本文選題：成纖維細(xì)胞生長(zhǎng)因子受體3 + 成纖維細(xì)胞生長(zhǎng)因子受體3��； 參考：《第三軍醫(yī)大學(xué)》2017年博士論文

【摘要】：骨性關(guān)節(jié)炎(Osteoarthritis,OA)是發(fā)生在關(guān)節(jié)中最常見的一種慢性退行性疾病。骨性關(guān)節(jié)炎會(huì)多發(fā)生在負(fù)重關(guān)節(jié)并且造成負(fù)重軟骨的軟骨缺損,最終可能導(dǎo)致關(guān)節(jié)疼痛以及關(guān)節(jié)活動(dòng)受限的臨床癥狀,病情發(fā)展到最后常常導(dǎo)致患者失去行走能力。目前臨床上能阻止或緩解骨性關(guān)節(jié)炎的措施非常有限。因此,理解骨性關(guān)節(jié)炎發(fā)生過程中的關(guān)節(jié)軟骨的穩(wěn)態(tài)維持的機(jī)制,對(duì)研究治療或者延緩骨性關(guān)節(jié)炎的發(fā)生和發(fā)展的新型防治措施有重要的意義。成纖維生長(zhǎng)因子(Fibroblast growth factor,FGF)信號(hào)在骨形成和發(fā)育過程中的作用非常關(guān)鍵。成纖維生長(zhǎng)因子(FGFs)家族由22種配體和4種受體組成。成纖維生長(zhǎng)因子(FGFs)通過結(jié)合成纖維生長(zhǎng)因子受體(FGFRs)來發(fā)揮作用。FGFRs在骨形成過程中有特異性的時(shí)空表達(dá)模式。成纖維生長(zhǎng)因子受體3(FGFR3)是在軟骨發(fā)育與軟骨穩(wěn)態(tài)維持中都發(fā)揮重要作用的一種跨膜酪氨酸激酶受體蛋白。FGFR3在骨發(fā)育早期的時(shí)候先在間充質(zhì)凝集中心的軟骨細(xì)胞中表達(dá),接著在生長(zhǎng)板軟骨和關(guān)節(jié)軟骨中的增殖帶和肥大前帶的軟骨細(xì)胞中表達(dá)。人的FGFR3的基因突變會(huì)導(dǎo)致一系列的骨骼畸形。FGFR3的增強(qiáng)型點(diǎn)突變導(dǎo)致以身材矮小為臨床表現(xiàn)的骨骼發(fā)育不良,包括致死性軟骨發(fā)育不良(thanatophoric dysplasia,TD I/II),軟骨發(fā)育不全(Achondroplasia,ACH)等;而人的FGFR3的失活性點(diǎn)突變會(huì)導(dǎo)致CATSHL綜合征,即聽力喪失、高身材和屈曲指。FGFR3被認(rèn)為是軟骨內(nèi)成骨的發(fā)育過程中的負(fù)性調(diào)節(jié)分子,但FGFR3信號(hào)在關(guān)節(jié)軟骨中的直接作用還需要進(jìn)一步研究。FGFR3在成年人的關(guān)節(jié)軟骨中有豐富的表達(dá),在OA病人的關(guān)節(jié)軟骨中表達(dá)下降。全身敲除FGFR3的小鼠自發(fā)發(fā)生骨性關(guān)節(jié)炎。并且,ACH病人雖然有嚴(yán)重的內(nèi)彎腿以及肥胖等引發(fā)OA的高危因素,但是卻很少出現(xiàn)OA癥狀。這些發(fā)現(xiàn)提示了FGFR3有延緩OA發(fā)生和發(fā)展的作用。由于ACH病人和FGFR3全敲除小鼠都有骨骼結(jié)構(gòu)上的變化,因此FGFR3對(duì)維持關(guān)節(jié)軟骨穩(wěn)態(tài)的直接作用,還有待研究。FGF2在動(dòng)物模型中可調(diào)節(jié)關(guān)節(jié)軟骨的代謝,并且可在OA動(dòng)物模型中延緩OA進(jìn)程。但是,FGF2是否在人的關(guān)節(jié)軟骨中起保護(hù)作用仍有爭(zhēng)議。FGF18被認(rèn)為在關(guān)節(jié)軟骨的降解過程中起保護(hù)軟骨的作用。FGF2和FGF18在OA進(jìn)程中的不同作用的具體機(jī)制仍未闡述清楚。旁分泌性的FGFs,比如FGF2和FGF18,是通過結(jié)合FGFRs后激活包括MAPK,PKC-γ,PI-3K/AKT和STAT等下游信號(hào)通路,來起到其生物學(xué)作用的。不同的FGFRs在維持軟骨穩(wěn)態(tài)中起不同的生物學(xué)作用。FGFR1信號(hào)促進(jìn)分解因子的表達(dá),比如matrix metalloproteinase(MMP)13和a disintegrin and metalloproteinase with thrombospoindin motifs(ADAMTS)5,并抑制軟骨基質(zhì)生成。而激活FGFR3信號(hào)則抑制軟骨肥大化和促進(jìn)軟骨基質(zhì)合成。FGFR3在骨性關(guān)節(jié)炎病人的關(guān)節(jié)軟骨中其表達(dá)下調(diào)。并且類似的在小鼠關(guān)節(jié)軟骨中的結(jié)果也報(bào)道過。此外,不管是在生長(zhǎng)板或是關(guān)節(jié)軟骨,FGFR3信號(hào)被認(rèn)為是調(diào)節(jié)軟骨肥大化和軟骨特異性的細(xì)胞外基質(zhì)的生成,并且Fgfr3缺失導(dǎo)致小鼠關(guān)節(jié)出現(xiàn)早期關(guān)節(jié)炎的癥狀。因此,在軟骨中激活FGFR3信號(hào)可能是治療骨性關(guān)節(jié)炎的潛在治療手段。和FGF18相似,FGF9是FGFR3的相對(duì)特異性配體,能在軟骨中激活FGFR3信號(hào),提示FGF9在關(guān)節(jié)軟骨的穩(wěn)態(tài)維持中發(fā)揮作用。在骨發(fā)育過程中,FGF9最先在頂端外胚層嵴表達(dá),接著在骨膜或軟骨膜、松質(zhì)骨和關(guān)節(jié)中表達(dá),但在生長(zhǎng)板軟骨幾乎不表達(dá)。骨性關(guān)節(jié)炎目前治療措施僅僅局限在解決疼痛和抗炎治療等對(duì)癥方面,最后只能控制表面癥狀而難以緩解OA的進(jìn)展。為了尋找有效的緩解OA進(jìn)程的生物因子,我們把視線放到FGFR3的相對(duì)特異性配體FGF9上。但FGF9對(duì)關(guān)節(jié)軟骨損傷修復(fù)的影響和作用尚不清楚。我們構(gòu)建了FGFR3軟骨特異性誘導(dǎo)敲除和增強(qiáng)小鼠的DMM手術(shù)誘導(dǎo)的骨性關(guān)節(jié)炎模型,來研究FGFR3在關(guān)節(jié)軟骨中穩(wěn)態(tài)維持的作用和機(jī)制。接著,為了進(jìn)一步尋找治療骨性關(guān)節(jié)炎的生物因子,我們通過觀察關(guān)節(jié)腔內(nèi)注射FGF9到DMM手術(shù)誘導(dǎo)骨性關(guān)節(jié)炎小鼠模型中,來研究FGF9是否可能成為靶向調(diào)節(jié)FGFR3的骨性關(guān)節(jié)炎的新型治療因子。研究方法第一部分:1.建立成年期可誘導(dǎo)條件性敲除或增強(qiáng)fgfr3小鼠,即在1月或2月齡的同窩Fgfr3f/f;Col2a1-Cre ERT2(Fgfr3 c KO)小鼠和Fgfr3f/f(Cre-negative)小鼠,或1月或2月齡的同窩Fgfr3K644E/neo;Col2a1-Cre ERT2(Fgfr3 c Act)小鼠和Fgfr3K644E/neo(Cre-negative)小鼠,同時(shí)腹腔內(nèi)注射1mg/10g/天Tamoxifen(TM)腹腔內(nèi)注射5天。對(duì)小鼠行DMM(Destabilization of the Medial Meniscus)手術(shù)。2.通過藏紅-固綠染色法觀測(cè)小鼠膝關(guān)節(jié)組織學(xué)結(jié)構(gòu),并且使用OARSI(Osteoarthritis research Society International)推薦的評(píng)測(cè)方法對(duì)關(guān)節(jié)軟骨進(jìn)行評(píng)分;通過免疫組織化學(xué)染色法觀測(cè)膝關(guān)節(jié)軟骨組織的FGFR3、Collagen II、Collagen X、MMP13、AggrecanNeo的表達(dá)情況。3.建立老年期Fgfr3ACH/+小鼠自發(fā)OA模型,并在6月齡、12月齡、20月齡分別取材,通過藏紅-固綠染色法觀測(cè)小鼠膝關(guān)節(jié)組織學(xué)結(jié)構(gòu),通過免疫組化染色法觀察小鼠膝關(guān)節(jié)軟骨組織中Collagen X和MMP13的表達(dá)情況。4.取Fgfr3f/f;Col2a1-CreERT2(Fgfr3 c KO)和Fgfr3f/f(Cre-negative)小鼠的股骨頭的關(guān)節(jié)軟骨進(jìn)行體外組織塊培養(yǎng),然后用4-hydroxytamoxifen處理,接著用IHH信號(hào)阻斷劑(GDC0449,SMOi)處理,并提取RNA然后反轉(zhuǎn)錄,利用實(shí)時(shí)熒光定量PCR檢測(cè)Ihh、Gli、Runx2、Mmp13、Adamts5、Col10a1、Col2a1和Aggrecan的表達(dá)。第二部分:1.為了研究FGF9在體內(nèi)對(duì)關(guān)節(jié)軟骨的作用,我們?cè)谛∈驞MM關(guān)節(jié)炎模型中注射FGF9。先對(duì)小鼠行DMM手術(shù),接著在DMM手術(shù)后2周注射FGF9。先把FGF9溶液(2.5μg粉劑溶解在5μl生理鹽水中)與纖維蛋白原溶液混合(3μg/μl)后注射在關(guān)節(jié)腔中,接著注射1μl凝血酶(0.2 unit)使纖維蛋白原轉(zhuǎn)變?yōu)槔w維蛋白,這樣就可以使FGF9緩慢釋放到關(guān)節(jié)腔內(nèi)。在手術(shù)后第8周和12周時(shí)處死小鼠,取小鼠膝關(guān)節(jié)進(jìn)行組織切片觀察;2.建立人關(guān)節(jié)軟骨體外培養(yǎng)模型,研究了外源性FGF9的處理對(duì)白介素-1β(interleukin-1β,IL-1β)誘導(dǎo)的人關(guān)節(jié)軟骨退變的作用,并且通過藏紅固綠染色法觀察人關(guān)節(jié)軟骨的組織學(xué)結(jié)構(gòu),接著再通過免疫組化染色法觀察人關(guān)節(jié)軟骨的collagen II,collagen X和MMP13的表達(dá)情況;通過WB檢測(cè)人關(guān)節(jié)軟骨aggrecan和MMP13的蛋白表達(dá)變化;4.通過Micro-CT掃描重建,觀察FGF9關(guān)節(jié)腔內(nèi)注射后小鼠膝關(guān)節(jié)軟骨下骨的變化情況,通過藏紅固綠染色法以及阿爾新藍(lán)/蘇木精/伊紅染色法觀察小鼠的膝關(guān)節(jié)中組織學(xué)結(jié)構(gòu)變化。5.通過免疫組織化學(xué)染色法觀察FGF9注射后小鼠膝關(guān)節(jié)軟骨中的collagen II,collagen X,MMP13以及Cleaved caspase-3的表達(dá)情況,以及在骨贅形成處Collagen II,PCNA和SOX9的表達(dá)情況。實(shí)驗(yàn)結(jié)果:第一部分:FGFR3抑制成年小鼠膝關(guān)節(jié)骨性關(guān)節(jié)炎的發(fā)展1.成年小鼠軟骨特異性敲除Fgfr3后關(guān)節(jié)軟骨降解過程加速。2.成年小鼠軟骨特異性敲除Fgfr3后Collagen II表達(dá)降低,Collagen X、MMP13和AggrecanNeo表達(dá)升高。3.成年小鼠軟骨特異性增強(qiáng)Fgfr3后關(guān)節(jié)軟骨降解過程減緩。4.Fgfr3ACH/+小鼠其老年自發(fā)OA的進(jìn)程減緩。5.成年小鼠軟骨特異性增強(qiáng)Fgfr3后Collagen X、MMP13表達(dá)降低,老年Fgfr3ACH/+小鼠Collagen X、MMP13表達(dá)降低。6.體外關(guān)節(jié)軟骨組織中敲除Fgfr3后,IHH信號(hào)和Runx2表達(dá)升高,而阻斷IHH信號(hào)會(huì)抑制已上調(diào)表達(dá)的Runx2、Mmp13的表達(dá)。第二部分:外源性FGF9緩解關(guān)節(jié)軟骨損傷后引起的骨性關(guān)節(jié)炎1.關(guān)節(jié)內(nèi)注射FGF9延緩小鼠骨關(guān)節(jié)炎模型中關(guān)節(jié)軟骨降解。DMM手術(shù)加關(guān)節(jié)腔內(nèi)FGF9治療組的股骨和脛骨的評(píng)分其最高分和總分都顯著低于DMM手術(shù)加空白鹽水的治療組;而DMM誘導(dǎo)并注射FGF9后,MMP13和Collagen X的表達(dá)相比對(duì)照降低。2.FGF9對(duì)炎癥環(huán)境中的人關(guān)節(jié)軟骨退變有保護(hù)作用,外源性FGF9處理后能明顯導(dǎo)致IL-1β處理后的人關(guān)節(jié)軟骨細(xì)胞其MMP13的表達(dá)降低、aggrecan的表達(dá)增加。3.關(guān)節(jié)腔內(nèi)注射FGF9促進(jìn)DMM手術(shù)后的關(guān)節(jié)周圍骨贅的形成。FGF9處理后能顯著增加DMM手術(shù)誘導(dǎo)的關(guān)節(jié)附近形成的骨贅的大小;在小鼠8周及12周時(shí)注射FGF9能明顯提高DMM誘導(dǎo)術(shù)后的關(guān)節(jié)周圍骨贅其大小。4.FGF9促進(jìn)關(guān)節(jié)周圍骨贅形成過程中的細(xì)胞增殖和軟骨細(xì)胞的分化。在DMM手術(shù)后的小鼠關(guān)節(jié)中,我們發(fā)現(xiàn)SOX9在關(guān)節(jié)周圍的骨贅處有大量表達(dá),并且FGF9治療后會(huì)明顯提高SOX9其表達(dá)水平;關(guān)節(jié)腔注射FGF9會(huì)明顯上調(diào)關(guān)節(jié)骨贅處的細(xì)胞PCNA的表達(dá)。結(jié)論:一、FGFR3抑制成年小鼠膝關(guān)節(jié)骨性關(guān)節(jié)炎的發(fā)展;二、關(guān)節(jié)腔注射FGF9緩解小鼠關(guān)節(jié)軟骨損傷后引起的骨性關(guān)節(jié)炎,同時(shí)可促進(jìn)骨性關(guān)節(jié)炎中骨贅的形成。
[Abstract]:Osteoarthritis (OA) is the most common chronic degenerative disease occurring in the joints. Osteoarthritis occurs mostly in the heavy joint and causes the cartilage defect of the heavy cartilage. It may eventually lead to joint pain and the clinical symptoms of limited joint activity, and the development of the disease often leads to the loss of walking in the patient. At present, the measures to prevent or alleviate osteoarthritis are very limited. Therefore, understanding the mechanism of the steady state of the articular cartilage in the process of osteoarthritis is of great significance for the study of the new prevention and treatment of the occurrence and development of osteoarthritis. Fibroblast growth factor (Fibroblast growth) Factor, FGF) signal plays a key role in bone formation and development. The fibroblast growth factor (FGFs) family consists of 22 ligands and 4 receptors. Fibroblast growth factor (FGFs) plays a role in the specific spatio-temporal expression of.FGFRs in the process of bone formation by combining fibroblast growth factor receptor (FGFRs). Long factor receptor 3 (FGFR3) is a transmembrane tyrosine kinase receptor protein.FGFR3, a transmembrane tyrosine kinase receptor protein, which plays an important role in the development of cartilage development and cartilage homeostasis. It is expressed in the chondrocytes of the mesenchymal agglutination center at the early stage of bone development, followed by the proliferating zone in the growth plate cartilage and joint soft bone and the cartilaginous cells in the front of the hypertrophy. Gene mutations in human FGFR3 can lead to a series of enhanced point mutations in the skeletal deformity of.FGFR3, resulting in skeletal dysplasia in short stature, including fatal cartilage dysplasia (thanatophoric dysplasia, TD I/II), cartilage dysplasia (Achondroplasia, ACH), and other mutations in the human FGFR3 inactive point. CATSHL syndrome, such as hearing loss, high stature and flexion finger.FGFR3, is considered as a negative regulator in the development of endochondral osteogenesis, but the direct role of FGFR3 signals in articular cartilage needs further study of the rich expression of.FGFR3 in the articular cartilage of adults and the expression of the cartilage in the articular cartilage of the OA patients. Reduced FGFR3 mice spontaneously osteoarthritis. And, while ACH patients have severe internal kits and obesity and other high risk factors for OA, there are few OA symptoms. These findings suggest that FGFR3 has the effect of retarding the occurrence and development of OA. Both ACH patients and FGFR3 full knockout mice have skeletal structural changes. Therefore, the direct effect of FGFR3 on the maintenance of articular cartilage homeostasis, it remains to be studied that.FGF2 can regulate the metabolism of articular cartilage in animal models, and can delay the OA process in the OA animal model. However, it is still controversial whether FGF2 plays a protective role in human articular cartilage and.FGF18 is considered to protect the cartilage during the degradation of articular cartilage. The specific mechanisms of the effects of bone on.FGF2 and FGF18 in the OA process are still not clear. Paracrine FGFs, such as FGF2 and FGF18, plays a biological role by activating downstream signaling pathways such as MAPK, PKC- gamma, PI-3K/AKT and STAT by combining FGFRs. Different FGFRs plays different organisms in the maintenance of cartilage homeostasis. .FGFR1 signals promote the expression of decomposition factors, such as matrix metalloproteinase (MMP) 13 and a disintegrin and metalloproteinase with thrombospoindin motifs (ADAMTS) 5, and inhibit the formation of cartilage matrix. The expression in the cartilaginous cartilage is down. And similar results have been reported in the articular cartilage of the mice. In addition, the FGFR3 signal is considered to be the formation of the extracellular matrix that regulates cartilage hypertrophy and cartilage specificity, regardless of the growth plate or articular cartilage, and the absence of Fgfr3 leads to the symptoms of early arthritis in the joints of mice. Therefore, Activation of FGFR3 signal in cartilage may be a potential treatment for osteoarthritis. Similar to FGF18, FGF9 is a relative specific ligand for FGFR3, which activates FGFR3 signals in cartilage, suggesting that FGF9 plays a role in the steady state maintenance of articular cartilage. During bone development, FGF9 is first expressed in the apical ectodermal ridge and then in the periosteum. Or cartilaginous membrane, expressed in cancellous bone and joints, but almost unexpressed in the growth plate cartilage. Osteoarthritis is currently only limited to the treatment of pain and anti-inflammatory treatment. Finally, it can only control surface symptoms and difficult to alleviate the progress of OA. In order to find effective biological factors to alleviate the OA process, we put our eyes to F GFR3's relative specific ligand FGF9. But the effect and effect of FGF9 on the repair of articular cartilage injury is not clear. We constructed a FGFR3 cartilage specific induced knockout and enhanced DMM operation induced osteoarthritis model in mice to study the role and mechanism of FGFR3 in the homeostasis of articular cartilage. In the treatment of osteoarthritis, we observe whether FGF9 may be a new therapeutic factor for targeting osteoarthritis of FGFR3 by observing the intravaric injection of FGF9 to DMM to induce osteoarthritis in mice. Part 1.: the first part of the study is to induce conditional knockout or increase FGFR3 in the adult period. Mice, that is, in January or 2 month old of the same nest Fgfr3f/f; Col2a1-Cre ERT2 (Fgfr3 C KO) mice and Fgfr3f/f (Cre-negative) mice, or January or 2 month old of the same fossa Fgfr3K644E/neo; Col2a1-Cre ERT2 (Fgfr3) mice and mice, and intraperitoneal injection of peritoneal injection for 5 days. M (Destabilization of the Medial Meniscus) operation.2. was used to observe the histological structure of the knee joint by the method of red solid green staining, and the articular cartilage was scored by the evaluation method recommended by OARSI (Osteoarthritis research Society International), and the cartilage tissue of the knee was observed by immunohistochemical staining. The expression of llagen II, Collagen X, MMP13, AggrecanNeo.3. was used to establish the spontaneous OA model of senile Fgfr3ACH/+ mice, and were obtained in 6 month old, 12 month old, 20 month old respectively. The histological structure of the knee joint was observed by the method of Tibetan red solid green staining, and the Collagen X and MMP13 table in the cartilage tissue of the knee of mice was observed by immunohistochemical staining. The articular cartilage of the femoral head of Col2a1-CreERT2 (Fgfr3 C KO) and Fgfr3f/f (Cre-negative) mice was cultured in vitro, and then treated with 4-hydroxytamoxifen, then the IHH signal blocker (GDC0449, SMOi) was then treated with the IHH signal blocking agent. The expression of Adamts5, Col10a1, Col2a1 and Aggrecan. Second: 1. in order to study the role of FGF9 in the articular cartilage in the body, we injected FGF9. in the mouse DMM arthritis model before DMM surgery, and then injected FGF9 solution (2.5 micron g powder in 5 mu saline) and fibrinogen solution at 2 weeks after DMM operation. The mixture (3 g/ Mu L) was injected into the articular cavity, then 1 l thrombin (0.2 unit) was injected into the fibrinogen to transform the fibrinogen into the fibrin, so that the FGF9 could be slowly released into the articular cavity. The mice were killed at eighth and 12 weeks after the operation, and the knee joints were taken to observe the tissue section. 2. to establish the culture model of human articular cartilage in vitro. The effect of exogenous FGF9 on the degeneration of human articular cartilage induced by interleukin -1 beta (interleukin-1 beta, IL-1 beta) was investigated, and the histological structure of human articular cartilage was observed by the method of Tibetan red solid green staining, and then the expression of collagen II, collagen X and MMP13 were observed by immunohistochemical staining; WB examination was carried out by WB. The changes in the protein expression of aggrecan and MMP13 in human articular cartilage were measured. 4. the changes of the subchondral bone in the knee joint of the mice after the intra-articular injection of FGF9 were observed by Micro-CT scanning. The histological structural changes in the knee joints of the mice were observed by the Tibetan red green staining and alino blue / hematoxylin / eosin staining and.5. through the immune tissue. The expression of collagen II, collagen X, MMP13 and Cleaved caspase-3 in the knee cartilage of mice after FGF9 injection, and the expression of Collagen II, PCNA and SOX9 in the formation of osteophyte. Experimental results: the first part: inhibiting the development of osteoarthritis of the knee joint in adult mice, the cartilage specific of 1. adult mice The degradation process of articular cartilage after knockout of Fgfr3 accelerates the decrease of Collagen II expression, Collagen X, Collagen X, MMP13 and AggrecanNeo expression in adulthood mice, Collagen X, MMP13 and AggrecanNeo expression increase in.3. adult mice. The cartilage degradation in.3. adult mice slows down the process of cartilage degradation in.4.Fgfr3ACH/+ mice. Cartilage specificity enhanced Fgfr3 Collagen X, MMP13 expression decreased, Collagen X in the elderly Fgfr3ACH/+ mice, MMP13 expression reduced.6. in articular cartilage tissue after knockout Fgfr3, IHH signal and Runx2 expression increased, but blocking the signal will inhibit the expression of the expression. The second part: exogenous cartilage injury relieves articular cartilage injury The 1. intra-articular injection of FGF9 in the posterior articular osteoarthritis delayed the osteoarthritis model of mice and the articular cartilage degradation.DMM operation and the femoral and tibia score of the FGF9 group in the joint intracavitary group were significantly lower than those in the treatment group with DMM and blank saline; while DMM induced and injected FGF9, the expression of MMP13 and Collagen X was compared. The reduction of.2.FGF9 has a protective effect on the degeneration of articular cartilage in the inflammatory environment. Exogenous FGF9 can obviously lead to the decrease of the expression of MMP13 in human articular chondrocytes after IL-1 beta treatment. The expression of aggrecan is increased by.3. in the intra-articular injection of FGF9 to promote the formation of osteophyte around the joint after DMM surgery. The size of osteophyte in the vicinity of the joint induced by DMM operation; the injection of FGF9 at 8 and 12 weeks in mice can significantly increase the size of the osteophyte around the joint after DMM induction and promote the proliferation of cells and the differentiation of chondrocytes during the formation of the osteophyte around the joint. In the joints of the mice after DMM, we found that SOX9 is in the joint. There is a large amount of expression in the surrounding osteophyte, and the expression level of SOX9 can be significantly increased after FGF9 treatment; the injection of FGF9 in the articular cavity can obviously increase the expression of PCNA in the joint osteophyte. Conclusion: 1, FGFR3 inhibits the development of osteoarthritis of the knee joint in adult mice; two, the joint cavity injection of FGF9 alleviates the bone caused by the injury of articular cartilage in mice. Arthritis can also promote osteophyte formation in osteoarthritis.
【學(xué)位授予單位】：第三軍醫(yī)大學(xué)
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2017
【分類號(hào)】：R684.3

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