老年基礎(chǔ)醫(yī)學(xué)進(jìn)展-骨代謝基礎(chǔ)理論課件

老年基礎(chǔ)醫(yī)學(xué)進(jìn)展-骨代謝基礎(chǔ)理論課件1老年基礎(chǔ)醫(yī)學(xué)進(jìn)展-骨代謝基礎(chǔ)理論課件2老年基礎(chǔ)醫(yī)學(xué)進(jìn)展-骨代謝基礎(chǔ)理論課件3復(fù)旦大學(xué)附屬華東醫(yī)院老年醫(yī)學(xué)研究所程群骨代謝基礎(chǔ)理論復(fù)旦大學(xué)附屬華東醫(yī)院骨代謝基礎(chǔ)理論4內(nèi)容

骨轉(zhuǎn)換正常骨骼生理骨質(zhì)疏松骨丟失機(jī)制骨組織中細(xì)胞的起源及發(fā)育骨轉(zhuǎn)換的關(guān)鍵通路及其與骨質(zhì)疏松的關(guān)系抗骨質(zhì)疏松藥物分析內(nèi)容骨轉(zhuǎn)換5正常骨骼生理骨組織組成特點(diǎn)骨組織中不同細(xì)胞功能骨轉(zhuǎn)換骨轉(zhuǎn)換的調(diào)控（鈣磷調(diào)節(jié)激素、局部細(xì)胞因子）信號(hào)通路蛋白與骨代謝正常骨骼生理骨組織組成特點(diǎn)6骨骼的功能結(jié)構(gòu)支持保護(hù)運(yùn)動(dòng)調(diào)節(jié)礦鹽代謝鈣

磷骨骼的功能結(jié)構(gòu)7骨組織:結(jié)締組織細(xì)胞外基質(zhì)25%水25%蛋白質(zhì)或有機(jī)物

95%膠原纖維 5%硫酸軟骨素50%礦鹽結(jié)晶

羥磷灰石結(jié)晶 (鈣磷)

其他金屬元素:鎂、鋅、鍶、鉛、金等

骨組織:結(jié)締組織細(xì)胞外基質(zhì)8Bone骨組成Bonecomposition70%礦物質(zhì)

(Ca2+

和

PO4-

組成羥磷灰石)22%蛋白質(zhì)

(95%I型膠原

+5%蛋白聚糖及其他)8%水兩組主要骨骼類型Twomajortypesofbone密質(zhì)骨(骨皮質(zhì),i.e.,長(zhǎng)骨)：機(jī)械運(yùn)動(dòng)和保護(hù)功能松質(zhì)骨(骨松質(zhì),i.e.,椎骨)：鈣磷代謝調(diào)節(jié)功能四種細(xì)胞Fourtypesofcells成骨細(xì)胞

破骨細(xì)胞骨細(xì)胞骨襯里細(xì)胞Bone骨組成Bonecomposition9兩種骨結(jié)構(gòu)密質(zhì)骨（CompactBone）松質(zhì)骨（SpongyBone）兩種骨結(jié)構(gòu)密質(zhì)骨10遠(yuǎn)端骨骺近端骨骺骨干黃骨髓骨骺線骨膜密質(zhì)骨松質(zhì)骨骨內(nèi)膜透明軟骨Sharpey’s纖維長(zhǎng)骨的解剖遠(yuǎn)端骨骺近端骨骺骨干黃骨髓骨骺線骨膜密質(zhì)骨松質(zhì)骨骨內(nèi)膜透明軟11松質(zhì)骨中央小管密質(zhì)骨Haversian

系統(tǒng)骨膜骨細(xì)胞松質(zhì)骨中央小管密質(zhì)骨Haversian系統(tǒng)骨膜骨細(xì)胞12密質(zhì)骨密質(zhì)骨排列單位稱為哈弗氏小管哈弗氏小管由血管、淋巴管和神經(jīng)組成小管周圍為同心圓分布的骨細(xì)胞和礦化骨基質(zhì)哈弗氏小管與骨骼的應(yīng)力方向一致當(dāng)骨骼應(yīng)力方向改變后這些哈弗氏小管也隨之變化密質(zhì)骨密質(zhì)骨排列單位稱為哈弗氏小管13骨陷窩中的骨細(xì)胞中央管基質(zhì)中的微管密質(zhì)骨中的haversian系統(tǒng)骨陷窩中的骨細(xì)胞中央管基質(zhì)中的微管密質(zhì)骨中的haversia14松質(zhì)骨或稱小梁骨松質(zhì)骨或稱小梁骨15松質(zhì)骨（小梁骨）骨髓中沿著應(yīng)力分布的細(xì)的小梁狀結(jié)構(gòu)小梁周圍充滿紅色骨髓，完成造血功能在長(zhǎng)骨的兩端、扁平骨的內(nèi)部如股骨、頭顱骨、肋骨等松質(zhì)骨不包含骨單位，其表面積大，骨轉(zhuǎn)換快NotrueOsteons.松質(zhì)骨（小梁骨）骨髓中沿著應(yīng)力分布的細(xì)的小梁狀結(jié)構(gòu)Notr16成骨細(xì)胞骨細(xì)胞破骨細(xì)胞吞噬骨骼生成新骨成熟靜態(tài)的成骨細(xì)胞在骨轉(zhuǎn)換中起作用的細(xì)胞成骨細(xì)胞骨細(xì)胞破骨細(xì)胞吞噬骨骼生成新骨成熟靜態(tài)的成骨細(xì)胞在骨17骨組織中的細(xì)胞成骨細(xì)胞破骨細(xì)胞骨細(xì)胞骨襯里細(xì)胞

形成骨基質(zhì)

分泌I型膠原

調(diào)節(jié)礦化

位于骨基質(zhì)表面

基質(zhì)極化分布于周圍

分化終末期為骨細(xì)胞

溶解骨組織

大的多核細(xì)胞邊緣呈皺褶狀伴有明顯的吸收帶

細(xì)胞核排列于骨吸收表面的另一側(cè)

豐富的高爾基體、線粒體和溶酶體囊泡

來源于成骨細(xì)胞

維持骨基質(zhì)

位于骨陷窩中

伸出絲狀偽足通過骨小管相連

與鄰近骨細(xì)胞形成縫隙連接

平坦、瘦長(zhǎng)型細(xì)胞

失活狀態(tài)

覆蓋于失活骨組織表面

被認(rèn)為是成骨細(xì)胞的前體細(xì)胞骨組織中的細(xì)胞成骨細(xì)胞破骨細(xì)胞骨細(xì)胞骨襯里細(xì)胞形成骨基質(zhì)18骨形成胚胎期所有結(jié)締組織均來源于間質(zhì).骨形成被稱為osteogenesisorossification

有兩種骨形成方式膜內(nèi)成骨：直接從纖維結(jié)締組織包膜成骨.軟骨內(nèi)成骨：軟骨內(nèi)血管張入，軟骨逐漸轉(zhuǎn)變?yōu)楣?骨形成胚胎期所有結(jié)締組織均來源于間質(zhì).19cartilagecalcifiedcartilageboneepiphysealplateepiphyseallineEndochondralOssification2oossificationcenterFetus:1st2monthsAdultChildhoodJustbeforebirthcartilagecalcifiedcartilagebo20CentersofOssificationCentersofOssificationCentersofOssificationCenters21垂體前葉的GH,受到甲狀腺的T3和T4的調(diào)節(jié)青春期-性激素：雌激素和雄激素GH分泌不足-侏儒癥GH分泌過多–巨人癥激素調(diào)節(jié)骨生長(zhǎng)垂體前葉的GH,受到甲狀腺的T3和T4的調(diào)節(jié)激素調(diào)節(jié)骨生22Parathyroidhormone-激活破骨細(xì)胞Calcitonin-抑制破骨細(xì)胞保持動(dòng)態(tài)平衡骨平衡：骨重建和修復(fù)Parathyroidhormone-激活破骨細(xì)胞保持動(dòng)23影響骨生長(zhǎng)的因素礦物質(zhì)維生素激素運(yùn)動(dòng)影響骨生長(zhǎng)的因素礦物質(zhì)24FactorsThatAffectBoneGrowthMineralsCalcium Makesbonematrixhard

Hypocalcemia:lowbloodcalciumlevels.

Hypercalcemia:highbloodcalciumlevels.Phosphorus MakesbonematrixhardMagnesium DeficiencyinhibitsosteoblastsBoron Mayinhibitcalciumloss, increaselevelsofestrogensManganese Inhibitsformationofnewbone tissueFactorsThatAffectBoneGrowt25FactorsThatAffectBoneGrowthVitaminsVitaminA Controlsactivity,distribution,and coordinationofsteoblasts/osteoclastsVitaminB12 MayinhibitosteoblastactivityVitaminC Helpsmaintainbonematrix, deficiencyleadstodecreasedcollagen productionwhichinhibitsbone growthandrepair

VitaminD (Calcitriol)Helpsbuildboneby increasingcalciumabsorption. Deficienciesresultin“Rickets”in childrenFactorsThatAffectBoneGrowt26FactorsThatAffectBoneGrowthHormonesHumanGrowthHormone Promotesgeneralgrowthofall bodytissueandnormalgrowthin childrenInsulin-likeGrowthFactorStimulatesuptakeofamino

acidsandproteinsynthesisInsulin Promotesnormalbonegrowthand maturityThyroidHormones Promotesnormalbonegrowthand maturityEstrogenand Increasesosteogenesisatpuberty、Testosterone

andisresponsibleforgender differencesofskeletonsFactorsThatAffectBoneGrowt27SkeletalProblems疾病

/基因骨質(zhì)疏松

多發(fā)性骨髓瘤轉(zhuǎn)移性骨腫瘤類風(fēng)濕性關(guān)節(jié)炎Paget’s骨病SkeletalProblems疾病/基因28骨轉(zhuǎn)換機(jī)制基礎(chǔ)多細(xì)胞單位Multi-cellularUnit(BMU)Becomes“machinery”thatremodelsbone受到分子信號(hào)調(diào)控功能單位持續(xù)數(shù)周-數(shù)月

(10m/day)皮質(zhì)骨BMU呈縱向延伸松質(zhì)骨BMU在骨表面進(jìn)行Nonetincrease/decreaseinbonevolume骨生長(zhǎng)期BMU在骨膜外表面進(jìn)行

骨轉(zhuǎn)換機(jī)制基礎(chǔ)多細(xì)胞單位Multi-cellularUni29BMU的啟動(dòng)微骨折刺激Developsinresponsetomicrocracks接受負(fù)重后骨細(xì)胞信號(hào)誘導(dǎo)Signaledbyosteocytesinresponsetoloading局部激素、細(xì)胞因子和生長(zhǎng)因子影響Signaled(oratleastinfluenced)bylocalhormones,cytokinesandgrowthfactorsBMU的啟動(dòng)微骨折刺激Developsinrespons30激活的BMU分期細(xì)胞活化Cellularactivation成骨細(xì)胞與破骨細(xì)胞持續(xù)地募集細(xì)胞募集位于骨轉(zhuǎn)換交界面骨吸收Resorption破骨細(xì)胞活性僅維持12天，然后凋亡活化的破骨細(xì)胞釋放IGF,FGF等，從而趨化成骨細(xì)胞骨形成及礦化FormationandMineralization類骨質(zhì)由成骨細(xì)胞合成礦化在骨轉(zhuǎn)換啟動(dòng)的第13天開始

(1m/day)礦化速度與類骨質(zhì)形成速度相同骨吸收凹陷被填滿后礦化仍繼續(xù)激活的BMU分期細(xì)胞活化Cellularactivatio31老年基礎(chǔ)醫(yī)學(xué)進(jìn)展-骨代謝基礎(chǔ)理論課件32骨轉(zhuǎn)換過程骨轉(zhuǎn)換過程33骨轉(zhuǎn)換的結(jié)果骨吸收啟動(dòng)骨轉(zhuǎn)換皮質(zhì)骨-沿哈弗氏系統(tǒng)縱向“鉆洞”松質(zhì)骨-骨表面進(jìn)行骨組織對(duì)負(fù)荷（應(yīng)力）的應(yīng)答反應(yīng)維持骨組織材料特性對(duì)微損傷的修復(fù)參與血鈣的調(diào)節(jié)骨組織每4-5年轉(zhuǎn)換一次骨轉(zhuǎn)換的結(jié)果骨吸收啟動(dòng)骨轉(zhuǎn)換34骨轉(zhuǎn)換–被調(diào)控的偶聯(lián)過程成骨前體細(xì)胞成骨細(xì)胞破骨細(xì)胞單核前體細(xì)胞成骨細(xì)胞上表達(dá)溶骨因子的受體體外培養(yǎng)的破骨細(xì)胞可被活化的成骨細(xì)胞激活新形成的骨基質(zhì)中含有成骨細(xì)胞釋放的細(xì)胞因子破骨細(xì)胞生長(zhǎng)因子可趨化和激活成骨細(xì)胞破骨細(xì)胞完成骨吸收老化凋亡時(shí)釋放細(xì)胞因子骨轉(zhuǎn)換–被調(diào)控的偶聯(lián)過程成骨前體細(xì)胞成骨細(xì)胞破骨細(xì)胞單核前35鈣平衡的激素調(diào)節(jié)36維生素D,PTH和降鈣素共同維持血鈣穩(wěn)定鈣平衡的激素調(diào)節(jié)36維生素D,PTH和降鈣素共同維持血鈣鈣磷代謝穩(wěn)態(tài)：骨轉(zhuǎn)換和骨修復(fù)鈣磷代謝穩(wěn)態(tài)：37鈣平衡鈣平衡38骨強(qiáng)度骨強(qiáng)度決定因素幾何結(jié)構(gòu)骨礦鹽密度材料特性骨強(qiáng)度骨強(qiáng)度決定因素39年齡相關(guān)的骨幾何結(jié)構(gòu)變化年齡相關(guān)的骨幾何結(jié)構(gòu)變化40骨丟失機(jī)制（1）：骨轉(zhuǎn)換加速正常骨轉(zhuǎn)換骨轉(zhuǎn)換加速骨丟失機(jī)制（1）：骨轉(zhuǎn)換加速正常骨轉(zhuǎn)換骨轉(zhuǎn)換加速41骨丟失的機(jī)制（2）：骨轉(zhuǎn)換失平衡吸收增加和/或形成減少平衡失平衡骨丟失的機(jī)制（2）：骨轉(zhuǎn)換失平衡吸收增加平衡失平衡42絕經(jīng)后骨丟失機(jī)制正常骨轉(zhuǎn)換骨轉(zhuǎn)換加速，呈負(fù)平衡絕經(jīng)后骨丟失機(jī)制正常骨轉(zhuǎn)換骨轉(zhuǎn)換加速，呈負(fù)平衡43破骨細(xì)胞功能＞成骨細(xì)胞功能成骨細(xì)胞破骨細(xì)胞破骨細(xì)胞功能＞成骨細(xì)胞功能成骨細(xì)胞破骨細(xì)胞44老年基礎(chǔ)醫(yī)學(xué)進(jìn)展-骨代謝基礎(chǔ)理論課件45破骨細(xì)胞生理機(jī)能及可能的作用靶點(diǎn)破骨細(xì)胞生理機(jī)能及可能的作用靶點(diǎn)46成骨生理機(jī)能及可能作用靶點(diǎn)成骨生理機(jī)能及可能作用靶點(diǎn)47骨生物學(xué)與骨質(zhì)疏松

骨轉(zhuǎn)換正常骨骼生理骨質(zhì)疏松骨丟失機(jī)制骨組織中細(xì)胞的起源及發(fā)育骨轉(zhuǎn)換的關(guān)鍵通路及其與骨質(zhì)疏松的關(guān)系抗骨質(zhì)疏松藥物分析骨生物學(xué)與骨質(zhì)疏松骨轉(zhuǎn)換48成骨細(xì)胞增殖分化的調(diào)控PTH,glucocorticoid,Wnt,TGFb,BMPs,FGF,IGF骨髓間充質(zhì)干細(xì)胞前成骨細(xì)胞成熟的成骨細(xì)胞幼稚成骨細(xì)胞襯里細(xì)胞骨細(xì)胞BMP2,7b-catenin,Runx2,Osterix,NFAT2成骨細(xì)胞增殖分化的調(diào)控PTH,glucocorticoid49PPARg對(duì)成骨細(xì)胞和脂肪細(xì)胞的調(diào)控作用多潛能干細(xì)胞osteoblastsPPARgadipocytes+-PPARg對(duì)成骨細(xì)胞和脂肪細(xì)胞的調(diào)控作用多潛能干細(xì)胞oste50噻唑烷二酮對(duì)骨折風(fēng)險(xiǎn)的作用利用英國(guó)的全科醫(yī)生研究數(shù)據(jù)庫(kù)巢式病例-對(duì)照研究服用rosiglitazone,Pioglitazone或其它口服降糖藥或胰島素進(jìn)行年齡、性別和BMI的校正

TZDs與骨折相關(guān)尤其髖部和前臂，且與藥物的劑量相關(guān)噻唑烷二酮對(duì)骨折風(fēng)險(xiǎn)的作用利用英國(guó)的全科醫(yī)生研究數(shù)據(jù)庫(kù)巢式病51Wnt信號(hào)通路ActivatingmutationofLRP5:highbonemasssyndromeLittleD,etal.NEJM,2002;346:1513-1421BoydenPA,etal.AMJHumGenet.2002;70:11-19.Absent/reducedsclerostin:SclerosteosisvanBuchemdiseaseBalemansW,etal.HumMolGenet.2001;10:573-543.WntFrizzled成骨細(xì)胞DkkSclerostinLRP5/6

b-cateninRunx2Wnt信號(hào)通路Activatingmutationof52Runx2對(duì)骨骼正常發(fā)育的作用Runx2失活性雜合突變成骨細(xì)胞功能障礙鎖骨顱骨發(fā)育畸形1,OttoTD,etalCell1997;89:765-7712,MundiosS,etalCell1997;89:773-779Runx2對(duì)骨骼正常發(fā)育的作用Runx2失活性雜合突變1,53Sclerosteosis（骨硬化癥）and

VanBuchemDisease與sclerostin產(chǎn)生減少或缺乏相關(guān)常染色體隱形遺傳性疾病骨內(nèi)膜骨質(zhì)增生不易骨折身材過高及并指(sclerosteosis)Sclerosteosis（骨硬化癥）and

Van54WntFrizzled成骨細(xì)胞DkkSclerostinLRP5/6

b-cateninRunx2LRP5mutationinducehighbonedensityWntFrizzled成骨細(xì)胞DkkSclerostinLR55破骨細(xì)胞形成和活性的調(diào)節(jié)因子PU1M-CSFRANKLC-fosNFkBavb3TRAF6C-src組織蛋白酶K碳酸酐酶IIH+ATP酶氯化物通道骨吸收募集增殖分化極化E2,glucocorticoids,PTH,1,25(OH)2D3,IL-1,TNFa,IFNg破骨細(xì)胞形成和活性的調(diào)節(jié)因子PU1M-CSFRANKLavb56破骨細(xì)胞成熟和功能調(diào)控：

RANKligand及其受體1,25(OH)2D雌二醇糖皮質(zhì)激素PTHrP/PTHIL-1,6,11TNFaNFkBJNKTRAFs成骨細(xì)胞破骨細(xì)胞前體分化融合存活成熟的破骨細(xì)胞+OPGRANKLRANK—+破骨細(xì)胞成熟和功能調(diào)控：

RANKligand及其受體1,57OPGknoct-outmice:SevereOsteoporosisRANKLRANKOPGSimonetWCCell1997;89:309-319OPGknoct-outmice:SevereOst58RNAKLorRANKKO:OsteopetrosisRANKLRANKOPGRANKLRANKOPGKongetalNature397,1997KimetalPNAS972000LietalPNAS,97,2000RNAKLorRANKKO:Osteopetrosi59ExtraOPGNormalOPGLackofOPGOsteoprotegerin(OPG)Seminalpaperpublishedin1997“Osteoprotegerin:Anovelsecretedproteininvolvedintheregulationofbonedensity”,Simonetetal,Cell,234:137-142OPGmemberofTNFreceptorsuperfamily–solublereceptorShowntoaffectbonedensityExtraOPGNormalOPGLackofOPG60OPG/RANKL/RANKReceptorRANKLandOPGaresecretedbyosteoblastsandbonemarrowstromalcellsRANKLfunctionstopromoteosteoclastformationandactivationandinhibitapoptosisOPGfunctionsasadecoyreceptortopreventRANKLsignaling;ratioofRANKLtoOPGdictatesbonemassandstructuralpropertiesCurrentextensiveresearchiselucidatingtheroleofOPG

andRANKLinawidevarietyofbone-relateddiseasesOPGOsteoclast

PrecursorBoneOsteoblastsOsteoclastRANKLigandRANKHormones

CytokinesRANKOPG/RANKL/RANKReceptorRAN61Denosumab(OPGmimetic)FullyhumanmonoclonalantibodytoRANKLigandIgG2HighaffinityforRANKLigand(Kd3x10–12M)DoesnotbindtoTNFα,T