-566(develop)-561.3(slow-delivery)-569.2(systems)-569(to)-566(signicantly)]TJ T* [(enhance)-337.5(the)-332.5(efciency)-342(of)-332(BMPs)-333.3(in)-335.7(promoting)-333.1(the)-338.9(osteogenic)]TJ 0 -1.2266 TD [(differentiation)-455(of)-452.2(ASCs)]TJ /F4 1 Tf 10.8754 0 TD [(in)-448.9(vitro)]TJ /F3 1 Tf 3.6357 0 TD (and)Tj /F4 1 Tf 2.1245 0 TD [(in)-448.9(vivo)]TJ /F3 1 Tf 2.9781 0 TD [(.)-451.8(ASCs)-450.3(and)-448.5(the)]TJ -19.6137 -1.2203 TD [(BMP-slow-delivery)-370.5(scaffolds)-372.1(synergistically)-368.4(enhance)-369.2(the)-370.5(os-)]TJ T* [(teogenic)-506.8(events.)-514.5(Composite)-509.4(scaffolds)-504.9(that)-509.7(comprise)-505.9(of)-509.1(or-)]TJ 0 -1.2266 TD [(ganic)-598.2(and)-593.9(inorganic)-602.2(phases)-601.1(are)-594.5(especially)-598(promising)-600.3(for)]TJ 0 -1.2203 TD [(inducing)-685.8(osteogenesis)-691.2(of)-679.8(ASCs.)-687.2(For)-684.4(example,)-683.4(a)-682.4(HA/)]TJ /F9 1 Tf 25.7912 0 TD (b)Tj /F3 1 Tf .5564 0 TD (-)Tj -26.3476 -1.2203 TD [(tricalcium)-362.8(phosphate)-367.5(\()]TJ /F9 1 Tf 10.0218 0 TD (b)Tj /F3 1 Tf .5501 0 TD [(-TCP\))-365.9(scaffold)-364.4(that)-364.2(can)-362.6(facilitate)-364.3(the)]TJ -10.5719 -1.2203 TD [(sustained)-431.1(release)-422.1(of)-426.9(BMP-2)-426.8(over)-427.7(a)-423.1(20-day)-423.7(period)-428.6(has)-421.5(been)]TJ 0 -1.2266 TD [(shown)-467.7(to)-464.8(signicantly)-472.4(augment)-461.9(the)-471.6(osteogenic)-466.7(differentia-)]TJ 0 -1.2203 TD [(tion)-244.1(of)-243.5(ASCs)]TJ /F4 1 Tf 5.7286 0 TD [(in)-240.3(vitro)]TJ /F3 1 Tf 2.9781 0 TD (.)Tj 6.7246 0 0 5.9768 142.3559 225.6377 Tm (46)Tj 8.9663 0 0 8.9663 151.2566 221.6693 Tm [(In)-239.5(addition,)-243.4(many)-245.2(other)-247.5(scaffolds)-245.6(with)]TJ -9.9523 -1.2203 TD [(similar)-439.6(properties)-442(have)-433.5(shown)-442.4(promise)-437.1(in)-436.9(this)-438.7(type)-436.1(of)-439.5(ap-)]TJ 0 -1.2267 TD [(plication,)-646.3(for)-642.6(example,)-645.5(a)-638.1(poly)-644.4(\(DL-lactic-coglycolic)-647.6(acid\))]TJ 0 -1.2203 TD [(\(PLGA\))-315.3(scaffold)-313.9(with)-312.5(a)-315.7(brin/hyaluronic)-311.8(acid)-315.2(coating)]TJ 6.7246 0 0 5.9768 276.5479 192.7559 Tm (47)Tj 8.9663 0 0 8.9663 286.0724 188.7874 Tm (and)Tj -24.9881 -1.2203 TD [(a)-416.8(gelatin/)]TJ /F9 1 Tf 4.4956 0 TD (b)Tj /F3 1 Tf .5564 0 TD [(-TCP)-409.7(scaffold.)]TJ 6.7246 0 0 5.9768 163.9559 181.8141 Tm (48)Tj 8.9663 0 0 8.9663 174.3873 177.8456 Tm [(These)-418.5(slow-release)-419.1(systems)-417.3(can)]TJ -12.532 -1.2266 TD [(stimulate)-368.1(osteogenic)-365.5(differentiation,)-375.7(extracellular)-368.2(matrix)-364.3(de-)]TJ 0 -1.2203 TD [(position,)-319.2(maturation,)-309.4(and)-315.7(mineralization)-318(of)-306.7(ASCs.)]TJ 6.7246 0 0 5.9768 259.9369 159.874 Tm (49)Tj 8.9663 0 0 8.9663 269.4613 155.9055 Tm (Further,)Tj -23.1355 -1.2203 TD [(besides)-373.8(the)-376.8(slowly)-377.6(released)-374.5(BMP-2,)-372.8(the)-376.8(scaffold)-377.1(biomaterial)]TJ 0 -1.2266 TD [(itself)-293.7(may)-286(also)-285.3(play)-287(a)-290.4(role)-285.1(in)-291.4(the)-288.3(osteogenic)-289.6(differentiation)-296.9(of)]TJ 0 -1.2203 TD (ASCs)Tj /F4 1 Tf 2.8453 0 TD [(in)-429.9(vitro)]TJ /F3 1 Tf 3.1678 0 TD (.)Tj 6.7246 0 0 5.9768 118.148 126.9921 Tm (48)Tj 8.9663 0 0 8.9663 128.7496 123.0236 Tm [(These)-431.1(benets)-429.7(can)-432.1(be)-427.9(attributed)-431.1(to)-433.2(the)-427.4(in-)]TJ -7.4421 -1.2203 TD [(teraction)-269.3(between)-268.8(BMP-2)-268.7(and)]TJ /F9 1 Tf 13.2149 0 TD (b)Tj /F3 1 Tf .5501 0 TD [(-TCP:)-267.2(BMP-2)-268.7(can)-267.7(increase)-266.8(the)]TJ -13.765 -1.2203 TD [(dissolution)-425.3(of)]TJ /F9 1 Tf 6.5569 0 TD (b)Tj /F3 1 Tf .5501 0 TD [(-TCP,)-425.2(while)]TJ /F9 1 Tf 5.7602 0 TD (b)Tj /F3 1 Tf .5501 0 TD [(-TCP)-422.3(can)-419.5(resorb)-420.8(BMP-2)-426.8(from)]TJ -13.4172 -1.2266 TD [(media)-250.1(and)-246.2(provide)-245.9(Ca)]TJ 6.7246 0 0 5.9768 149.7826 94.1669 Tm (2)Tj /F8 1 Tf .6744 0 TD (+)Tj /F3 1 Tf 8.9663 0 0 8.9663 161.348 90.1417 Tm [(and)-246.2(PO)]TJ 6.7246 0 0 5.9768 190.9417 88.6677 Tm (4)Tj .4974 .9201 TD (3)Tj /F8 1 Tf .666 0 TD (-)Tj /F3 1 Tf 8.9663 0 0 8.9663 205.8519 90.1417 Tm [(that)-244.1(are)-246.7(needed)-249.4(for)-250.5(bone)]TJ -16.0412 -1.2203 TD (mineralization.)Tj 6.7246 0 0 5.9768 121.3228 83.1685 Tm (45)Tj 8.9663 0 0 8.9663 72 68.2583 Tm [(Consistent)-819.7(with)-812(the)-813.1(ndings)-812.4(of)]TJ /F4 1 Tf 16.5281 0 TD [(in)-809.3(vitro)]TJ /F3 1 Tf 4.3628 0 TD [(studies,)-816.8(a)]TJ -22.0037 -1.2267 TD [(controlled-released)-400.6(system)-390.7(is)-390.5(thought)-389.3(to)-395.3(maximize)-389(the)-389.4(pro-)]TJ 27.9978 74.5598 TD [(moting)-378.9(effect)-379.9(of)-376.3(BMPs)-377.5(on)-379.2(the)]TJ /F4 1 Tf 13.6385 0 TD [(in)-379.4(vivo)]TJ /F3 1 Tf 3.2816 0 TD [(osteogenesis)-381.4(of)-376.3(ASCs.)]TJ -16.9201 -1.2203 TD [(For)-380.9(example,)-379.9(a)-378.9(PLGA/HA)-375.6(composite)-382(scaffold)-383.4(is)-377.9(capable)-374.2(of)]TJ 0 -1.2266 TD [(releasing)-401.9(BMP-2)-401.5(over)-396.1(a)-397.9(4-week)-397.8(period)]TJ /F4 1 Tf 17.7421 0 TD [(in)-398.3(vitro)]TJ /F3 1 Tf 3.5345 0 TD [(and)-397.9(thereby)]TJ -21.2766 -1.2203 TD [(stimulates)-565.4(bone)-554.2(regeneration)-562.3(following)-557.2(transplantation)-560.8(of)]TJ T* [(undifferentiated)-345.5(human)-340.3(ASCs)]TJ /F4 1 Tf 13.6322 0 TD [(in)-335.1(vivo)]TJ /F3 1 Tf 2.8643 0 TD (.)Tj 6.7246 0 0 5.9768 463.2377 685.9274 Tm (49)Tj 8.9663 0 0 8.9663 472.9889 681.9589 Tm [(This)-333.7(method)-335.9(avoids)]TJ -17.8369 -1.2266 TD (an)Tj /F4 1 Tf 1.5554 0 TD [(in)-480.5(vitro)]TJ /F3 1 Tf 3.6989 0 TD [(culture)-480.8(period,)-482.1(and)-480.1(thus)-487.1(maximally)-479.2(favors)-479.7(the)]TJ -5.2543 -1.2203 TD [(application)-416.6(potential)-419.6(of)-407.9(ASCs)-412.3(in)-411.6(clinic.)-413.8(The)-410.9(contribution)-418.1(of)]TJ T* [(the)-585.5(transplanted)-585.6(human)-580.6(ASCs)-576.7(to)-578.6(newly)-581.9(formed)-579.8(bone)-585.9(is)]TJ 0 -1.2266 TD [(corroborated)-567.1(by)-558.9(the)-560.2(presence)-562.1(of)-559.7(human)-561.6(nuclear)-564.1(antigen-)]TJ 0 -1.2203 TD [(positive)-481.5(cells)-475.5(and)-473.8(the)-471.7(expression)-484.2(of)-471.1(specic)-475.6(human)-479.4(osteo-)]TJ T* [(genic)-446.8(proteins)-443.4(in)-436.9(the)-440(area)-442.2(of)-439.5(new)-441.2(bone)-440.4(formation)-441.1(in)-443.2(nude)]TJ T* [(mice)-335.4(models.)]TJ 6.7246 0 0 5.9768 365.3857 609.2219 Tm (2,44,49,50)Tj /F11 1 Tf 8.9663 0 0 8.9663 313.0582 583.3132 Tm [(Gene)-338.8(technology)]TJ /F3 1 Tf 1.1128 -1.8336 TD [(Over)-301.6(the)-307.3(past)-306.2(decade,)-298.4(BMPs)-308(and)-303.1(their)-305.2(signaling)-298.9(have)-307(also)]TJ -1.1128 -1.2203 TD [(been)-431.2(introduced)-428.4(using)-425(gene)-424.9(technologies)-429.3(to)-426.9(induce)-427.8(the)-421.1(os-)]TJ 0 -1.2266 TD [(teogenic)-538.5(differentiation)-543.5(of)-528(ASCs.)-535.4(These)-538.6(gene)-532.4(technologies)]TJ 0 -1.2203 TD [(include)-355.4(gene)-349(transfection)-356.6(of)-344.7(BMPs)-352.2(and)-347.3(the)-351.5(key)-343.8(BMP)-350.9(signal-)]TJ T* [(ing)-384.4(components,)-388.2(and)-379(gene)-387(knockdown)-379.2(of)-382.6(the)-383.1(BMP)-382.5(antago-)]TJ 0 -1.2266 TD [(nists)-496.9(\(Fig.)-496.3(1\).)-489.8(Human)-495(ASCs)-500.9(transfected)-495.3(with)]TJ /F4 1 Tf 21.1059 0 TD (BMP-2)Tj /F3 1 Tf 3.4586 0 TD (have)Tj -24.5645 -1.2203 TD [(been)-241.6(shown)-233.8(to)-237.2(signicantly)-238.5(promote)-233.2(bone)-238.1(formation)-238.8(in)-234.5(many)]TJ T* [(an)16.1(im)17.9(a)13.1(l)-294.4(m)15.1(o)0(d)19.5(e)0(l)15.5(s)0(,)-282.4(i)15.4(nc)16.3(lu)20.4(di)18.8(ng)-279.7(ec)13.5(t)12.2(o)0(p)21.2(i)0(c)-281(b)0(o)18.1(n)0(e)-281.5(i)0(n)18.4(d)0(u)20.9(c)0(t)12.9(i)15.4(on)-284.4(in)-278.8(mi)17.9(ce)19.8(,)]TJ 6.7246 0 0 5.9768 535.6912 494.1353 Tm [(51)22(5)22(3)]TJ 8.9663 0 0 8.9663 313.0582 479.2251 Tm [(cr)19(it)15(ic)22.5(al)15.9(-)12.2(s)0(i)20.4(z)0(e)-258.7(b)0(o)18.1(n)0(e)-262.5(d)0(e)22.4(f)0(e)18.6(c)0(t)19.2(s)-273.2(of)-256.2(ra)18.8(ts)17.2(,)]TJ 6.7246 0 0 5.9768 435.3448 483.1936 Tm [(54)22(,5)25(5)]TJ 8.9663 0 0 8.9663 452.5794 479.2251 Tm [(a)13.1(n)0(d)-259.3(s)0(p)16.3(i)0(n)18.4(e)-265.5(fu)17.1(si)20.4(on)-259.1(in)-259.8(ra)18.8(ts)17.2(.)]TJ 6.7246 0 0 5.9768 545.5558 483.1936 Tm (56)Tj 8.9663 0 0 8.9663 313.0582 468.2267 Tm [(Further,)-443.8(cotransfectio)5.1(n)-446(o)0(f)]TJ /F4 1 Tf 11.8365 0 TD (RUNX2)Tj /F3 1 Tf 3.8696 0 TD (or)Tj /F4 1 Tf 1.3721 0 TD (VEGF)Tj /F3 1 Tf 3.035 0 TD (with)Tj /F4 1 Tf 2.4533 0 TD (BMP-2)Tj /F3 1 Tf 3.4081 0 TD (is)Tj -25.9745 -1.2203 TD [(shown)-619.5(to)-622.9(enhance)-622.1(bone)-617.5(regeneration)-612.9(and)-619.2(accelerate)-621.6(the)]TJ T* [(healing)-485.6(of)-490.1(segmental)-484.2(defects)-491.2(more)-481.5(effectively)-486.8(than)]TJ /F4 1 Tf 23.7046 0 TD (BMP-2)Tj /F3 1 Tf -23.7046 -1.2266 TD (alone)Tj /F4 1 Tf 2.9275 0 TD [(in)-562.7(vivo)]TJ /F3 1 Tf 3.0856 0 TD (.)Tj 6.7246 0 0 5.9768 369.1842 439.37 Tm (57,58)Tj 8.9663 0 0 8.9663 389.3668 435.3448 Tm [(In)-561.9(addition)-556.7(to)]TJ /F4 1 Tf 7.1575 0 TD (BMP-2)Tj /F3 1 Tf 2.9655 0 TD [(,)-559.3(signicant)-559.3(bone)]TJ -18.6336 -1.2203 TD [(formation)-295.7(can)-293(also)-291.7(be)-295.2(achieved)-293.8(by)-293.4(transfection)-293.4(of)-294.1(ASCs)-298.5(with)]TJ /F4 1 Tf T* (BMP-4)Tj /F3 1 Tf 2.9655 0 TD (,)Tj 6.7246 0 0 5.9768 341.9149 417.4298 Tm (32,33)Tj /F4 1 Tf 8.9663 0 0 8.9663 359.9999 413.4613 Tm (BMP-6)Tj /F3 1 Tf 2.9591 0 TD (,)Tj 6.7246 0 0 5.9768 388.7999 417.4298 Tm (5)Tj 8.9663 0 0 8.9663 395.1495 413.4613 Tm (or)Tj /F4 1 Tf 1.2583 0 TD (BMP-7)Tj /F3 1 Tf 2.9591 0 TD (.)Tj 6.7246 0 0 5.9768 435.2314 417.4298 Tm (59,60)Tj 8.9663 0 0 8.9663 323.0361 402.4629 Tm [(On)-303.6(the)-307.3(other)-310.7(hand,)-303.1(the)-307.3(gene)-304.8(knockdown)-309.6(of)]TJ /F4 1 Tf 19.443 0 TD (noggin)Tj /F3 1 Tf 2.8074 0 TD [(,)-306.4(one)-303.2(of)]TJ -23.3632 -1.2203 TD [(the)-389.5(BMP)-388.9(antagonists,)-383.4(signicantly)-390.2(upregulates)-393.2(BMP)-382.5(signal-)]TJ T* [(ing)-378.1(and)-379(enhances)-383.1(BMP-2-induced)-377.5(osteogenic)-384.5(differentiation)]TJ T* [(of)-370(ASCs)]TJ /F4 1 Tf 4.0151 0 TD [(in)-373(vitro)]TJ /F3 1 Tf 3.4776 0 TD (and)Tj /F4 1 Tf 2.0423 0 TD [(in)-366.7(vivo)]TJ /F3 1 Tf 2.8959 0 TD (.)Tj 6.7246 0 0 5.9768 426.7841 373.6062 Tm (2,61)Tj 8.9663 0 0 8.9663 441.8644 369.6377 Tm (Interestingly,)Tj /F4 1 Tf 6.1459 0 TD (noggin)Tj /F3 1 Tf 3.1804 0 TD (knock-)Tj -23.6919 -1.2266 TD [(down)-257.4(also)-260(increases)-261.8(angiogenesis,)-257.9(which)-257.8(is)-257.8(essential)-259.5(for)-256.9(bone)]TJ 0 -1.2203 TD (formation.)Tj 6.7246 0 0 5.9768 354.2739 351.666 Tm (61)Tj 8.9663 0 0 8.9663 368.7306 347.6975 Tm [(Moreover,)-862.8(simultaneous)-863.3(overexpression)-867.7(of)]TJ /F4 1 Tf -6.2091 -1.2203 TD (BMP-2)Tj /F3 1 Tf 3.3385 0 TD [(and)-366.3(repression)-369(of)]TJ /F4 1 Tf 8.1629 0 TD (noggin)Tj /F3 1 Tf 3.1804 0 TD [(synergistically)-368.4(enhance)-369.2(the)]TJ -14.6818 -1.2266 TD [(osteogenesis)-343.5(of)-332(ASCs.)]TJ 6.7246 0 0 5.9768 399.7416 329.7826 Tm (62)Tj /F11 1 Tf 8.9663 0 0 8.9663 313.0582 303.8739 Tm [(The)-337(induction)-335.2(of)-330.4(endogenous)-336.5(BMPs)]TJ /F3 1 Tf 1.1128 -1.8336 TD [(Many)-575.2(active)-572.5(agents)-578.1(can)-571.2(upregulate)-581.6(endogenous)-572.3(BMPs)]TJ -1.1128 -1.2266 TD [(\(Fig.)-300.3(2\),)-293.7(which)-302.1(at)-297.2(least)-295.6(partially)-294.8(accounts)-304.6(for)-294.8(their)-298.8(promoting)]TJ 0 -1.2203 TD [(effect)-487.4(on)-480.4(the)-484.3(osteogenesis)-482.6(of)-483.8(ASCs.)-478.5(The)-486.8(expression)-484.2(of)-477.5(en-)]TJ T* [(dogenous)-316.1(BMPs,)-317.2(such)-315.2(as)-310.6(BMP-2,)-315.9(BMP-4,)-309.6(and)-315.7(BMP-6,)-309.6(can)-318.3(be)]TJ T* [(detected)-303.1(in)-297.8(osteogenic)-308.6(medium.)]TJ 6.7246 0 0 5.9768 438.5762 247.5779 Tm (3,37,38)Tj 8.9663 0 0 8.9663 461.4235 243.6094 Tm [(The)-303.5(expression)-300.9(level)-298.5(of)]TJ -16.5471 -1.2266 TD [(endogenous)-344.7(BMPs)-333.3(is)-340(also)-335.9(adopted)-338.8(as)-335.9(an)-331.7(important)-338.6(parame-)]TJ 0 -1.2203 TD [(ter)-298.2(to)-294.1(evaluate)-295.8(the)-294.6(potency)-289.8(of)-294.1(an)-293.7(osteogenic)-296(medium.)]TJ 6.7246 0 0 5.9768 523.0486 225.6377 Tm (3,38)Tj 8.9663 0 0 8.9663 537.4487 221.6693 Tm (The)Tj -25.0261 -1.2203 TD [(types)-336.2(of)-332(endogenous)-332(BMPs)-333.3(are)-328.9(also)-329.6(dependent)-336.8(on)-328.6(the)-332.6(types)]TJ 0 -1.2267 TD [(of)-420.6(active)-420.7(reagents)-426.9(in)-417.9(the)-421.1(osteogenic)-422.4(medium.)-423.2(For)-418.9(example,)]TJ 0 -1.2203 TD [(endogenous)-344.7(BMP-6)-344.6(can)-337.3(be)-339.4(induced)-342.3(by)-337.6(both)-339.8(dexamethasone)]TJ T* [(and)-562.3(vitamin)-565.2(D)]TJ 6.7246 0 0 5.9768 375.4771 176.3149 Tm (3)Tj 8.9663 0 0 8.9663 378.8787 177.8456 Tm [(,)-559.3(whereas)-562.8(BMP-2)-559.6(is)-561.3(only)-557.9(detected)-568.7(in)-557(the)]TJ -7.3409 -1.2266 TD [(presence)-353.5(of)-344.7(vitamin)-343.9(D)]TJ 6.7246 0 0 5.9768 401.6125 165.3732 Tm (3)Tj 8.9663 0 0 8.9663 405.0141 166.8472 Tm (.)Tj 6.7246 0 0 5.9768 407.2251 170.8724 Tm (38)Tj 8.9663 0 0 8.9663 417.033 166.8472 Tm [(These)-348.9(results)-350(suggest)-342(that)-351.6(the)-345.2(dif-)]TJ -11.5962 -1.2203 TD [(ferent)-403.2(active)-401.8(agents)-394.7(in)-398.9(osteogenic)-403.4(medium)-394.9(induce)-402.5(the)-395.8(oste-)]TJ T* 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-1.1128 -1.2203 TD -.0174 Tc [(e)-4.7(ffe)-4.7(ct)-5.2(s)-688.9(o)-1.2(n)-691(t)1.1(he)-693.8(proc)-4(es)-17.4(s)-677.6(o)-1.2(f)-688.1(o)-1.2(st)-5.2(eogene)-4.6(sis)-688.9(b)-2.8(oth)]TJ /F4 1 Tf 21.0237 0 TD -.0169 Tc [(in)-691.5(vitro)]TJ /F3 1 Tf 4.0024 0 TD -.0176 Tc (and)Tj /F4 1 Tf -25.0261 -1.2266 TD -.0162 Tc [(in)-532.8(vivo.)]TJ /F3 1 Tf 6.7246 0 0 5.9768 90.7086 532.5164 Tm -.0195 Tc [(75)8.4(77)]TJ 8.9663 0 0 8.9663 111.5716 528.4912 Tm -.016 Tc [(Thei)5.8(r)-535.2(e)-3.3(xact)-534.9(functions)-535.8(a)3.5(re)-534.4(highly)-532.6(dependent)-535(o).2(n)]TJ -5.5262 -1.2203 TD [(factors)-624.4(i)-.7(ncluding)-621.2(cell)-620.3(type)]TJ 12.6016 0 TD -.0165 Tc [(and)-626.5(d)5.8(ifferentiation)-626.9(stage.)]TJ 6.7246 0 0 5.9768 276.1511 521.5179 Tm -.0195 Tc (75)Tj 8.9663 0 0 8.9663 288.17 517.5494 Tm -.0154 Tc (For)Tj -25.2221 -1.2203 TD -.0164 Tc [(mouse)-370.4(A)1.2(SCs,)-367.1(s)-16.4(i)16.7(gnaling)-368.6(t)2.1(hrou)-16.4(g)15.8(h)-367.5(BMPR-IB)-367.2(p)-16.4(l)16.7(a)-3.3(yed)-367.2(a)-363.7(more)-370.4(sig-)]TJ T* -.0158 Tc [(nicant)-496.8(r)2.5(ole)-496.2(i)-.4(n)-499.7(o).4(steogenic)-495.6(d).2(iffer)-15.8(e)15.2(nti)6(a)-2.7(tion,)-499.3(w)1.5(her)-15.8(e)15.2(as)-497.6(sig)5.1(n)-.2(ali)6(n)-.2(g)]TJ 0 -1.2266 TD -.0161 Tc [(th)5.8(r)-16.1(o)12(ugh)-462.1(B)-.1(MPR-IA)-460.1(seemed)-461.7(to)-461.5(be)-458.6(more)-464.9(relatively)-456.8(r)-16.1(e)14.9(lev)-16.1(a)15.3(nt)-465.5(to)]TJ 0 -1.2203 TD -.0155 Tc [(ad)6.8(ip)-15.5(o)12(g)5.4(enesis.)]TJ 6.7246 0 0 5.9768 113.3858 477.6943 Tm -.0195 Tc (43)Tj 8.9663 0 0 8.9663 122.9102 473.7259 Tm -.0186 Tc [(Da)-5.5(ta)-346.9(from)-345(2)-5.5(T)3.7(3)-346.9(m)-3.5(ouse)-347.3(ca)-5.5(lv)-18.6(a)12.8(r)-18.6(i)15.1(a)-5.5(l)-344.6(s)-.9(te)-5.9(m)-345(c)1.1(e)-5.8(l)-3.2(ls)-348.7(cor)-18.6(-)]TJ -6.7908 -1.2203 TD -.0173 Tc [(robora)-4.2(te)-4.5(d)-323.8(t)-5.1(he)-327(distinc)-3.9(t)-327.6(fu)-17.3(n)15.9(c)-3.9(tions)-328.4(o)-1.1(f)-327.6(t)-5.1(hese)-333.3(two)-329.9(B)-1.3(MP)-328.5(r)-17.3(e)13.7(c)-3.9(e)1.8(p)-17.3(t)12.5(ors)-17.3(.)]TJ 6.7246 0 0 5.9768 294.5196 466.7527 Tm -.0195 Tc (77)Tj 8.9663 0 0 8.9663 62.022 451.7857 Tm -.0173 Tc [(Ther)-17.3(e)13.7(f)-5.1(ore,)-285.8(t)-5.1(h)-1.7(e)-282.8(t)1.2(ype)-289.1(o)-1.1(f)-283.3(r)1(e)-4.5(c)-3.9(ept)-5.1(o)-1.1(r)-283.6(a)2.2(nd)-285.9(lev)-17.3(e)13.7(l)-286.4(o)-1.1(f)-283.3(e)-4.5(xpr)-17.3(e)13.7(ss)-17.3(i)15.8(o)-1.1(n)-286.2(o)-1.1(n)-286.3(s).4(t)-5.1(e)1.8(m)]TJ T* -.0159 Tc [(cells)-289.1(can)-284.8(b)-1.3(e)-287.7(a)-281(s)-15.9(w)12.8(itch)-284.8(for)-282.2(t)-3.7(heir)-288.5(commitment.)-284.4(It)-288.3(is)-289.1(also)-290.6(i)5.9(m)-.8(por)-15.9(t)14.5(ant)]TJ T* -.0158 Tc [(to)-385.3(note)-388.7(that)-395.6(R)5.3(A)-390.2(signaling)-386.9(i)-.4(s)-390.2(i)-.4(ndi)6(s)-15.8(p)13.1(e)3.3(ns)-15.8(a)15(b)-1.2(le)-388.7(for)-389.5(o).4(steogenic)-388.1(d).2(if-)]TJ 0 -1.2266 TD -.0147 Tc [(fe)4.4(r)3.6(e)-2(nt)3.8(ia)4.8(tion)-321.6(in)-315.3(mou)2.9(s)-14.7(e)-306.8(A)2.9(SCs)3(,)]TJ 6.7246 0 0 5.9768 169.8519 422.929 Tm -.0279 Tc (43)Tj 8.9663 0 0 8.9663 179.1496 418.9038 Tm -.0155 Tc [(al)6.3(though)-322.4(this)-320.3(is)-320.3(not)-325.8(t)3(he)-325.2(case)-318.9(for)]TJ -13.0631 -1.2203 TD -.017 Tc [(human)-646.4(A).6(SCs.)]TJ 6.7246 0 0 5.9768 118.0913 411.9306 Tm -.0195 Tc (78)Tj 8.9663 0 0 8.9663 130.2803 407.9621 Tm -.0184 Tc [(Cons)-18.4(e)12(q)-3.8(ue)-5.7(nt)-6.2(ly,)-647.3(p)-.8(re)-5.6(ca)]TJ 9.0291 0 TD -.0178 Tc [(utions)-645.1(mu)-17.8(s)11.1(t)-644.2(be)-643.7(taken)]TJ -16.6419 -1.2203 TD 0 Tc [(w)17.3(h)15.6(e)12.7(n)-313.2(e)12.8(x)16.8(t)18.5(r)0(a)31.4(p)17.6(o)16.2(l)15.4(a)13.1(t)18.5(i)15.4(n)15.6(g)-314.2(d)16(a)19.5(t)12.2(a)-315.7(f)18.5(ro)28.1(m)-313.7(m)15.1(o)16.2(u)17.6(s)17.7(e)-316(AS)31.7(C)12.5(s)-317.5(t)18.5(o)-318.9(h)15.6(u)17.6(m)15.1(a)19.5(n)15.6(s)17.7(.)]TJ 29.1107 36.6666 TD [(ERK)-421(also)-418.1(appears)-421(to)-420.6(be)-415.3(a)-416.8(key)-419.7(switch)-420.6(of)-420.6(adipogenic)-419(and)]TJ -1.1128 -1.2203 TD [(osteogenic)-801.8(differentiation)-796.4(of)-793.6(mesenchymal)-800.1(stem)-789.6(cells.)]TJ 6.7246 0 0 5.9768 545.4424 718.8093 Tm (79)Tj 8.9663 0 0 8.9663 313.0582 703.8423 Tm [(Consistent)-402.4(with)-401(this)-400.7(nding,)-396.7(ERK)-395.7(is)-396.9(also)-399.2(important)-401.8(for)-396(the)]TJ T* [(adipogenic)-406.4(and)-404.2(osteogenic)-409.8(commitment)-407.2(in)-405.3(ASCs.)]TJ 6.7246 0 0 5.9768 512.277 696.8691 Tm [(68,80)-9.4(83)]TJ 8.9663 0 0 8.9663 541.1904 692.9006 Tm (In-)Tj -25.4434 -1.2203 TD [(hibition)-360.2(of)-351(ERK)-351.5(by)-350.3(PD98059)-354.4(blocks)-350.9(the)-351.5(expression)-357.8(of)-357.3(osteo-)]TJ 0 -1.2266 TD [(genic)-560.6(differentiation-related)-570(proteins)-563.5(in)-557(a)-555.9(dose-dependent)]TJ 0 -1.2203 TD [(manner)-421.8(and)-416.9(switches)-421.8(ASCs)-418.7(to)-420.6(adipogenic)-419(differentiation.)]TJ 6.7246 0 0 5.9768 545.4424 663.9872 Tm (83)Tj 8.9663 0 0 8.9663 313.0582 649.077 Tm [(Further,)-462.8(ERK)-465.3(is)-453.8(indispensable)-464.4(for)-465.5(the)-459(effects)-463.4(of)-458.5(sesamin,)]TJ 6.7246 0 0 5.9768 545.4424 653.0455 Tm (81)Tj 8.9663 0 0 8.9663 313.0582 638.0786 Tm (akermanite,)Tj 6.7246 0 0 5.9768 359.4897 642.1038 Tm (68)Tj 8.9663 0 0 8.9663 370.4881 638.0786 Tm (wedelolactone,)Tj 6.7246 0 0 5.9768 429.392 642.1038 Tm (82)Tj 8.9663 0 0 8.9663 440.3904 638.0786 Tm [(and)-473.8(oncostatin)-478.5(M)]TJ 6.7246 0 0 5.9768 512.7872 642.1038 Tm (80)Tj 8.9663 0 0 8.9663 523.729 638.0786 Tm [(in)-474.8(pro-)]TJ -23.4959 -1.2203 TD [(moting)-423.1(the)-421.1(osteogenic)-428.7(differentiation)-423.4(and)-423.2(inhibiting)-419.3(adipo-)]TJ T* [(genic)-807.2(differentiation)-809.1(of)-799.9(ASCs.)-807.3(However,)-805.2(how)-798.1(ERK)-806.7(is)]TJ T* [(modulated)-390.5(during)-389.4(osteogenesis)-394(of)-388.9(ASCs)-387.1(remains)-385.3(to)-388.9(be)-383.7(elu-)]TJ 0 -1.2266 TD (cidated.)Tj 1.1128 -1.2203 TD [(Wnt)-274.8(signaling)-273.6(also)-279(has)-269.8(an)-274.8(important)-275.3(role)-278.8(in)-272.5(the)-275.6(osteogenic)]TJ -1.1128 -1.2203 TD [(commitment)-451.4(of)-445.8(mesenchymal)-452.4(stem)-448.2(cells)-450.2(\(Fig.)-445.7(3\).)-445.5(Wnt5a,)-447.4(a)]TJ 0 -1.2266 TD [(noncanonical)-390.5(Wnt)-382.3(ligand,)-380.7(promotes)-379.9(the)-383.1(osteogenesis)-387.7(by)-381.9(re-)]TJ 0 -1.2203 TD [(pressing)-610.3(PPAR-)]TJ /F9 1 Tf 7.2397 0 TD (g)Tj /F3 1 Tf 1.1065 0 TD [(transactivation)-613(through)-610.8(CaMKII-TAK1/)]TJ -8.3462 -1.2203 TD [(TAB2-NLK)-342(signaling)-343.2(cascade)-336.9(and)-341(the)-338.9(subsequent)-340.3(activation)]TJ 0 -1.2266 TD [(of)-433.2(the)-427.4(histone)-432.1(methyltransferase,)-436.7(SETDB1)-432(\(SET)-428.6(domain)-427.1(bi-)]TJ 0 -1.2203 TD [(furcated)-485.2(1\).)]TJ 6.7246 0 0 5.9768 359.6031 521.5179 Tm (84,85)Tj 8.9663 0 0 8.9663 379.0487 517.5494 Tm [(SETDB1)-476.3(leads)-481.5(to)-477.5(the)-484.3(formation)-479.1(of)-477.5(a)-480.1(core-)]TJ -7.3599 -1.2203 TD [(pressor)-463.3(complex)-455.5(that)-459.1(inactivates)-460.6(PPAR-)]TJ /F9 1 Tf 18.0709 0 TD (g)Tj /F3 1 Tf .9548 0 TD [(function)-463.6(through)]TJ -19.0256 -1.2203 TD [(histone)-419.4(H3-K9)-407(methylation.)-413.9(Thus,)-410.3(noncanonical)-415.8(Wnt5a)-406.6(has)]TJ 0 -1.2266 TD [(emerged)-454.3(as)-449.7(a)-448.4(fate)-449.3(determinant)-454.4(of)-452.2(mesenchymal)-446(stem)-454.5(cells)]TJ 0 -1.2203 TD [(through)-750(shifting)-747.6(from)-741.3(adipogenesis)-744.8(to)-743(osteogenesis.)]TJ 6.7246 0 0 5.9768 537.0518 477.6943 Tm (84,85)Tj 8.9663 0 0 8.9663 313.0582 462.7841 Tm [(Exogenous)-621.8(Wnt5a)-615.2(induces)-612.4(osteogenic)-618.4(differentiation)-625.7(and)]TJ 0 -1.2266 TD [(downregulates)-363.3(PPAR-)]TJ /F9 1 Tf 9.8448 0 TD (g)Tj /F3 1 Tf .8536 0 TD [(expression)-357.8(in)-354.7(human)-353(ASCs.)]TJ 6.7246 0 0 5.9768 519.7038 455.8109 Tm (86)Tj 8.9663 0 0 8.9663 529.5684 451.7857 Tm (How-)Tj -24.1472 -1.2203 TD [(ever,)-541.6(the)-541.2(interaction)-541.7(between)-540.7(endogenous)-540.7(Wnt)-534(and)-537(BMP)]TJ T* [(signaling)-570.8(during)-572.8(the)-566.5(osteogenesis)-577.4(of)-566(ASCs)-570.4(needs)-570.2(further)]TJ 0 -1.2266 TD (elucidation.)Tj 1.1128 -1.2203 TD [(In)-492.4(contrast)-488.5(with)-489.6(their)-494.9(ambiguous)-490.5(effects)]TJ /F4 1 Tf 19.0383 0 TD [(in)-493.2(vitro)]TJ /F3 1 Tf 3.231 0 TD [(,)-483.5(BMPs)]TJ -23.3821 -1.2203 TD [(have)-724.4(a)-714(more)-715.4(denite)-721.4(effect)-721.3(on)-720.6(promoting)-718.8(the)]TJ /F4 1 Tf 23.4201 0 TD [(in)-720.8(vivo)]TJ ET q 1 i 191.622 365.216 m 552.189 365.216 l 552.189 57.43 l 191.622 57.43 l W n q 360.926 0 0 307.786 191.622 57.43 cm /Im3 Do Q Q BT /F6 1 Tf 8.9663 0 0 8.9663 62.022 352.2897 Tm [(FIG.)-336.8(3.)]TJ /F3 1 Tf 4.0909 0 TD [(Schematic)-342.8(diagram)]TJ -4.0909 -1.1128 TD [(depicting)-335(the)-338.9(signaling)-336.9(path-)]TJ 0 -1.1065 TD [(ways)-335.7(of)-332(BMPs)-333.3(in)-335.7(ASCs)-336.5(and)]TJ 0 -1.1128 TD [(the)-338.9(main)-332.8(switches)-333.3(for)-339.1(the)-332.5(os-)]TJ T* [(teogenic)-336.1(commitment)-337.6(of)]TJ 0 -1.1065 TD [(ASCs.)-333.1(BMPR-IA,)-336.8(BMP)-338.3(recep-)]TJ 0 -1.1128 TD [(tor)-332.7(type-IA;)-341.8(BMPR-IB,)-332(BMP)]TJ T* [(receptor)-340.2(type-IB;)-337.1(BMPR-II,)]TJ T* [(BMP)-306.7(receptor)-314.9(type-II;)-310.9(CaMK-)]TJ 0 -1.1065 TD [(II,)-335.9(calcium/calmodulin-)]TJ 0 -1.1128 TD [(dependent)-336.8(kinase)-340.9(II;)-329.6(ERK,)]TJ T* [(extracellular)-336.6(signal-regulated)]TJ T* [(kinase;)-337.5(LPL,)-332.7(lipoprotein)-339.5(li-)]TJ 0 -1.1065 TD [(pase;)-333.8(NF-)]TJ /F9 1 Tf 4.2616 0 TD (k)Tj /F3 1 Tf .5501 0 TD [(B,)-334.7(nuclear)-336.5(factor)]TJ /F9 1 Tf -4.8117 -1.1128 TD (k)Tj /F3 1 Tf .5501 0 TD [(B;)-334.7(NLK,)-337.5(Nemo-like)-334.5(kinase;)]TJ -.5501 -1.1128 TD (PPAR-)Tj /F9 1 Tf 2.9465 0 TD (g)Tj /F3 1 Tf .4995 0 TD [(,)-338(peroxisome)-334.4(pro-)]TJ -3.446 -1.1065 TD [(liferator-activated)-340.9(receptor)]TJ 0 -1.1128 TD [(gamma;)-330.3(RUNX2,)-341.1(Runt-re-)]TJ T* [(lated)-335.2(transcription)-342.9(factor)-332(2;)]TJ T* [(TAB2,)-332.3(TGF-)]TJ /F9 1 Tf 5.2986 0 TD (b)Tj /F3 1 Tf .5564 0 TD [(-activated)-335.7(ki-)]TJ -5.855 -1.1065 TD [(nase)-332.9(1/MAP3K7-binding)]TJ 0 -1.1128 TD [(protein)-340.9(2;)-331.2(TAK1,)-332.1(transform-)]TJ T* [(ing)-333.8(growth)-335.8(factor)]TJ /F9 1 Tf 8.1249 0 TD (b)Tj /F3 1 Tf .5501 0 TD (-activated)Tj -8.675 -1.1128 TD [(kinase-1;)-242.6(TAZ,)-239.2(transcriptional)]TJ 0 -1.1065 TD [(coactivator)-337.8(with)-337.8(PDZ-bind-)]TJ 0 -1.1128 TD [(ing)-333.8(motif;)-336.5(TNF-)]TJ /F13 1 Tf 6.9678 0 TD (a)Tj /F3 1 Tf .5501 0 TD [(,)-338(tumor)-331.7(ne-)]TJ -7.5179 -1.1128 TD [(crosis)-337.7(factor-alpha.)]TJ /F12 1 Tf 8.675 0 TD (/)Tj /F3 1 Tf 1.195 0 TD (,)Tj -9.8701 -1.1065 TD (promotion;)Tj /F12 1 Tf 5.2417 0 TD (x)Tj /F3 1 Tf .999 0 TD [(,)-331.7(inhibition.)]TJ -6.2407 -1.1128 TD [(Color)-281.8(images)-278.1(available)-273.4(online)]TJ T* [(at)-335.1(www.liebertpub.com/teb)]TJ /F5 1 Tf 0 76.5388 TD (88)Tj 47.5546 0 TD [(ZHANG)-333.3(ET)-338.7(AL.)]TJ ET endstream endobj 77 0 obj <>stream Adobed         s!1AQa"q2B#R3b$r%C4Scs5D'6Tdt& EFVU(eufv7GWgw8HXhx)9IYiy*:JZjzm!1AQa"q2#BRbr3$4CS%cs5DT &6E'dtU7()󄔤euFVfvGWgw8HXhx9IYiy*:JZjz?N*S6*ثb͊6*ثb͊6*ثb͊6*ثb͊6*ثb͊6*ثb͊6*ثb͊6*ثb͊6*ثb͊6*ثb͊6*ثb͊6* Vm miiU|MK$b.EVbded4ncX\u྽֮(1M u&d2Ѝ|ڗ痬uh즖Q5F[G$`AOtto-VGl.3 |>M}9u7 [N] [ƵSSxa{MΛSl wE,WrZv!dNoʟ-~Yߘ@izjV^G9hX#o]^##Υ*.-..4ٵ[mݣbD*FNXYK`?;~om54M. 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c{Ͽ94'[>k\f]vlUٱWf]vlUٱWf]vlUٱWf]vlUٱWf]vlUٱWf]vlUٱWf]vlUٱWf]vlUٱWf]vlUٱWf]vlUٱWf]:?Ly=/aI\/voc\*ݛX"ʷf?ȿٿr/voc\*ݛX"ʷf?ȿٿr/voc\*ݛX"ʷf?ȿnL?ʿٿ rvo\*݃ϴ?qvkۏdtæoØUٱWf]vlUٱWf]vlUٱWf]vlUٱWf]_1{'q>C?6zN_pvDͧt_ٿWT/ K!tvWJʗfC_RHc]+*] K!tvo$1.C_RHc]+*] K!tvo$1.-7WvsS%-}쟳}[??g4%S^͊6*ثb͊6*ثb͊6*ثb͊6* endstream endobj 81 0 obj <>stream LAPDCC+AdvPSMP13 RS AdvPSMP13Brd\0vS{`v_{kcg>Oz[x{qr|s5GKywn~L2G9' Ӗ1hר endstream endobj 82 0 obj <> endobj 83 0 obj <>/XObject<>/ProcSet [/PDF /Text /ImageB /ImageC /ImageI]/Font<>>>/Thumb 85 0 R/MediaBox[0 0 612 792]/Rotate 0>> endobj 86 0 obj <>/ProcSet[/PDF/Text]/Font<>>> endobj 84 0 obj <>stream /GS1 gs BT /F3 1 Tf 8.9663 0 0 8.9663 59.7543 725.7825 Tm 0 0 0 1 k 0 Tc 0 Tw [(osteogenesis)-501.5(of)-490.1(ASCs.)-497.5(Endogenous)-493.2(cytokines)-500(that)-490.7(are)-493.3(ele-)]TJ 0 -1.2203 TD [(vated)-402(during)-402.1(acute)-398.9(inammation)-399.9(may)-399.8(also)-399.1(signicantly)-402.8(fa-)]TJ 0 -1.2266 TD [(cilitate)-383.3(the)-376.8(osteogenic)-384.5(commitment)-381.9(of)-376.3(ASCs)]TJ /F4 1 Tf 19.9804 0 TD [(in)-373(vivo)]TJ /F3 1 Tf 3.2816 0 TD [(\(Fig.)-376.2(3\).)]TJ -23.262 -1.2203 TD [(Tumor)-372.1(necrosis)-372.6(factor-alpha)-371.4(\(TNF-)]TJ /F9 1 Tf 15.5354 0 TD (a)Tj /F3 1 Tf .5501 0 TD [(\))-367.2(i)0(s)-371.6(one)-366.5(of)-370(the)-376.8(main)-364.4(cy-)]TJ -16.0855 -1.2203 TD [(tokines)-559.6(responsible)-559.6(for)-554(acute)-550.6(inammation.)]TJ 6.7246 0 0 5.9768 239.9243 685.9274 Tm (87)Tj 8.9663 0 0 8.9663 251.6031 681.9589 Tm (TNF-)Tj /F9 1 Tf 2.3015 0 TD (a)Tj /F3 1 Tf 1.1065 0 TD (acti-)Tj -24.8048 -1.2266 TD [(vates)-1019.9(nuclear)-1013(factor-)]TJ /F9 1 Tf 10.3696 0 TD (k)Tj /F3 1 Tf .5501 0 TD [(B)-1014.7(\(NF-)]TJ /F9 1 Tf 3.642 0 TD (k)Tj /F3 1 Tf .5501 0 TD [(B\),)-1011.7(which)-1016.6(inhibits)-1016.3(the)]TJ -15.1118 -1.2203 TD [(transactivation)-398(of)-395.3(PPAR-)]TJ /F9 1 Tf 11.1157 0 TD (g)Tj /F3 1 Tf .8915 0 TD [(through)-395.9(a)-391.5(physical)-395.7(association.)]TJ 6.7246 0 0 5.9768 292.1385 663.9872 Tm (85)Tj 8.9663 0 0 8.9663 59.7543 649.077 Tm (NF-)Tj /F9 1 Tf 1.7009 0 TD (k)Tj /F3 1 Tf .5501 0 TD [(B)-451.9(activation)-455.8(also)-449.7(leads)-449.9(to)-452.2(upregulation)-452.2(of)-452.2(TAZ)-451.2(\(tran-)]TJ -2.251 -1.2266 TD [(scriptional)-525.2(coactivator)-521.2(with)-514.8(PDZ-binding)-520(motif)-87(\),)-515.5(a)-518(coacti-)]TJ 0 -1.2203 TD [(vator)-453.1(of)-452.2(RUNX2-dependent)-454.1(transcription,)-459.6(and)-448.5(suppression)]TJ T* [(of)-496.4(PPAR-)]TJ /F9 1 Tf 4.3059 0 TD (g)Tj /F3 1 Tf .4995 0 TD [(-dependent)-495.3(transcription.)]TJ 6.7246 0 0 5.9768 204.6047 620.1636 Tm (88)Tj 8.9663 0 0 8.9663 215.7732 616.1951 Tm [(Through)-493.2(these)-491.8(three)]TJ -17.4007 -1.2203 TD [(pathways,)-374.9(TNF-)]TJ /F9 1 Tf 7.2144 0 TD (a)Tj /F3 1 Tf .9231 0 TD [(can)-375.2(help)-374.9(to)-370(commit)-374.2(the)-376.8(osteogenic)-378.2(differ-)]TJ -8.1376 -1.2266 TD [(entiation)-358.4(of)-351(ASCs)-349.1(in)]TJ /F4 1 Tf 9.3958 0 TD [(in)-347.7(vivo)]TJ /F3 1 Tf 3.231 0 TD [(microenvironments.)-352.6(The)-354(role)-348.3(of)]TJ -12.6269 -1.2203 TD (TNF-)Tj /F9 1 Tf 2.3015 0 TD (a)Tj /F3 1 Tf .8536 0 TD [(in)-297.8(their)-305.2(osteogenic)-302.3(differentiation)-309.6(is)-295.7(supported)-303.1(by)-299.7(the)]TJ -3.1551 -1.2203 TD [(nding)-286.3(that)-282(ASCs)-285.9(can)-280.4(be)-282.5(used)-277.5(to)-287.8(heal)-278.2(acute,)-281.6(but)-284.5(not)-284.8(chronic,)]TJ 0 -1.2266 TD [(calvarial)-427.2(defects)-421.6(in)-424.2(nude)-425(mice.)]TJ 6.7246 0 0 5.9768 184.0251 565.3983 Tm (89)Tj 8.9663 0 0 8.9663 194.57 561.3731 Tm (TNF-)Tj /F9 1 Tf 2.3015 0 TD (a)Tj /F3 1 Tf .9737 0 TD [(that)-421.2(occurs)-422(during)]TJ -18.3112 -1.2203 TD [(acute)-342(inammation)-336.7(may)-336.6(help)-337(to)-338.4(commit)-336.3(the)-332.5(osteogenesis)-343.5(of)]TJ T* [(ASCs,)-383.7(leading)-384(to)-382.6(a)-385.2(much)-381(more)-380.3(denite)-386.2(effect)-386.2(of)-382.6(exogenous)]TJ 0 -1.2266 TD [(BMPs)-308(in)-304.1(inducing)-306.4(the)-307.3(osteogenesis)-311.8(of)-300.4(ASCs)]TJ /F4 1 Tf 19.5441 0 TD [(in)-303.5(vivo)]TJ /F3 1 Tf 3.1362 0 TD [(than)-303.9(that)]TJ /F4 1 Tf -22.6803 -1.2203 TD [(in)-335.1(vitro)]TJ /F3 1 Tf 3.0729 0 TD (.)Tj /F11 1 Tf -3.0729 -2.4406 TD [(The)-337(roles)-336.2(of)-330.4(BMP)-332.6(signaling)-335(in)-336.5(the)-334.8(promotion)]TJ 0 -1.2266 TD [(of)-336.7(osteogenic)-335.9(differentiation)-335.3(of)-330.4(ASCs)]TJ /F3 1 Tf 1.1128 -1.8336 TD [(BMP)-382.5(signaling)-381.1(plays)-383.2(a)-378.9(crucial)-386.6(role)-380(in)-380(the)-383.1(osteogenesis)-387.7(of)]TJ -1.1128 -1.2203 TD [(ASCs.)-421.6(The)-417.3(upregulation)-427(of)-414.2(BMP)-420.5(signaling)-419.1(signicantly)-421.8(en-)]TJ T* [(hances)-329.3(and)-322(accelerates)-325.8(the)-326.2(process.)-325.7(This)-321.1(is)-327.3(supported)-328.4(by)-318.7(the)]TJ 0 -1.2266 TD [(fact)-284.3(that)-282(the)-282(osteogenesis)-286.6(of)-281.4(ASCs)-279.6(positively)-287.1(correlates)-280(to)-281.4(the)]TJ 0 -1.2203 TD [(expression)-484.2(levels)-476.8(of)-471.1(BMPR-II,)-476.6(Smad-1/5,)-478.2(RUNX2,)-473.8(and)-473.8(os-)]TJ T* (terix.)Tj 6.7246 0 0 5.9768 79.6535 417.4298 Tm [(4,90)-9.4(94)]TJ 8.9663 0 0 8.9663 69.7323 402.4629 Tm [(Different)-351.7(active)-351.2(agents)-350.4(may)-342.9(modulate)-349.5(the)-351.5(osteogenesis)-349.8(of)]TJ -1.1128 -1.2203 TD [(ASCs)-545.1(by)-540(targeting)-541.6(different)-543(genes)-546.4(and)-537(proteins)-544.6(for)-541.4(BMP)]TJ T* [(signaling)-558.2(pathways)-549(\(Fig.)-553.2(1\).)-553(For)-551.7(example,)-556.9(microRNA-26a)]TJ T* [(inhibits)-472.5(osteogenic)-473(differentiation)-474(of)-464.8(human)-473.1(ASCs)-462.9(via)-471.7(tar-)]TJ 0 -1.2266 TD [(geting)-559.9(the)-560.2(Smad1)-560.8(transcription)-564.2(factor.)]TJ 6.7246 0 0 5.9768 218.6078 362.6078 Tm (95)Tj 8.9663 0 0 8.9663 230.3432 358.6393 Tm [(In)-555.6(addition,)-559.6(Shh)]TJ -19.0256 -1.2203 TD [(promotes)-519(bone)-516.3(repair)-517.9(by)-514.7(ASCs,)-510.1(which)-517(is)-517(associated)-516.4(with)]TJ T* [(upregulation)-344.8(of)-332(phospho-Smad1/5/8.)]TJ 6.7246 0 0 5.9768 210.6708 340.7243 Tm (66)Tj 8.9663 0 0 8.9663 220.422 336.7558 Tm [(Simvastatin)-337.3(promo-)]TJ -17.9191 -1.2266 TD [(tion)-345.3(of)-344.7(ASC)-341.5(osteogenesis)]TJ 6.7246 0 0 5.9768 159.0803 329.7826 Tm (3)Tj 8.9663 0 0 8.9663 165.4866 325.7574 Tm [(may)-336.6(be)-345.8(possibly)-338.8(mediated)-348.3(by)-337.6(the)]TJ -11.7922 -1.2203 TD [(activation)-310.4(of)-306.7(Ras/Smad/ERK/BMP-2)-310.3(pathway.)]TJ 6.7246 0 0 5.9768 248.7117 318.7842 Tm (96)Tj 8.9663 0 0 8.9663 258.1794 314.8157 Tm (Moreover,)Tj -22.1302 -1.2203 TD [(sesamin)-430.2(can)-432.1(stimulate)-431.3(the)-427.4(osteogenic)-435.1(differentiation)-436(of)-426.9(hu-)]TJ 0 -1.2266 TD [(man)-259.7(ASCs)-254.3(with)-255.6(the)-256.7(upregulation)-256.2(of)-256.2(BMP-2,)-259(and)-252.5(further)-259.9(exert)]TJ 0 -1.2203 TD [(its)-334.1(effect)-341.9(via)-332.6(p38)-335.5(and)-328.4(ERK1/2)-334.5(MAPK)-339.5(signaling)-330.5(pathways.)]TJ 6.7246 0 0 5.9768 291.1747 285.9023 Tm (68)Tj /F5 1 Tf 8.9663 0 0 8.9663 59.7543 259.9936 Tm (Conclusion)Tj /F3 1 Tf 1.1128 -1.8273 TD [(BMPs)-301.6(and)-296.8(their)-305.2(signaling)-298.9(pathways)-302.5(play)-299.7(paramount)-303.8(roles)]TJ -1.1128 -1.2266 TD [(in)-316.7(the)-313.6(osteogenic)-314.9(differentiation)-322.2(of)-313.1(ASCs)]TJ /F4 1 Tf 18.2226 0 TD [(in)-316.1(vitro)]TJ /F3 1 Tf 3.3638 0 TD (and)Tj /F4 1 Tf 1.9917 0 TD [(in)-309.8(vivo)]TJ /F3 1 Tf 2.839 0 TD (.)Tj -26.4171 -1.2203 TD [(Various)-435.6(cytokines)-436.8(and)-429.5(gene)-431.2(technologies)-442(have)-427.2(been)-437.6(devel-)]TJ T* [(oped)-550.8(to)-547(promote)-549.3(the)-547.5(osteogenesis)-552.1(of)-547(ASCs)-551.5(through)-547.6(pro-)]TJ 0 -1.2267 TD [(moting)-303(BMPs-induced)-309.3(osteogenic)-308.6(signaling)-298.9(and)-303.1(suppressing)]TJ 0 -1.2203 TD [(adipogenesis.)-418.9(BMPs-ASCs-based)-419.6(bone)-408.8(tissue)-418.9(engineering)-418.5(is)]TJ T* [(very)-334.5(promising)-341(for)-332.7(the)-332.5(repair)-334.5(of)-338.4(large-size)-335.3(bone)-332.9(defects.)]TJ /F5 1 Tf 0 -2.447 TD (Acknowledgments)Tj /F3 1 Tf 1.1128 -1.8336 TD [(This)-409.6(study)-408.9(was)-413.4(supported)-410.6(by)-407.2(a)-410.5(grant)-406.8(from)-412.5(the)-408.4(National)]TJ -1.1128 -1.2203 TD [(Natural)-624.7(Science)-617.1(Foundation)-625.3(of)-616.6(China)-617(\(2011/81170937)-617.3(to)]TJ T* [(Prof.)-406.6(Dr.)-403.4(Y.)-399.2(Zhou\),)-407.2(and)-404.2(the)-402.1(Program)-405.4(for)-402.3(New)-399.9(Century)-408.7(Ex-)]TJ 0 -1.2267 TD [(cellent)-395.7(Talents)-396.8(in)-392.6(University)-398.8(from)-393.5(Ministry)-395.5(of)-395.3(Education)-395.7(of)]TJ 0 -1.2203 TD [(China)-338.8(\(NCET-11-0026\).)]TJ /F5 1 Tf 0 -2.447 TD [(Disclosure)-336.7(Statement)]TJ /F3 1 Tf 1.1128 -1.8336 TD [(The)-335.1(authors)-338.3(indicate)-335.1(no)-334.9(potential)-337.4(conicts)-335.5(of)-332(interest.)]TJ /F5 1 Tf 26.8913 74.5598 TD (References)Tj /F3 1 Tf 8.4682 0 0 8.4682 315.0424 705.94 Tm [(1.)-501.9(Sokolsky-Papkov,)-339.8(M.,)-330.4(Agashi,)-334.5(K.,)-335.2(Olaye,)-328(A.,)-336.8(Shakesheff,)-333.6(K.,)]TJ 1.2519 -1.2385 TD [(and)-325.7(Domb,)-325.9(A.J.)-329.4(Polymer)-328.6(carriers)-324.7(for)-325.3(drug)-329.7(delivery)-328.9(in)-325.3(tissue)]TJ 0 -1.2318 TD [(engineering.)-343.2(Adv)-333.5(Drug)-337.8(Del)-335.5(Rev)]TJ /F6 1 Tf 14.5545 0 TD (59,)Tj /F3 1 Tf 1.5867 0 TD [(187,)-332.1(2007.)]TJ -17.3931 -1.2385 TD [(2.)-501.9(Levi,)-278.6(B.,)-275.1(Hyun,)-277.2(J.S.,)-275.9(Nelson,)-285.3(E.R.,)-276.3(Li,)-270.9(S.,)-278.8(Montoro,)-282.7(D.T.,)-272.7(Wan,)]TJ 1.2519 -1.2318 TD [(D.C.,)-322.7(Jia,)-327.4(F.J.,)-324.2(Glotzbach,)-326.2(J.C.,)-322.2(James,)-322.3(A.W.,)-325.3(Lee,)-325.6(M.,)-323.7(Huang,)]TJ 0 -1.2385 TD [(M.,)-290.3(Quarto,)-296.8(N.,)-291.5(Gurtner,)-295.3(G.C.,)-292.6(Wu,)-292.6(J.C.,)-295.4(and)-285.6(Longaker)-10.3(,)-285.6(M.T.)]TJ 0 -1.2318 TD [(Nonintegrating)-307.6(knockdown)-299.1(and)-299(customized)-298.8(scaffold)-306(design)]TJ 0 -1.2385 TD [(enhances)-433.7(human)-422.9(adipose-derived)-428(stem)-429.6(cells)-426.7(in)-425.7(skeletal)-420.9(re-)]TJ 0 -1.2318 TD [(pair.)-334.2(Stem)-338.9(Cells)]TJ /F6 1 Tf 7.3576 0 TD (29,)Tj /F3 1 Tf 1.58 0 TD [(2018,)-334.2(2011.)]TJ -10.1895 -1.2385 TD [(3.)-501.9(Zhou,)-384(Y.,)-380.5(Ni,)-381(Y.,)-380.5(Liu,)-380.9(Y.,)-380.5(Zeng,)-377.5(B.,)-382.2(Xu,)-378.9(Y.,)-380.5(and)-379.3(Ge,)-383.2(W.)-376.8(The)]TJ 1.2519 -1.2318 TD [(role)-427.2(of)-429.1(simvastatin)-429.4(in)-425.7(the)-425.5(osteogenesis)-437.1(of)-422.4(injectable)-435.8(tissue-)]TJ 0 -1.2385 TD [(engineered)-390.6(bone)-390.9(based)-385.6(on)-386.6(human)-382.7(adipose-derived)-394.5(stromal)]TJ 0 -1.2318 TD [(cells)-339.7(and)-332.4(platelet-rich)-344.8(plasma.)-334.1(Biomaterials)]TJ /F6 1 Tf 19.3479 0 TD (31,)Tj /F3 1 Tf 1.5867 0 TD [(5325,)-327.5(2010.)]TJ -22.1865 -1.2385 TD [(4.)-501.9(Ge,)-309.5(W.,)-300.9(Shi,)-311.8(L.,)-301.9(Zhou,)-310.3(Y.,)-306.9(Liu,)-300.5(Y.,)-306.9(Ma,)-308.1(G.E.,)-302.8(Jiang,)-308(Y.,)-306.9(Xu,)-305.3(Y.,)]TJ 1.2519 -1.2318 TD [(Zhang,)-369.3(X.,)-367.1(and)-365.9(Feng,)-364.3(H.)-367.4(Inhibition)-372.7(of)-362.2(osteogenic)-376.3(differenti-)]TJ 0 -1.2385 TD [(ation)-569(of)-569.7(human)-570.1(adipose-derived)-575.3(stromal)-576.4(cells)-567.3(by)-569.7(retino-)]TJ 0 -1.2318 TD [(blastoma)-384.7(binding)-375.3(protein)-386.2(2)-377(repression)-382.3(of)-375.5(RUNX2-activated)]TJ 0 -1.2385 TD [(transcription.)-342.4(Stem)-338.9(Cells)]TJ /F6 1 Tf 11.2138 0 TD (29,)Tj /F3 1 Tf 1.58 0 TD [(1112,)-334.2(2011.)]TJ -14.0457 -1.2318 TD [(5.)-501.9(Sheyn,)-453.6(D.,)-443.9(Pelled,)-456(G.,)-447.2(Zilberman,)-445.5(Y.,)-447.4(Talasazan,)-451.7(F.,)-447.6(Frank,)]TJ 1.2519 -1.2385 TD [(J.M.,)-314.1(Gazit,)-305.9(D.,)-310(and)-312.4(Gazit,)-312.6(Z.)-309.2(Nonvirally)-311.1(engineered)-317(porcine)]TJ T* [(adipose)-540.2(tissue-derived)-545(stem)-536.7(cells:)-538.2(use)-531.4(in)-539.5(posterior)-540.1(spinal)]TJ 0 -1.2318 TD [(fusion.)-338.9(Stem)-338.9(Cells)]TJ /F6 1 Tf 8.3283 0 TD (26,)Tj /F3 1 Tf 1.58 0 TD [(1056,)-334.2(2008.)]TJ -11.1602 -1.2385 TD [(6.)-501.9(Prichard,)-471.8(H.L.,)-468.4(Reichert,)-475.9(W.,)-468.3(and)-466.3(Klitzman,)-474.4(B.)-464.9(IFATS)-474.7(col-)]TJ 1.2519 -1.2318 TD [(lection:)-476.6(adipose-derived)-474.8(stromal)-476(cells)-466.9(improve)-472.6(the)-472.4(foreign)]TJ 0 -1.2385 TD [(body)-335.2(response.)-343.1(Stem)-332.2(Cells)]TJ /F6 1 Tf 12.0439 0 TD (26,)Tj /F3 1 Tf 1.5867 0 TD [(2691,)-334.2(2008.)]TJ -14.8825 -1.2318 TD [(7.)-501.9(Bianco,)-316.4(P.,)-306.2(and)-312.4(Robey,)-311.7(P.G.)-309.4(Stem)-312.2(cells)-312.9(in)-311.9(tissue)-315.8(engineering.)]TJ 1.2519 -1.2385 TD (Nature)Tj /F6 1 Tf 3.4277 0 TD (414,)Tj /F3 1 Tf 2.0821 0 TD [(118,)-338.8(2001.)]TJ -6.7617 -1.2318 TD [(8.)-501.9(Zuk,)-496.4(P.A.,)-498(Zhu,)-503.2(M.,)-491.1(Mizuno,)-503.6(H.,)-492.3(Huang,)-500.3(J.,)-496.9(Futrell,)-503.3(J.W.,)]TJ 1.2519 -1.2385 TD [(Katz,)-488.3(A.J.,)-494.5(Benhaim,)-490.7(P.,)-487(Lorenz,)-489.4(H.P.,)-486.1(and)-493.1(Hedrick,)-492.4(M.H.)]TJ 0 -1.2318 TD [(Multilineage)-388.9(cells)-379.8(from)-380.9(human)-382.7(adipose)-379.6(tissue:)-387.2(implications)]TJ 0 -1.2385 TD [(for)-338.7(cell-based)-337.3(therapies.)-337.6(Tissue)-335.1(Eng)]TJ /F6 1 Tf 16.0273 0 TD (7,)Tj /F3 1 Tf 1.0779 0 TD [(211,)-338.8(2001.)]TJ -18.3571 -1.2318 TD [(9.)-501.9(Rada,)-653.3(T.,)-656.7(Reis,)-650.5(R.L.,)-657.9(and)-653.8(Gomes,)-653.3(M.E.)-657(Adipose)-658.6(tissue-)]TJ 1.2519 -1.2385 TD [(derived)-243.2(stem)-235.4(cells)-239.3(and)-238.7(their)-241.5(application)-240.6(in)-238.3(bone)-237(and)-238.7(cartilage)]TJ 0 -1.2318 TD [(tissue)-335.9(engineering.)-343.2(Tissue)-335.1(Eng)-334(Part)-335.6(B)-340(Rev)]TJ /F6 1 Tf 18.8793 0 TD (15,)Tj /F3 1 Tf 1.5867 0 TD [(113,)-332.1(2009.)]TJ -22.2133 -1.2385 TD [(10.)-497.3(Yoshimura,)-243.4(K.,)-241.5(Shigeura,)-237.3(T.,)-241.7(Matsumoto,)-239.6(D.,)-236.3(Sato,)-243.7(T.,)-235(Takaki,)]TJ 1.7473 -1.2318 TD [(Y.,)-253.3(Aiba-Kojima,)-259.9(E.,)-255(Sato,)-257(K.,)-254.9(Inoue,)-255.7(K.,)-254.9(Nagase,)-261.2(T.,)-248.4(Koshima,)]TJ 0 -1.2385 TD [(I.,)-445.7(and)-439.6(Gonda,)-448.5(K.)-437.9(Characterization)-451.8(of)-442.5(freshly)-445.1(isolated)-449.9(and)]TJ 0 -1.2318 TD [(cultured)-420.9(cells)-420(derived)-417.3(from)-421(the)-418.8(fatty)-418.9(and)-412.8(uid)-421.8(portions)-419.5(of)]TJ 0 -1.2385 TD [(liposuction)-343.9(aspirates.)-334.4(J)-334.1(Cell)-337.4(Physiol)]TJ /F6 1 Tf 15.9738 0 TD (208,)Tj /F3 1 Tf 2.0821 0 TD [(64,)-336.7(2006.)]TJ -19.8032 -1.2318 TD [(11.)-497.3(Dominici,)-264.5(M.,)-263.5(Le)-267(Blanc,)-261.5(K.,)-261.6(Mueller,)-266.9(I.,)-264.9(Slaper-Cortenbach,)-273.7(I.,)]TJ 1.7473 -1.2385 TD [(Marini,)-375.7(F.,)-374(Krause,)-378.9(D.,)-376.9(Deans,)-378.1(R.,)-373.8(Keating,)-380.7(A.,)-376.9(Prockop,)-372.6(D.,)]TJ 0 -1.2318 TD [(and)-453(Horwitz,)-451.1(E.)-444.8(Minimal)-457.3(criteria)-449.1(for)-452.5(dening)-450.9(multipotent)]TJ 0 -1.2385 TD [(mesenchymal)-558.3(stromal)-563(cells.)-551.6(The)-558.6(International)-563.8(Society)-561.1(for)]TJ 0 -1.2318 TD [(Cellular)-540(Therapy)-537(position)-543.5(statement.)-539.6(Cytotherapy)]TJ /F6 1 Tf 23.4518 0 TD (8,)Tj /F3 1 Tf 1.2854 0 TD (315,)Tj -24.7372 -1.2385 TD (2006.)Tj -1.7473 -1.2318 TD [(12.)-497.3(Fraser,)-424.9(J.K.,)-426(Wulur,)-432.9(I.,)-418.9(Alfonso,)-431(Z.,)-427.4(and)-426.2(Hedrick,)-425.4(M.H.)-425.6(Fat)]TJ 1.7473 -1.2385 TD [(tissue:)-534.5(an)-534.8(underappreciated)-542(source)-534.2(of)-536.2(stem)-530(cells)-533.8(for)-539.5(bio-)]TJ 0 -1.2318 TD [(technology.)-341.5(Trends)-338.6(Biotechnol)]TJ /F6 1 Tf 13.7712 0 TD (24,)Tj /F3 1 Tf 1.5867 0 TD [(150,)-332.1(2006.)]TJ -17.1052 -1.2385 TD [(13.)-497.3(Chen,)-255.2(H.T.,)-260.9(Lee,)-251.9(M.J.,)-253.8(Chen,)-261.9(C.H.,)-250.6(Chuang,)-263.2(S.C.,)-251.4(Chang,)-260.4(L.F.,)]TJ 1.7473 -1.2318 TD [(Ho,)-475.8(M.L.,)-480.7(Hung,)-478.1(S.H.,)-472.1(Fu,)-479.5(Y.C.,)-473.6(Wang,)-480.1(Y.H.,)-473.4(Wang,)-473.4(H.I.,)]TJ 0 -1.2385 TD [(Wang,)-339.5(G.J.,)-337.1(Kang,)-333.6(L.,)-335.4(and)-339.1(Chang,)-334(J.K.)-334.5(Proliferation)-345.8(and)-332.4(dif-)]TJ 0 -1.2318 TD [(ferentiation)-368.7(potential)-357.8(of)-362.1(human)-355.9(adipose-derived)-367.7(mesenchy-)]TJ 0 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[(aker,)-335.5(M.T.)-329(Adipose-derived)-345.4(adult)-331.1(stromal)-335.4(cells)-333(heal)-334.7(critical-)]TJ 0 -1.2318 TD [(size)-336.7(mouse)-333.9(calvarial)-336.8(defects.)-334.9(Nat)-337.7(Biotechnol)]TJ /F6 1 Tf 19.8567 0 TD (22,)Tj /F3 1 Tf 1.58 0 TD [(560,)-338.8(2004.)]TJ -23.1907 -1.2385 TD [(51.)-504(Dragoo,)-243.6(J.L.,)-245.4(Choi,)-245.6(J.Y.,)-243.7(Lieberman,)-246.9(J.R.,)-243.7(Huang,)-245.9(J.,)-242.5(Zuk,)-242(P.A.,)]TJ 1.754 -1.2318 TD [(Zhang,)-402.8(J.,)-396.5(Hedrick,)-405.3(M.H.,)-396.5(and)-399.4(Benhaim,)-403.7(P.)-402.2(Bone)-399.2(induction)]TJ 0 -1.2385 TD [(by)-355.5(BMP-2)-357.9(transduced)-367.8(stem)-355.9(cells)-359.8(derived)-363.7(from)-354.1(human)-362.6(fat.)-360(J)]TJ 0 -1.2318 TD [(Orthop)-334.2(Res)]TJ /F6 1 Tf 5.4161 0 TD (21,)Tj /F3 1 Tf 1.5867 0 TD [(622,)-332.1(2003.)]TJ -8.7568 -1.2385 TD [(52.)-504(Dragoo,)-317.2(J.L.,)-312.4(Samimi,)-314.4(B.,)-315.3(Zhu,)-315.7(M.,)-317(Hame,)-318.6(S.L.,)-315.2(Thomas,)-312.4(B.J.,)]TJ 1.754 -1.2318 TD [(Lieberman,)-534.8(J.R.,)-531.5(Hedrick,)-539.2(M.H.,)-530.4(and)-533.3(Benhaim,)-537.6(P.)-529.4(Tissue-)]TJ 0 -1.2385 TD [(engineered)-317(cartilage)-311(and)-312.4(bone)-310.6(using)-310.8(stem)-309(cells)-312.9(from)-313.9(human)]TJ 0 -1.2318 TD [(infrapatellar)-340.8(fat)-335.6(pads.)-335(J)-334.1(Bone)-332.3(Joint)-338.7(Surg)-340(Br)]TJ /F6 1 Tf 19.1672 0 TD (85,)Tj /F3 1 Tf 1.5867 0 TD [(740,)-332.1(2003.)]TJ -22.5079 -1.2385 TD [(53.)-504(Dragoo,)-303.8(J.L.,)-312.4(Lieberman,)-307.1(J.R.,)-303.9(Lee,)-312.2(R.S.,)-306.8(Deugarte,)-304.7(D.A.,)-307.6(Lee,)]TJ 1.754 -1.2318 TD [(Y.,)-634.9(Zuk,)-637(P.A.,)-631.9(Hedrick,)-639.7(M.H.,)-637.6(and)-633.7(Benhaim,)-638(P.)-636.6(Tissue-)]TJ 0 -1.2385 TD [(engineered)-310.3(bone)-310.6(from)-313.9(BMP-2-transduced)-316.7(stem)-309(cells)-312.9(derived)]TJ 0 -1.2318 TD [(from)-334(human)-335.8(fat.)-333.3(Plast)-338.3(Reconstr)-343.8(Surg)]TJ /F6 1 Tf 16.6165 0 TD (115,)Tj /F3 1 Tf 2.0821 0 TD [(1665,)-334.2(2005.)]TJ -20.4526 -1.2385 TD [(54.)-504(Peterson,)-396.9(B.,)-388.9(Zhang,)-396.1(J.,)-389.8(Iglesias,)-392.7(R.,)-393.9(Kabo,)-391.4(M.,)-390.7(Hedrick,)-392(M.,)]TJ 1.754 -1.2318 TD [(Benhaim,)-350.1(P.,)-346.4(and)-345.8(Lieberman,)-347.3(J.R.)-346.4(Healing)-353.4(of)-342.1(critically)-353.6(sized)]TJ 0 -1.2385 TD [(femoral)-537.8(defects,)-542.4(using)-538.4(genetically)-541.4(modied)-535.3(mesenchymal)]TJ 0 -1.2318 TD [(stem)-402.8(cells)-399.9(from)-407.6(human)-402.8(adipose)-406.4(tissue.)-400.6(Tissue)-408.7(Eng)]TJ /F6 1 Tf 23.0836 0 TD (11,)Tj /F3 1 Tf 1.6469 0 TD (120,)Tj -24.7305 -1.2385 TD (2005.)Tj -1.754 -1.2318 TD [(55.)-504(Lin,)-388.5(Y.,)-387.2(Tang)-8.1(,)-386(W.,)-387.9(Wu,)-393.1(L.,)-388.9(Jing,)-386.3(W.,)-394.6(Li,)-384.7(X.,)-393.9(Wu,)-386.4(Y.,)-393.9(Liu,)-387.6(L.,)]TJ 1.754 -1.2385 TD [(Long,)-540.5(J.,)-543.7(and)-540(Tian,)-544.6(W.)-537.5(Bone)-546.5(regeneration)-551.5(by)-536.2(BMP-2)-545.4(en-)]TJ 0 -1.2318 TD [(hanced)-582.7(adipose)-580.4(stem)-583.5(cells)-580.7(loading)-578.8(on)-580.8(alginate)-581.1(gel.)-577.9(His-)]TJ 0 -1.2385 TD [(tochem)-333.2(Cell)-337.4(Biol)]TJ /F6 1 Tf 7.6655 0 TD (129,)Tj /F3 1 Tf 2.0821 0 TD [(203,)-338.8(2008.)]TJ -11.5016 -1.2318 TD [(56.)-504(Hsu,)-503.2(W.K.,)-497.8(Wang,)-500.2(J.C.,)-502.9(Liu,)-501.4(N.Q.,)-499(Krenek,)-503.5(L.,)-496.1(Zuk,)-503.1(P.A.,)]TJ 1.754 -1.2385 TD [(Hedrick,)-345.1(M.H.,)-349.7(Benhaim,)-343.4(P.,)-346.4(and)-345.8(Lieberman,)-347.3(J.R.)-346.4(Stem)-345.6(cells)]TJ 0 -1.2318 TD [(from)-380.9(human)-376(fat)-375.7(as)-382.8(cellular)-375.8(delivery)-382.4(vehicles)-377.9(in)-378.8(an)-380.8(athymic)]TJ 0 -1.2385 TD [(rat)-326.1(posterolateral)-337(spine)-327.8(fusion)-327.8(model.)-328.4(J)-327.4(Bone)-325.6(Joint)-332(Surg)-326.7(Am)]TJ /F6 1 Tf 0 -1.2318 TD (90,)Tj /F3 1 Tf 1.58 0 TD [(1043,)-334.2(2008.)]TJ -3.334 -1.2385 TD [(57.)-504(Lee,)-298.8(S.J.,)-302.6(Kang,)-300.2(S.W.,)-300.8(Do,)-300.2(H.J.,)-295.2(Han,)-306.3(I.,)-298.4(Shin,)-302.2(D.A.,)-300.9(Kim,)-299.5(J.H.,)]TJ 1.754 -1.2318 TD [(and)-439.6(Lee,)-439.4(S.H.)-440.9(Enhancement)-451.6(of)-435.8(bone)-444.5(regeneration)-444.4(by)-442.5(gene)]TJ 0 -1.2385 TD [(delivery)-543.1(of)-542.9(BMP2/Runx2)-548.9(bicistronic)-549.6(vector)-545.4(into)-546.8(adipose-)]TJ T* [(derived)-336.9(stromal)-335.4(cells.)-337.4(Biomaterials)]TJ /F6 1 Tf 15.6256 0 TD (31,)Tj /F3 1 Tf 1.5867 0 TD [(5652,)-334.2(2010.)]TJ -18.9663 -1.2318 TD [(58.)-504(Lin,)-415.3(C.Y.,)-406.6(Lin,)-415.3(K.J.,)-412.6(Kao,)-414.5(C.Y.,)-413.3(Chen,)-415.9(M.C.,)-410.1(Lo,)-412.6(W.H.,)-413.9(Yen,)]TJ 1.754 -1.2385 TD [(T.C.,)-281.2(Chang,)-280.4(Y.H.,)-279.3(and)-278.9(Hu,)-283.2(Y.C.)-281.7(The)-277.4(role)-286.6(of)-281.8(adipose-derived)]TJ 0 -1.2318 TD [(stem)-442.9(cells)-446.8(engineered)-450.9(with)-442.3(the)-445.6(persistently)-447.2(expressing)-453.8(hy-)]TJ 0 -1.2385 TD [(brid)-534.6(baculovirus)-536.2(in)-532.8(the)-532.6(healing)-536.5(of)-529.5(massive)-539.1(bone)-531.5(defects.)]TJ 0 -1.2318 TD (Biomaterials)Tj /F6 1 Tf 5.791 0 TD (32,)Tj /F3 1 Tf 1.5867 0 TD [(6505,)-334.2(2011.)]TJ -9.1317 -1.2385 TD [(59.)-504(Yang,)-305.3(M.,)-303.6(Ma,)-301.4(Q.J.,)-302.7(Dang,)-301.7(G.T.,)-309.5(Ma,)-301.4(K.,)-301.7(Chen,)-308.8(P.,)-299.5(and)-305.7(Zhou,)]TJ 1.754 -1.2318 TD (C.Y.)Tj /F4 1 Tf 2.2227 0 TD [(In)-357.8(vitro)]TJ /F3 1 Tf 3.4947 0 TD (and)Tj /F4 1 Tf 2.0285 0 TD [(in)-356.3(vivo)]TJ /F3 1 Tf 3.2403 0 TD [(induction)-356.2(of)-348.8(bone)-357.5(formation)-354.1(based)]TJ -10.9861 -1.2385 TD (on)Tj /F4 1 Tf 1.359 0 TD [(ex)-246.4(vivo)]TJ /F3 1 Tf 3.0796 0 TD [(gene)-249.7(therapy)-250(using)-243.8(rat)-245.8(adipose-derived)-253.9(adult)-250.7(stem)]TJ -4.4386 -1.2318 TD [(cells)-333(expressing)-340(BMP-7.)-335.6(Cytotherapy)]TJ /F6 1 Tf 16.6165 0 TD (7,)Tj /F3 1 Tf 1.0846 0 TD [(273,)-332.1(2005.)]TJ -19.455 -1.2385 TD [(60.)-504(Kang,)-367.1(Y.,)-367.1(Liao,)-368(W.M.,)-365.8(Yuan,)-371.4(Z.H.,)-366.3(Sheng,)-366.5(P.Y.,)-367.7(Zhang,)-369.3(L.J.,)]TJ 1.754 -1.2318 TD [(Yuan,)-264.3(X.W.,)-261.9(and)-265.5(Lei,)-258.2(L.)]TJ /F4 1 Tf 10.4439 0 TD [(In)-264.1(vitro)]TJ /F3 1 Tf 3.3139 0 TD (and)Tj /F4 1 Tf 1.9415 0 TD [(in)-262.6(vivo)]TJ /F3 1 Tf 3.0528 0 TD [(induction)-269.1(of)-261.7(bone)]TJ 8.4682 0 0 8.4682 325.644 725.7825 Tm [(formation)-273.7(based)-271.8(on)-266.1(adeno-associated)-274(virus-mediated)-274.9(BMP-7)]TJ 0 -1.2318 TD [(gene)-477.3(therapy)-477.6(using)-478.2(human)-476.4(adipose-derived)-481.5(mesenchymal)]TJ 0 -1.2385 TD [(stem)-335.8(cells.)-337.4(Acta)-334.3(Pharmacol)-337.1(Sin)]TJ /F6 1 Tf 13.9854 0 TD (28,)Tj /F3 1 Tf 1.58 0 TD [(839,)-332.1(2007.)]TJ -17.3127 -1.2318 TD [(61.)-497.3(Levi,)-546.4(B.,)-549.6(Nelson,)-546.4(E.R.,)-550.8(Hyun,)-545(J.S.,)-550.3(Glotzbach,)-547.1(J.P.,)-551(Li,)-545.4(S.,)]TJ 1.7473 -1.2385 TD [(Nauta,)-347(A.,)-343.4(Montoro,)-349.7(D.T.,)-346.4(Lee,)-339(M.,)-343.8(Commons,)-350.2(G.C.,)-346.1(Hu,)-343.4(S.,)]TJ 0 -1.2318 TD [(Wu,)-239.1(J.C.,)-241.8(Gurtner,)-248.4(G.C.,)-239(and)-245.4(Longaker,)-242.3(M.T.)-241.9(Enhancement)-244.1(of)]TJ 0 -1.2385 TD [(human)-463(adipose-derived)-474.8(stromal)-462.6(cell)-461.1(angiogenesis)-466.6(through)]TJ 0 -1.2318 TD [(knockdown)-406.3(of)-395.6(a)-397.1(BMP-2)-404.8(inhibitor.)-401.7(Plast)-398.6(Reconstr)-404(Surg)]TJ /F6 1 Tf 24.7372 0 TD (129,)Tj /F3 1 Tf -24.7372 -1.2385 TD [(53,)-336.7(2012.)]TJ -1.7473 -1.2318 TD [(62.)-497.3(Ramasubramanian,)-494.3(A.,)-484(Shiigi,)-483.2(S.,)-486.3(Lee,)-486.2(G.K.,)-483.4(and)-486.4(Yang,)-479.4(F.)]TJ 1.7473 -1.2385 TD [(Non-viral)-494(delivery)-489.5(of)-482.7(inductive)-492.7(and)-486.4(suppressive)-492.9(genes)-489.8(to)]TJ 0 -1.2318 TD [(adipose-derived)-622.1(stem)-610.3(cells)-614.2(for)-613.2(osteogenic)-617.3(differentiation.)]TJ 0 -1.2385 TD [(Pharm)-335.4(Res)]TJ /F6 1 Tf 5.1483 0 TD (28,)Tj /F3 1 Tf 1.58 0 TD [(1328,)-334.2(2011.)]TJ -8.4756 -1.2318 TD [(63.)-497.3(Mundy,)-241.1(G.,)-239.6(Garrett,)-243.3(R.,)-239.9(Harris,)-241.5(S.,)-238.6(Chan,)-243.3(J.,)-242.5(Chen,)-241.8(D.,)-236.3(Rossini,)]TJ 1.7473 -1.2385 TD [(G.,)-474(Boyce,)-468.6(B.,)-476(Zhao,)-470.3(M.,)-471(and)-473(Gutierrez,)-475.2(G.)-469.6(Stimulation)-475.4(of)]TJ 0 -1.2318 TD [(bone)-451.2(formation)]TJ /F4 1 Tf 7.3777 0 TD [(in)-450(vitro)]TJ /F3 1 Tf 3.642 0 TD [(and)-452.9(in)-445.8(rodents)-454.5(by)-449.2(statins.)-455.9(Science)]TJ /F6 1 Tf -11.0196 -1.2385 TD (286,)Tj /F3 1 Tf 2.0821 0 TD [(1946,)-334.2(1999.)]TJ -3.8294 -1.2318 TD [(64.)-497.3(Maeda,)-429.8(T.,)-429.1(Matsunuma,)-433.9(A.,)-423.8(Kawane,)-437(T.,)-422.4(and)-432.9(Horiuchi,)-430.7(N.)]TJ 1.7473 -1.2385 TD [(Simvastatin)-405.7(promotes)-398.1(osteoblast)-401(differentiatio)-14.9(n)-392(and)-399.4(miner-)]TJ T* [(alization)-285.8(in)-285.1(MC3T3-E1)-285.9(cells.)-283.8(Biochem)-285.7(Biophys)-283.8(Res)-284.4(Commun)]TJ /F6 1 Tf 0 -1.2318 TD (280,)Tj /F3 1 Tf 2.0821 0 TD [(874,)-338.8(2001.)]TJ -3.8294 -1.2385 TD [(65.)-497.3(Levi,)-405.8(B.,)-402.3(James,)-402.6(A.W.,)-405.6(Xu,)-405.7(Y.,)-400.6(Commons,)-403.8(G.W.,)-402.2(and)-406.1(Long-)]TJ 1.7473 -1.2318 TD [(aker,)-248.4(M.T.)-255.3(Divergent)-252.8(modulation)-252.5(of)-248.3(adipose-derived)-260.6(stromal)]TJ 0 -1.2385 TD [(cell)-427.6(differentiation)-440.4(by)-422.4(TGF-beta1)-434.4(based)-425.8(on)-426.8(species)-429.1(of)-429.1(deri-)]TJ 0 -1.2318 TD [(vation.)-339.5(Plast)-338.3(Reconstr)-337.1(Surg)]TJ /F6 1 Tf 12.3452 0 TD (126,)Tj /F3 1 Tf 2.0821 0 TD [(412,)-338.8(2010.)]TJ -16.1746 -1.2385 TD [(66.)-497.3(James,)-295.5(A.W.,)-291.8(Leucht,)-288.9(P.,)-292.8(Levi,)-292(B.,)-288.5(Carre,)-296.6(A.L.,)-286.1(Xu,)-291.9(Y.,)-293.5(Helms,)]TJ 1.7473 -1.2318 TD [(J.A.,)-862.7(and)-854.6(Longaker,)-858.2(M.T.)-857.8(Sonic)-862.5(Hedgehog)-857.2(inuences)]TJ 0 -1.2385 TD [(the)-372(balance)-365.5(of)-368.8(osteogenesis)-370.2(and)-365.9(adipogenesis)-373.5(in)-365.5(mouse)-367.4(ad-)]TJ 0 -1.2318 TD [(ipose-derived)-253.3(stromal)-248.3(cells.)-243.7(Tissue)-248.1(Eng)-247(Part)-241.9(A)]TJ /F6 1 Tf 20.2517 0 TD (16,)Tj /F3 1 Tf 1.4929 0 TD [(2605,)-240.5(2010.)]TJ -23.492 -1.2385 TD [(67.)-497.3(Kim,)-286.1(Y.J.,)-283.8(Kim,)-286.1(J.T.,)-285.6(Bae,)-286.9(Y.C.,)-286.1(Suh,)-287.7(K.T.,)-284.6(and)-285.6(Jung,)-288.5(J.S.)-284.8(ICAT)]TJ 1.7473 -1.2318 TD [(participates)-284.6(in)-271.7(proliferation)-285.5(and)-278.9(osteogenic)-275.8(differentiatio)-14.9(n)-271.5(o)0(f)]TJ 0 -1.2385 TD [(human)-382.7(adipose)-379.6(tissue-derived)-384.3(mesenchymal)-384.2(stem)-382.7(cell.)-378.5(Life)]TJ 0 -1.2318 TD (Sci)Tj /F6 1 Tf 1.5733 0 TD (83,)Tj /F3 1 Tf 1.5867 0 TD [(851,)-332.1(2008.)]TJ -4.9073 -1.2385 TD [(68.)-497.3(Wanachewin,)-388.5(O.,)-379.3(Boonmaleerat,)-381.1(K.,)-382.1(Pothacharoen,)-388.3(P.,)-379.9(Reu-)]TJ 1.7473 -1.2318 TD [(trakul,)-417.5(V.,)-415.5(and)-419.5(Kongtawelert,)-422.6(P.)-415.6(Sesamin)-418.4(stimulates)-426.6(osteo-)]TJ 0 -1.2385 TD [(blast)-794.4(differentiation)-795.2(through)-794.5(p38)-790.4(and)-787.7(ERK1/2)-793.1(MAPK)]TJ 0 -1.2318 TD [(signaling)-659.3(pathways.)-650.5(BMC)-656.5(Complement)-657.1(Altern)-656.5(Med)]TJ /F6 1 Tf 25.2393 0 TD (12,)Tj /F3 1 Tf -25.2393 -1.2385 TD [(71,)-336.7(2012.)]TJ -1.7473 -1.2318 TD [(69.)-497.3(Yang,)-318.7(X.,)-320.3(Gong,)-324.3(P.,)-312.9(Lin,)-321.5(Y.,)-320.2(Zhang,)-322.4(L.,)-315.3(Li,)-317.8(X.,)-320.3(Yuan,)-317.9(Q.,)-319.1(Tan,)]TJ 1.7473 -1.2385 TD [(Z.,)-420.7(Wang,)-419.9(Y.,)-420.7(Man,)-418.9(Y.,)-414(and)-419.5(Tang,)-420.9(H.)-420.9(Cyclic)-417.1(tensile)-425.6(stretch)]TJ 0 -1.2318 TD [(modulates)-769.2(osteogenic)-771.2(differentiation)-775.2(of)-763.8(adipose-derived)]TJ 0 -1.2385 TD [(stem)-483.1(cells)-487(via)-478(the)-485.8(BMP-2)-478.4(pathway.)-484(Arch)-487.2(Med)-481.5(Sci)]TJ /F6 1 Tf 23.5054 0 TD (6,)Tj /F3 1 Tf 1.2318 0 TD (152,)Tj -24.7372 -1.2318 TD (2010.)Tj -1.7473 -1.2385 TD [(70.)-497.3(Kang,)-246.6(K.S.,)-241.4(Hong,)-242.2(J.M.,)-240.5(Seol,)-249.7(Y.J.,)-237(Rhie,)-246.8(J.W.,)-244.4(Jeong,)-240.7(Y.H.,)-245.8(and)]TJ 1.7473 -1.2318 TD [(Cho,)-513.2(D.W.)-508.3(Short-term)-516.6(evaluation)-514.9(of)-509.4(electromagnetic)-522.3(eld)]TJ 0 -1.2385 TD [(pretreatment)-318.6(of)-308.6(adipose-derived)-314.2(stem)-309(cells)-306.2(to)-308.6(improve)-311.9(bone)]TJ 0 -1.2318 TD [(healing.)-259.7(J)-253.7(Tissue)-254.8(Eng)-253.7(Regen)-253.2(Med)-253.8(2012)-256.1([Epub)-254.9(ahead)-254.9(of)-255(print];)]TJ 0 -1.2385 TD [(DOI:)-336.4(10.1002/term.1664.)]TJ -1.7473 -1.2318 TD [(71.)-497.3(Rosen,)-394.2(E.D.,)-386.6(and)-386(MacDougald,)-388.4(O.A.)-385.9(Adipocyte)-392.9(differentia-)]TJ 1.7473 -1.2385 TD [(tion)-305.8(from)-307.2(the)-305(inside)-310.3(out.)-302.4(Nat)-304.2(Rev)-305.7(Mol)-303(Cell)-310.6(Biol)]TJ /F6 1 Tf 21.1287 0 TD (7,)Tj /F3 1 Tf 1.0511 0 TD [(885,)-305.3(2006.)]TJ -23.9272 -1.2318 TD [(72.)-497.3(Jeon,)-243.7(M.J.,)-240.5(Kim,)-239.3(J.A.,)-240.1(Kwon,)-246(S.H.,)-237.8(Kim,)-239.3(S.W.,)-240.6(Park,)-243.9(K.S.,)-234.7(Park,)]TJ 1.7473 -1.2385 TD [(S.W.,)-501.7(Kim,)-500.4(S.Y.,)-507.6(and)-499.8(Shin,)-503(C.S.)-501.4(Activation)-506.8(of)-502.7(peroxisome)]TJ T* [(proliferator-activated)-539.5(receptor-gamma)-536.3(inhibits)-532.3(the)-525.9(Runx2-)]TJ 0 -1.2318 TD [(mediated)-457.3(transcription)-458.5(of)-455.9(osteocalcin)-452.7(in)-452.5(osteoblasts.)-458.1(J)-454.6(Biol)]TJ 0 -1.2385 TD (Chem)Tj /F6 1 Tf 2.9591 0 TD (278,)Tj /F3 1 Tf 2.0821 0 TD [(23270,)-336.3(2003.)]TJ -6.7885 -1.2318 TD [(73.)-497.3(Akune,)-343.3(T.,)-342.1(Ohba,)-337.6(S.,)-339(Kamekura,)-340.8(S.,)-345.7(Yamaguchi,)-337.4(M.,)-343.8(Chung,)]TJ 1.7473 -1.2385 TD [(U.I.,)-396.5(Kubota,)-393.6(N.,)-398.6(Terauchi,)-395.5(Y.,)-393.9(Harada,)-395.6(Y.,)-393.9(Azuma,)-388.3(Y.,)-393.9(Na-)]TJ 0 -1.2318 TD [(kamura,)-261.5(K.,)-261.6(Kadowaki,)-255.5(T.,)-261.7(and)-258.8(Kawaguchi,)-260.4(H.)-260.3(PPARgamma)]TJ 0 -1.2385 TD [(insufciency)-403.3(enhances)-406.9(osteogenesis)-403.7(through)-399.6(osteoblast)-401(for-)]TJ 0 -1.2318 TD [(mation)-463.9(from)-467.9(bone)-464.6(marrow)-464.4(progenitors.)-471.6(J)-461.3(Clin)-467.7(Invest)]TJ /F6 1 Tf 24.7372 0 TD (113,)Tj /F3 1 Tf -24.7372 -1.2385 TD [(846,)-332.1(2004.)]TJ -1.7473 -1.2318 TD [(74.)-497.3(Lin,)-261.3(Y.F.,)-254.7(Jing,)-259.1(W.,)-260.7(Wu,)-252.5(L.,)-261.7(Li,)-257.5(X.Y.,)-254.5(Wu,)-259.2(Y.,)-260(Liu,)-253.7(L.,)-261.7(Tang,)-253.5(W.,)]TJ 1.7473 -1.2385 TD [(Long,)-399.9(J.,)-396.5(Tian,)-404(W.D.,)-398.9(and)-392.7(Mo,)-401(X.M.)-400.9(Identication)-402.6(of)-402.3(osteo-)]TJ 0 -1.2318 TD 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