四連接素基因敲除小鼠表現(xiàn)出脊柱后凸畸形和骨質(zhì)疏松癥的特征

茹德文　顏玉峰　李　炳　謝　強(qiáng)　湯　日　沈　曉　余　果　杜嘉瑞　王爾松△

(1復(fù)旦大學(xué)附屬金山醫(yī)院神經(jīng)外科,2中心實(shí)驗(yàn)室　上?！?01508)

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四連接素基因敲除小鼠表現(xiàn)出脊柱后凸畸形和骨質(zhì)疏松癥的特征

茹德文1顏玉峰1李炳2謝強(qiáng)1湯日1沈曉1余果1杜嘉瑞1王爾松1△

(1復(fù)旦大學(xué)附屬金山醫(yī)院神經(jīng)外科,2中心實(shí)驗(yàn)室上海201508)

【摘要】目的研究四連接素 (tetranectin,TN)基因敲除對(duì)小鼠骨骼生長(zhǎng)發(fā)育的影響,從而探究該基因的正常生理功能及其缺失與疾病的關(guān)系。 方法通過基因同源重組的方法構(gòu)建出TN基因敲除 (TN(-/-))小鼠模型,分別對(duì)2月齡和8月齡的TN(-/-)雄性小鼠 (n=10)和同齡野生型(wild-type,WT)雄性小鼠 (n=10)進(jìn)行全身正側(cè)位X線攝片和脊柱后凸角度 (Cobb角)測(cè)量,并對(duì)8月齡TN(-/-)雄性小鼠 (n=10)和WT雄性小鼠 (n=10)的多部位骨骼進(jìn)行骨密度 (bone mineral density,BMD)及骨礦含量 (bone mineral content,BMC)測(cè)定和病理切片檢查,所得數(shù)據(jù)進(jìn)行統(tǒng)計(jì)學(xué)分析。結(jié)果TN(-/-)小鼠與同齡WT小鼠體質(zhì)量無明顯差異;2月齡及8月齡TN(-/-)小鼠Cobb角均較同齡WT小鼠顯著增大 (P<0.01),且隨月齡增加,Cobb角顯著增大 (P<0.01);8月齡TN(-/-)小鼠的胸椎椎間盤結(jié)構(gòu)不對(duì)稱,外側(cè)纖維環(huán)呈增大、疏松改變;與同齡WT小鼠相比,8月齡TN(-/-)小鼠全身、腰3椎體和左側(cè)股骨BMD及BMC顯著降低 (P<0.05),股骨及腰椎在組織學(xué)上也呈現(xiàn)出骨小梁變細(xì)、稀疏、排列紊亂或斷裂等特點(diǎn),且骨小梁成骨細(xì)胞減少,破骨細(xì)胞增多。結(jié)論TN(-/-)小鼠表現(xiàn)出脊柱后凸畸形和骨質(zhì)疏松癥的特征，提示TN與骨骼的正常生長(zhǎng)發(fā)育關(guān)系密切。TN(-/-)小鼠作為一種潛在的脊柱后凸畸形或骨質(zhì)疏松癥疾病動(dòng)物模型具有重大的研究意義。

【關(guān)鍵詞】四連接素;基因敲除;脊柱后凸畸形;骨質(zhì)疏松癥;小鼠

*This work was supported Science and Technology Commission of Shanghai Municipality,China (124119a1900) and Shanghai Municipal Commission of Health and Family Planning (20124339).

四連接素 (tetranectin,TN)屬于C型凝集素家族成員。自1986年從人類血漿中被分離純化出來之后[1],即被發(fā)現(xiàn)與多種疾病密切相關(guān)[2-6]。然而,其生物學(xué)功能和作用機(jī)制目前尚不清楚。研究表明,TN可能在組織重塑以及骨骼成骨過程中的礦化階段起到重要作用[7],而且與骨折的早期愈合密切相關(guān)[8]。為了進(jìn)一步探究TN與骨骼生長(zhǎng)發(fā)育之間的潛在關(guān)系,我們與上海南方模式生物研究中心合作研發(fā)了TN基因敲除的小鼠模型。本研究通過對(duì)TN基因敲除 (TN-/-)小鼠和其同齡野生型 (wild-type,WT)小鼠的骨骼系統(tǒng)進(jìn)行形態(tài)學(xué)、計(jì)量學(xué)及組織病理學(xué)的對(duì)比分析,探索TN與骨骼生長(zhǎng)發(fā)育的潛在關(guān)系,為進(jìn)一步研究TN的生理功能及作用機(jī)制奠定基礎(chǔ),也為TN-/-小鼠的進(jìn)一步應(yīng)用提供理論依據(jù)。

材 料 和 方 法

TN-/-小鼠與WT小鼠利用基因重組進(jìn)行基因敲除的方法構(gòu)建出C57BL/6 TN-/-小鼠,微生物學(xué)等級(jí)為SPF級(jí)。造模建系后進(jìn)行PCR及Western blot檢測(cè)。WT小鼠為同齡野生型小鼠。

分組隨機(jī)取2月齡TN-/-雄性小鼠和同齡WT雄性小鼠各10只,進(jìn)行全身X線攝片;隨機(jī)取8月齡TN-/-小鼠和同齡WT小鼠各10只,進(jìn)行全身X線攝片、骨密度 (bone mineral density,BMD)測(cè)定和病理學(xué)檢查。

小鼠全身X線攝片小鼠經(jīng)腹腔麻醉后,固定于膠片上,采用德國(guó)西門子MULTIX-TOP X線光機(jī)進(jìn)行全身正側(cè)位X線攝片,曝光參數(shù)為30 mA和38kV。

脊柱后凸角度 (Cobb角)測(cè)量X線攝片完成后,采用測(cè)量Cobb角 (胸7椎體至腰4椎體)的方法[9]分別測(cè)量各組小鼠脊柱后凸角度。

BMD及骨礦含量(bone mineral content,BMC)測(cè)定8月齡小鼠經(jīng)腹腔麻醉后,用Hologic QDR-4000DXA雙能X線骨密度儀進(jìn)行BMD及BMC測(cè)定,測(cè)定部位包括全身、腰3椎體和左側(cè)股骨。

病理學(xué)檢查8月齡小鼠經(jīng)腹腔麻醉后,采用經(jīng)心臟生理鹽水及4%多聚甲醛灌注固定組織。取小鼠的胸椎、腰椎及股骨組織,經(jīng)常規(guī)10% EDTA脫鈣、石蠟包埋、組織切片、HE染色后,使用OLYMPUS BX43普通光鏡行病理學(xué)檢查。

結(jié)果

PCR及Westernblot檢測(cè)剪取小鼠尾尖抽提DNA及蛋白質(zhì),分別從基因及蛋白表達(dá)水平進(jìn)行檢測(cè),鑒定出TN-/-小鼠(圖1)。

A:PCR detection of DNA extracted from the tip of the mouse’s tail.The DNA bands of WT mice were 575 bp and TN-/-mice were 711 bp.While the DNA binds of heterozygous mice were both 575 bp and 711bp. B:Western blot detection of protein extracted from the tip of the mouse’s tail.WT mice were tetranectin positive,while TN-/-mice were tetranectin negtive.

圖1鼠尾PCR及Western blot檢測(cè)結(jié)果

Fig 1PCR and Western blot detection of

TN in filial generation mice

各組小鼠體質(zhì)量各組小鼠體質(zhì)量比較結(jié)果 (圖2):2月齡TN-/-小鼠和WT小鼠的體質(zhì)量分別為(19.50±3.75) g和(18.50±3.78) g,兩組間體質(zhì)量差異無統(tǒng)計(jì)學(xué)意義 (P> 0.05);8月齡TN-/-小鼠和WT小鼠的體質(zhì)量分別為(30.80±5.27) g和(29.50±4.74) g,兩組間體質(zhì)量差異無統(tǒng)計(jì)學(xué)意義 (P>0.05)。

No statistical difference between TN-/-mice and their WT littermates (P>0.05).

圖2各組小鼠體質(zhì)量情況

Fig 2Body weight of each group

X線攝片WT小鼠未發(fā)現(xiàn)脊柱后凸畸形,而2月齡TN-/-小鼠中有5只出現(xiàn)明顯脊柱后凸畸形,8月齡TN-/-小鼠中有8只表現(xiàn)出明顯脊柱后凸畸形,且隨月齡增加,脊柱后凸程度有加重趨勢(shì);8月齡TN-/-小鼠X線片還顯示出BMD減低、骨小梁稀疏或塌陷、骨皮質(zhì)變薄的特點(diǎn) (圖3)。

Compared with their WT littermates,TN-/-mice exhibited features of kyphosis and the severity of kyphosis aggravated apparently with age in TN-/-mice.Moreover,eight-month-old TN-/-mice developed features of reduced BMD,sparse bony trabeculae and thinner cortical bone in multisite.

圖3TN-/-小鼠和WT小鼠脊柱后凸比較

Fig 3Radiographs of WT mice and TN-/-mice

脊柱后凸角度2月齡TN-/-小鼠脊柱后凸角度 (Cobb角)明顯大于同齡WT小鼠,差異有統(tǒng)計(jì)學(xué)意義 (P<0.01);8月齡TN-/-小鼠Cobb角也明顯大于同齡WT小鼠,差異有統(tǒng)計(jì)學(xué)意義 (P<0.01);且8月齡TN-/-小鼠較2月齡TN-/-小鼠Cobb角顯著性增大 (P<0.01),說明隨月齡增加,TN-/-小鼠脊柱后凸程度明顯加重 (表 1)。

表1　TN-/-小鼠和WT小鼠Cobb角比較

(1)vs. WT mice,P<0.01;(2)vs. 2-month-old TN-/-mice,P<0.01.

BMD及BMC分別對(duì)8月齡的WT小鼠和TN-/-小鼠進(jìn)行BMD及BMC測(cè)定后發(fā)現(xiàn),TN-/-小鼠全身、第3腰椎和左側(cè)股骨BMD及BMC均明顯低于同齡WT小鼠,差異有統(tǒng)計(jì)學(xué)意義 (表 2)。這說明,8月齡的TN-/-小鼠較WT小鼠骨量已明顯丟失,出現(xiàn)了骨質(zhì)疏松的特點(diǎn)。

表 2　8月齡WT小鼠與TN-/-小鼠全身、腰3椎體及左側(cè)股骨的BMD 和 BMC比較

vs. WT mice,(1)P<0.05;(2)P<0.01.

病理學(xué)檢查結(jié)果與同齡WT小鼠相比,8月齡TN-/-小鼠的胸椎椎間盤結(jié)構(gòu)明顯不對(duì)稱,外側(cè)纖維環(huán)呈增大、疏松改變,生長(zhǎng)板并未觀察到異常改變 (圖4);8月齡TN-/-小鼠股骨及腰椎在組織學(xué)上也呈現(xiàn)出骨小梁變細(xì)、稀疏、排列紊亂或斷裂等特點(diǎn),且骨小梁成骨細(xì)胞減少,破骨細(xì)胞增多 (圖5)。

Asymmetric thoracic intervertebral disc structure and expanded and loose fibrous ring of intervertebral disc were distinct in TN-/-mice.However,abnormal changes of growth plate were not observed (HE,×100).

圖48月齡WT小鼠與TN-/-小鼠胸椎椎間盤

病理學(xué)變化比較

Fig 4Pathological section observation of thoracic

intervertebral disc in 8-month-old TN-/-mice

and their WT littermates

討論

TN廣泛分布于多種細(xì)胞、細(xì)胞外基質(zhì)及組織中。目前認(rèn)為,TN在骨骼和肌肉細(xì)胞的分化及成熟、骨生成及礦化、組織重塑和骨折愈合等生理過程中起重要作用[7-8,10]。并且,TN在這些生理過程中作用的發(fā)揮可能都與纖溶酶原激活系統(tǒng) (plasminogen activitor system,PAS)中的纖溶酶原 (plasminogen,Plg)有關(guān)。TN可能在低鈣環(huán)境下與Plg的kringle 4區(qū)結(jié)合并使之激活而裂解成纖溶酶,從而在蛋白溶解過程中起調(diào)節(jié)作用[11]。蛋白溶解活性在骨骼形成過程中極其重要,有研究報(bào)道,基 質(zhì)金屬蛋白酶(matrix metallo-protein,MMP)系統(tǒng)中的基質(zhì)金屬蛋白酶-9/明膠酶B (MMP-9/gelatinase B)和膜型基質(zhì)金屬蛋白酶1 (MT1-MMP)基因缺失小鼠在骨骼生長(zhǎng)板血管化和骨化的過程中均出現(xiàn)異常[12-13],最終造成骨骼發(fā)育缺陷。而MMPs酶原的最重要的激活劑就是PAS中的纖溶酶。這說明,TN可能通過蛋白溶解系統(tǒng)在骨生成和骨骼發(fā)育的整個(gè)過程中發(fā)揮重要的生理功能。2001年Iba等[14]建立了TN-/-小鼠模型,并且發(fā)現(xiàn)部分6月齡以上TN-/-小鼠出現(xiàn)了明顯脊柱后凸畸形,而對(duì)6月齡以下TN-/-小鼠的情況未進(jìn)行描述。另外,作者還對(duì)4～6月齡的TN-/-小鼠的全身BMD進(jìn)行了測(cè)量,未發(fā)現(xiàn)與WT小鼠全身BMD有差異。但是,研究中沒有對(duì)全身多部位BMD及BMC進(jìn)行測(cè)定,也未對(duì)6月齡以上TN-/-小鼠的BMD及BMC進(jìn)行評(píng)估。我們于2012年成功構(gòu)建了TN-/-小鼠模型,并對(duì)不同月齡小鼠骨骼生長(zhǎng)發(fā)育情況進(jìn)行了研究。

研究結(jié)果顯示:與同齡WT小鼠相比,2月齡TN-/-小鼠的Cobb角與同齡WT小鼠相比顯著增大,已經(jīng)出現(xiàn)了明顯的脊柱后凸畸形,且8月齡TN-/-小鼠的Cobb角較2月齡TN-/-小鼠顯著性增大,說明隨月齡增加,TN-/-小鼠的脊柱后凸程度也明顯加重;同時(shí),病理學(xué)檢查顯示:8月齡TN-/-小鼠的胸椎椎間盤結(jié)構(gòu)明顯不對(duì)稱,外側(cè)纖維環(huán)呈增大、疏松改變,而生長(zhǎng)板并未觀察到異常改變,這表明TN-/-小鼠的脊柱后凸很可能是由于胸椎椎間盤病變所致。我們對(duì)8月齡TN-/-小鼠及同齡WT小鼠進(jìn)行BMD及BMC測(cè)定后發(fā)現(xiàn),8月齡TN-/-小鼠全身及第3腰椎、左側(cè)股骨等部位的BMD及BMC均明顯低于同齡WT小鼠,差異有統(tǒng)計(jì)學(xué)意義。這說明8月齡TN-/-小鼠出現(xiàn)了明顯骨量丟失,表現(xiàn)出骨質(zhì)疏松。X線攝片及組織病理學(xué)結(jié)果也與BMD及BMC的測(cè)定結(jié)果相符合,8月齡TN-/-小鼠多處骨骼呈現(xiàn)出BMD減低、骨小梁變細(xì)、稀疏、排列紊亂或斷裂等特點(diǎn),且骨小梁成骨細(xì)胞減少,破骨細(xì)胞增多。

Compaired with WT mice,TN-/-mice exhibited characteristics of thinner,sparse and rupture of femur bone trabeculas (A and B,×100). Decreased osteoblasts (shown in yellow triangle) and increased osteoclasts (shown in red triangle) were observed in the femur bone trabecula of TN-/-mice (C and D,×400). The features of thinner,sparse,disordered arrangement or rupture of bone trabeculas were also observed in the lumbar vertebras of TN-/-mice (E and F,×200)

圖58月齡WT小鼠與TN-/-小鼠股骨、腰椎病理學(xué)變化比較 (HE染色)

Fig 5Pathological section observation of femurs and lumbar vertebras in 8-month-old TN-/-mice and their WT littermates (HE staining)

脊柱后凸畸形嚴(yán)重影響患者的健康生活,可致背部疼痛,甚至發(fā)生嚴(yán)重的神經(jīng)功能損害或截癱,患者較為痛苦且致殘率高。而青年性脊柱后凸畸形,又稱休門病 (Scheuermann’s disease),在普通人群中的發(fā)病率可高達(dá)8.0%[15]。然而,其病因目前尚不清楚。有研究認(rèn)為,休門病的發(fā)生可能與膠原代謝異常有關(guān)[16-17]。我們的研究中發(fā)現(xiàn),TN-/-小鼠在2月齡時(shí)即出現(xiàn)了明顯脊柱后凸畸形,與休門病的表現(xiàn)類似。而TN通過激活蛋白溶解系統(tǒng)與膠原代謝也密切相關(guān)。休門病的發(fā)生過程中是否也發(fā)生了TN基因的突變或缺失？如果是這樣,那么TN-/-小鼠是否可以作為研究休門病的合適的疾病動(dòng)物模型？因此,對(duì)TN的進(jìn)一步研究有可能對(duì)休門病的病理病因研究和早期診治起到重大作用。

骨質(zhì)疏松癥是臨床常見的慢性進(jìn)行性疾病,嚴(yán)重威脅著老齡化人口的健康,其發(fā)生原因主要是骨量的過量丟失。Wewer等[7]研究發(fā)現(xiàn)在骨骼成骨過程中,TN有促進(jìn)骨質(zhì)礦化的作用。本研究中發(fā)現(xiàn),8月齡TN-/-小鼠BMD及BMC明顯降低,骨礦明顯丟失,出現(xiàn)骨質(zhì)疏松的特點(diǎn),X線片也顯示出骨質(zhì)疏松的表現(xiàn),且骨組織病理學(xué)上也呈現(xiàn)出骨質(zhì)疏松的典型特點(diǎn),這與Wewer等[7]的研究結(jié)果相一致。而Iba等[14]的研究數(shù)據(jù)顯示4～6月齡的TN-/-小鼠的全身BMD未明顯降低,原因可能是:(1) 全身BMD僅代表全身BMD的平均水平,不能確切反映出易發(fā)生骨質(zhì)疏松部位的骨質(zhì)變化情況;(2) 骨質(zhì)疏松的發(fā)生和年齡關(guān)系緊密,4～6月齡TN-/-小鼠骨質(zhì)疏松的程度可能尚不明顯。我們對(duì)8月齡TN-/-小鼠的研究中不僅測(cè)量了全身BMD,而且對(duì)腰椎、股骨等骨質(zhì)疏松易累及部位的BMD也進(jìn)行了測(cè)量,同時(shí)還測(cè)定了BMC,從兩個(gè)角度來評(píng)估8月齡TN-/-小鼠的骨質(zhì)疏松情況。并且,股骨和腰椎骨組織病理學(xué)結(jié)果也與BMD及BMC的測(cè)定結(jié)果相符合。結(jié)果顯示8月齡TN-/-小鼠表現(xiàn)出典型骨質(zhì)疏松癥的特征,這為骨質(zhì)疏松癥的研究提供了新的思路。

總而言之,我們的研究結(jié)果進(jìn)一步證實(shí)TN與骨骼生長(zhǎng)發(fā)育相關(guān)的生理過程有著密切聯(lián)系,為進(jìn)一步研究休門病等脊柱后凸畸形及骨質(zhì)疏松癥提供了新的思路。TN-/-小鼠作為一種潛在的脊柱后凸畸形或骨質(zhì)疏松癥疾病動(dòng)物模型具有重要的研究意義。

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Tetranectin knock-out mice exhibit features of kyphosis and osteoporosis

RU De-wen1,YAN Yu-feng1,LI Bing2,XIE Qiang1,TANG Ri1,SHEN Xiao1,YU Guo1,DU Jia-rui1,WANG Er-song1△

(1DepartmentofNeurosurgery,2CentralLaboratory,JinshanHospital,FudanUniversity,Shanghai201508,China)

【Abstract】ObjectiveTo investigate the effect of tetranectin (TN) deletion on mice skeleton growth and development,and to explore the physiological function of TN gene and the relationship between its deletion and diseases.MethodsTN gene knock-out (TN(-/-)) mice were generated by the method of gene homologous recombination.In two-month-old and eight-month-old TN(-/-) mice,X-ray radiography of whole body anteroposterior and lateral position were carried out,and the angle of kyphosis (namely Cobb’s angle) was detected,respectively,as well as their wild-type (WT) littermates. Moreover,bone mineral density (BMD),bone mineral content (BMC),and pathological sections of multisite were examined in eight-month-old TN(-/-) mice and their WT littermates.Results Body weight between TN(-/-) mice and their WT littermates showed no significant difference.Cobb’s angle of both two-month-old and eight-month-old TN(-/- )mice increased significantly compared with their littermates (P<0.01).Cobb’s angle increased significantly with age in TN(-/-) mice (P<0.01).Asymmetric thoracic intervertebral disc structure and expanded and loose fibrous ring of intervertebral disc were distinct in TN(-/-) mice.Compared with their WT littermates,eight-month-old TN(-/-) mice demonstrated a significant decrease of BMD and BMC in the whole body,third lumbar vertebra and left femur (P<0.05).Besides,it was observed that TN(-/- )mice exhibited characteristics of thinner,sparse,and disordered arrangement or rupture of femur and lumbar vertebras bone trabecula with decreased osteoblasts and increased osteoclasts.ConclusionsTN(-/-) mice exhibit features of kyphosis and osteoporosis,which suggests that there is a close relationship between tetranectin and the normal growth and development of skeleton.TN(-/-) mice may be a potential animal model for kyphosis or osteoporosis and deserves further study.

【Key words】tetranectin;gene knock-out;kyphosis;osteoporosis;mice

(收稿日期:2015-08-31;編輯:沈玲)

【中圖分類號(hào)】R682.2

【文獻(xiàn)標(biāo)識(shí)碼】A

doi:10.3969/j.issn.1672-8467.2016.02.006

上海市科學(xué)技術(shù)委員會(huì)基金(124119a1900);上海市衛(wèi)生和計(jì)劃生育委員會(huì)基金(20124339)

△Corresponding authorE-mail:wersong@aliyun.com