成纤维细胞生长因子受体3（FGFR3）对骨形成的直接调控作用
发布时间：2019-05-19 14:13
【摘要】：成纤维细胞生长因子受体(fibroblast growth factor receptors, FGFRs)属于受体酪氨酸蛋白激酶(receptor tyrosine kinase, RTK)家族。目前已发现4种FGFRs,即FGFR1、FGFR2、FGFR3、FGFR4。它们之间在氨基酸水平有55%~72%的一致性。 既往研究表明,FGF/FGFRs信号通路与骨骼发育、再生和骨骼疾病有密切联系。FGFR1、2、3功能增强或丧失突变可导致包括颅缝早闭(craniosynostosis, CS)、软骨发育不全(achondroplasia, ACH)和CATSHL (camptodactyly, tall stature, scoliosis, and hearing loss)综合征在内的多种人类骨骼系统遗传性疾病。 骨骼的发育是通过软骨内成骨(endochondral ossification)和膜内成骨(intramembranous ossification)两种方式来完成的。软骨内成骨又经过软骨形成(chondrogenesis)和骨形成(osteogensis)两个密切相关的过程。而膜内成骨则是一个单独的骨形成的过程,即间充质密集后直接分化为成骨细胞并成骨。 不同的FGFRs在软骨形成和骨形成过程中的作用不一致。总的讲,目前认为FGFR1、2主要调节膜内成骨过程,而FGFR3则主要参与调控软骨内成骨。已发现人类FGFR1(P252R)功能增强点突变和多种FGFR2功能增强点突变可影响颅缝膜内成骨过程,导致颅缝提前闭合,引起囟门早闭综合征;而FGFR3功能增强点突变通过抑制生长板软骨发育,导致软骨发育不全等软骨发育障碍性疾病。 FGFR3和FGFR1、2高度同源,也受可调节骨形成的内源性配体FGF2、18等激活,提示FGFR3可能参与调控骨形成过程。而人类FGFR3 A391E功能增强型点突变可引起Crouzon等囟门早闭征,则是FGFR3影响骨形成的直接证据。模拟人ACH的FGFR3突变小鼠出生后15天长骨骨小梁处成骨细胞分化标志基因Cbfa1等表达水平增高,成年期骨量减少;FGFR3敲除小鼠骨量减少,骨小梁矿化障碍。这些结果均提示FGFR3可影响成骨细胞功能和骨形成过程。 目前已有多名学者报道利用条件性基因敲除小鼠研究FGFR1、2对成骨细胞的直接调控作用,但关于FGFR3对成骨细胞及骨形成的直接调控作用及机制还不完全清楚。 骨损伤后的再生修复是局部骨骼的再发育过程。一些参与调控骨骼发育的分子如IHH/PTHrP、BMPs、Wnt等在骨再生过程中也起着重要调控作用。研究发现,FGFR3参与调节骨损伤后的再生过程,且在一定程度上,FGFR3对骨再生和骨生长发育中的软骨内成骨过程可能发挥相似的负性调控作用。而Rundle等发现FGFR3表达于骨折部位成骨细胞和骨膜下间充质细胞,提示FGFR3直接参与调控骨再生过程中的成骨细胞骨形成过程。那么FGFR3在骨再生过程中对成骨细胞骨形成的影响是否与FGFR3在成年期骨重建中的作用类似呢? 据此,本课题用成骨细胞特异性表达FGFR3功能增强点突变(FGFR3 K644E,Oc-cre)小鼠和模拟人软骨发育不全的FGFR3功能增强点突变(FGFR3~(G369C/+))小鼠两种基因敲入小鼠模型为研究对象,探讨生理和病理(骨损伤)情况下,FGFR3对成骨细胞及骨形成的直接调控作用。 主要研究内容 第一部分:成骨细胞特异性表达含功能增强点突变FGFR3对成年期小鼠骨形成的影响 1.对成骨细胞特异性表达FGFR3功能增强点突变(FGFR3K644E,Oc-cre)小鼠身长,尾长,体重等形态学指标进行大体观察。 2.利用藏红固绿染色观察新生小鼠胫骨生长板软骨发育情况。 3.利用X线摄片和Micro-CT观察成年小鼠股骨骨密度及骨组织结构的变化。 4.通过HE染色、钙绿素双标实验观察小鼠胫骨骨小梁的结构及矿化情况;测定血清钙磷含量,了解体内钙磷水平是否受骨骼代谢异常影响;定量PCR检测成骨细胞分化标志基因Cbfa1、OC、OP、Col1a1等的表达变化。 5.小鼠颅骨成骨细胞分离培养,测定生长曲线并进行成骨诱导。通过碱性磷酸酶染色、茜素红染色观察,结合检测成骨相关基因Cbfa1、OC、OP、Col1a1以及FGFR1、FGFR2和BMPRIA的表达,观察成骨细胞分化和矿化情况。 6.通过TRAP染色观察胫骨破骨细胞形成及活性。 第二部分:FGFR3功能增强对小鼠胫骨骨皮质损伤修复过程的影响 1.建立FGFR3功能增强小鼠(FGFR3~(G369C/+))胫骨皮质缺损模型。 2.利用HE染色和Micro-CT重建分析观察骨再生情况。 3.定量PCR检测新生骨组织中成骨细胞分化相关基因Cbfa1、OC、OP、Col1a1等mRNA水平表达变化。 主要实验结果 一. FGFR3K644E,Oc-cre小鼠骨形成增加,体型变小 1.成年期(2月龄)FGFR3K644E,Oc-cre小鼠体型变小,体重减轻;新生小鼠长骨生长板软骨发育无异常。 2.成年期FGFR3K644E,Oc-cre小鼠骨量增多,骨形成增加X线摄片显示FGFR3K644E,Oc-cre小鼠股骨放射密度增高;Micro-CT扫描显示FGFR3K644E,Oc-cre小鼠BV/TV,骨小梁数量( Tb.N)及骨小梁厚度( Tb.Th)均显著升高;HE染色FGFR3K644E,Oc-cre小鼠干骺端和骨骺部位骨小梁较野生小鼠明显增多、增长、增粗。提示成年期FGFR3K644E,Oc-cre骨量增多,骨形成增加。 3. FGFR3K644E,Oc-cre小鼠成骨细胞分化增强,矿化障碍 1) 2月龄FGFR3K644E,Oc-cre小鼠胫骨骨组织中成骨细胞分化标志基因Cbfa1、OP和Col1a1表达上调,表明成骨细胞分化增强;钙绿素双标实验提示FGFR3 K644E,Oc-cre小鼠矿化能力减弱;体内血清钙磷含量正常,提示骨骼矿化障碍没有影响全身钙磷水平。 2) FGFR3K644E,Oc-cre小鼠颅骨成骨细胞增殖减慢;经成骨诱导培养后碱性磷酸酶表达增加,钙结节形成减少;成骨细胞分化标志基因Cbfa1、OP、OC、Col1a1表达均显著上调,表明成骨细胞分化增强,矿化降低。 3) FGFR3K644E,Oc-cre小鼠成骨相关基因FGFR1、FGFR2及BMPRIA表达下调。 4.FGFR3K644E,Oc-cre小鼠破骨细胞骨吸收作用没有改变TRAP染色后计数结果显示FGFR3K644E,Oc-cre小鼠胫骨单位骨小梁面积上的破骨细胞数量与野生小鼠无明显差别,提示FGFR3K644E,Oc-cre小鼠破骨细胞数量及功能无明显改变。 二. FGFR3~(G369C/+)小鼠胫骨骨皮质损伤愈合延迟 1. FGFR3~(G369C/+)小鼠骨皮质损伤后局部新生骨组织增多Micro-CT扫描重建分析及HE染色显示FGFR3~(G369C/+)小鼠损伤局部新生骨组织数量和体积较野生小鼠增加;新生骨组织成骨细胞分化标记基因Cbfa1、OP等表达显著上调,提示成骨细胞分化增强。 2. FGFR3~(G369C/+)小鼠皮质骨愈合延迟MicroCT扫描重建分析及HE染色显示在损伤后第21天,野生型小鼠和FGFR3~(G369C/+)小鼠在皮质缺损处都出现了新生板层骨,但FGFR3~(G369C/+)小鼠的新生骨皮质厚度要小于野生小鼠。 主要结论 1.成骨细胞特异性表达FGFR3功能增强点突变小鼠体型变小,但生长板软骨未见明显异常,提示成骨异常在ACH侏儒体型发生中有一定作用。 2.成骨细胞特异性表达FGFR3功能增强点突变小鼠成年期骨形成增加,导致骨量增多。 3. FGFR3功能增强促进成骨细胞分化,抑制其矿化。 4. FGFR3功能增强对成骨细胞的影响可能部分是通过FGFR1、FGFR2及BMPRIA的继发性改变所致。 5. FGFR3功能增强导致小鼠骨皮质缺损愈合延迟。
[Abstract]:Fibroblast growth factor receptors (FGFRs) belong to the receptor tyrosine kinase (RTK) family. Four FGFRs, FGFR1, FGFR2, FGFR3, and FGFR4 have been found. And the amino acid level is between 55 and 72 percent. Previous studies have shown that the FGF/ FGFRs signaling pathway is closely related to bone development, regeneration and skeletal diseases Contact. FGFR1,2,3 functional enhancement or loss of mutations can lead to a variety of human skeletal system heritages, including cranio-early-closure (CS), achondroplasia, ACH, and CATSHL syndrome The development of the bone is through the endochondral bone and the intramembranous ossification. The endochondral bone, in turn, is formed by the formation of the cartilage and the bone formation (ostegosis). The process of bone formation is the process of the formation of a single bone, that is, the direct differentiation of the mesenchyme into the bone. The cells are not osteogenic. Different FGFRs are formed in the form of cartilage and bone. In general, FGFR1,2 mainly regulate the osteogenesis in the membrane, while FGFR3 is the main parameter. It has been found that human FGFR1 (P252R) function-enhanced point mutation and a variety of FGFR2 function-enhanced point mutations can affect the osteogenic process in the cranio-suture membrane, resulting in premature closure of the cranial suture, resulting in an early-closure syndrome, while the FGFR3 function-enhancing point mutation is through inhibition The development of the cartilage of the growth plate, which leads to the soft development of the cartilage, etc. Bone developmental disorders. FGFR3 and FGFR1,2 are highly homologous, and are also activated by the endogenous ligands FGF2,18, which can modulate bone formation, suggesting that FGFR3 It is possible to participate in the regulation of the bone formation process, while the human FGFR3 A391E functional enhancement point mutation can cause early closure of the Crouzon et al., and is the FGFR 3. Direct evidence of the formation of bone. The expression level of the osteoblast differentiation marker gene Cbfa1 was increased at 15 days after the birth of the FGFR3 mutant of the human ACH, and the expression level of the osteoblast differentiation marker gene Cbfa1 in the bone trabecula at 15 days after the birth of the mouse was increased, and the amount of the adult bone decreased; and the FGFR3 knocked out the mouse bone. The amount of bone trabecula is reduced, and the bone trabeculectomy is an obstacle. These results suggest that FGFR3 can be affected. Osteoclasts function and bone formation process. Several scholars have reported that using the conditional gene knockout mice to study the direct regulatory action of FGFR1,2 on osteoblasts, but with respect to the direct effect of FGFR3 on the formation of osteoblasts and bone The action and mechanism of the grafting are not completely clear. The bone injury The post-regeneration repair is the re-development of the local bone. Some molecules involved in the control of bone development, such as IHH/ PTHrP, BMPs, Wnt, It is found that FGFR3 is involved in the regeneration of bone regeneration and, to some extent, FGFR3 plays an important role in the regeneration of bone and in the growth and development of bone. The osteogenic process may play a similar negative control role, and Rundle et al. found that FGFR3 is expressed in the bone and subperiosteal mesenchymal cells of the fracture site, suggesting that FGFR3 is directly involved in the regulation. In the process of bone regeneration, the effect of FGFR3 on the bone formation of osteoblasts in the process of bone regeneration is similar to that of FG The role of FR3 in the reconstruction of the adult bone is similar, according to which the function of FGFR3 functional enhancement point mutation (FGFR3 K644E, Oc-cre) and the FGFR3 functional enhancement point mutation (FGFR3-(G369C/ +) The two genes of the mouse were knocked into the mouse model to study the object, and the physiological and pathological changes (bone injury) were discussed. GFR3 pair to Direct regulatory effects of osteocytes and bone formation. Part 1: Osteoblastic specificity Effect of the expression of FGFR3 with functional enhancement point mutation on bone formation in adult mice 1. The expression of FGFR3 in the osteoblast-specific expression was enhanced. Point mutation (FGFR3 K644E, The morphology of Oc-cre (Oc-cre) mouse's body length, tail length, body weight, etc. A.2. The development of the growth plate of the tibial growth plate of the newly-born mouse was observed by using the red solid green staining. Changes of bone mineral density and bone structure in adult mice were observed by X-ray film and Micro-CT.4. The structure and mineralization of the bone trabecula of the tibia were observed by HE staining and calcium-green-green double-scale experiment. The content of serum calcium and phosphorus was determined. Affected by bone metabolism; quantitative P CR detection of osteoblast differentiation marker gene Cbfa1, OC, OP, Chol 1. The expression changes of 1a1 and so on.5. The mouse's skull osteoblast was isolated and cultured, the growth curve was determined and the osteogenic induction was performed. The bone formation-related genes Cbfa1, OC, OP, Co were detected by the staining of alkaline phosphatase and the red staining of the bone. l1a1 and FGFR1, FGFR2, and BMPRIA The expression of TRAP was used to study the differentiation and mineralization of the osteoblast. To observe the formation and activity of osteoclast in the tibia. The second part: the function of FGFR3 enhances the damage to the cortical bone of the tibia. Effect of the repair process 1. Establishment of a FGFR3 function-enhancing mouse (FGF 3 ~ (G369C/ +)) tibial cortical defect model.2. The bone regeneration was observed by HE staining and micro-CT reconstruction. 3. Quantitation PC R. Detection of the Osteoblastic Differentiation-related Genes Cbfa1, OC, O in the New Bone Tissue Changes of mRNA level in P, Col1a1, etc. The main results are as follows: 1.FGFR3 K644E, Oc-cre mouse bone formation The body size decreased 1. The size of the FGFR3 K644E and Oc-cre mice became smaller and weight loss in the adult mice.2. The growth of the growth plate of the long bone in the new mice was not abnormal.2. The bone mass of FGFR3 K644E and Oc-cre mice increased, and the bone formation increased the X-ray film to show the increase of the radial density of the femur in the Oc-cre mice, and the micro-CT scan showed F. GFR3K644E, Oc-cre mice BV/ TV, trabecular number (Tb. N) and the thickness of the bone trabecula (Tb. Th) increased significantly; the HE staining of FGFR3 K644E In the Oc-cre mice, the bone trabecula of the dry and bone parts of the mouse was significantly increased, the growth and the increase of the bone trabecula were increased. 2-month-old FGFR3 K644E, Oc-cre mouse osteoblast differentiation enhancement, mineralization disorder 1)2-month-old FGFR3 K644E, Oc-cre mouse tibia bone tissue Up-regulation of expression of Cbfa1, OP and Col1a1 in bone cell differentiation marker genes, and Table The results showed that the bone mineralizing ability of FGFR3 K644E and Oc-cre mice was weakened, and the serum calcium and phosphorus content in the body was normal, suggesting that the bone mineralization disorder did not affect the whole body calcium and phosphorus level. The expression of alkaline phosphatase after osteoinductive culture is increased, and the formation of calcium nodules is reduced; and the osteoblast differentiation marker gene Cbfa1, OP, OC, Co The expression of l1a1 was up-regulated, indicating that the osteoblast differentiation was enhanced and the mineralization decreased.3) The expression of FGFR3 K644E, Oc-cre osteogenic related genes FGFR1, FGFR2 and BMPRIA was down-regulated. show F GFR3K644E, Oc-cre mouse tibial unit bone trabecula area No significant difference was found between the number of osteoclasts and wild mice, suggesting that the number and function of osteoclast in FGFR3 K644E and Oc-cre mice did not change significantly. Micro-CT scan and reconstruction of locally-born bone tissue after bone-cortical injury in FR3-(G369C/ +) mice Analysis and HE staining showed that the number and volume of local new bone tissue in FGFR3-(G369C/ +) mice increased significantly, and the expression of Cbfa1, OP and so on in new bone tissue was up-regulated, suggesting that the differentiation of osteoblasts was enhanced. reconstruction and analysis and HE staining showed a new lamellar bone in both wild-type and FGFR3-(G369C/ +) mice at the 21-day post-injury, but FGFR3-(G36 9 C/ +) The thickness of the new bone cortex of the mice is less than that of the wild mice. The expression of FGFR3 functional enhancement point mutant mice was small, but the growth plate There was no obvious abnormality in the cartilage, suggesting that the osteogenic abnormality could play a role in the body type of the ACH dwarf.2. The osteoblast-specific expression of the FGFR3 function The increase of the bone formation in the formation of the enhanced point mutant mice leads to an increase in bone mass.
【学位授予单位】：第三军医大学
【学位级别】：硕士
【学位授予年份】：2011
【分类号】：R363
[Abstract]:Fibroblast growth factor receptors (FGFRs) belong to the receptor tyrosine kinase (RTK) family. Four FGFRs, FGFR1, FGFR2, FGFR3, and FGFR4 have been found. And the amino acid level is between 55 and 72 percent. Previous studies have shown that the FGF/ FGFRs signaling pathway is closely related to bone development, regeneration and skeletal diseases Contact. FGFR1,2,3 functional enhancement or loss of mutations can lead to a variety of human skeletal system heritages, including cranio-early-closure (CS), achondroplasia, ACH, and CATSHL syndrome The development of the bone is through the endochondral bone and the intramembranous ossification. The endochondral bone, in turn, is formed by the formation of the cartilage and the bone formation (ostegosis). The process of bone formation is the process of the formation of a single bone, that is, the direct differentiation of the mesenchyme into the bone. The cells are not osteogenic. Different FGFRs are formed in the form of cartilage and bone. In general, FGFR1,2 mainly regulate the osteogenesis in the membrane, while FGFR3 is the main parameter. It has been found that human FGFR1 (P252R) function-enhanced point mutation and a variety of FGFR2 function-enhanced point mutations can affect the osteogenic process in the cranio-suture membrane, resulting in premature closure of the cranial suture, resulting in an early-closure syndrome, while the FGFR3 function-enhancing point mutation is through inhibition The development of the cartilage of the growth plate, which leads to the soft development of the cartilage, etc. Bone developmental disorders. FGFR3 and FGFR1,2 are highly homologous, and are also activated by the endogenous ligands FGF2,18, which can modulate bone formation, suggesting that FGFR3 It is possible to participate in the regulation of the bone formation process, while the human FGFR3 A391E functional enhancement point mutation can cause early closure of the Crouzon et al., and is the FGFR 3. Direct evidence of the formation of bone. The expression level of the osteoblast differentiation marker gene Cbfa1 was increased at 15 days after the birth of the FGFR3 mutant of the human ACH, and the expression level of the osteoblast differentiation marker gene Cbfa1 in the bone trabecula at 15 days after the birth of the mouse was increased, and the amount of the adult bone decreased; and the FGFR3 knocked out the mouse bone. The amount of bone trabecula is reduced, and the bone trabeculectomy is an obstacle. These results suggest that FGFR3 can be affected. Osteoclasts function and bone formation process. Several scholars have reported that using the conditional gene knockout mice to study the direct regulatory action of FGFR1,2 on osteoblasts, but with respect to the direct effect of FGFR3 on the formation of osteoblasts and bone The action and mechanism of the grafting are not completely clear. The bone injury The post-regeneration repair is the re-development of the local bone. Some molecules involved in the control of bone development, such as IHH/ PTHrP, BMPs, Wnt, It is found that FGFR3 is involved in the regeneration of bone regeneration and, to some extent, FGFR3 plays an important role in the regeneration of bone and in the growth and development of bone. The osteogenic process may play a similar negative control role, and Rundle et al. found that FGFR3 is expressed in the bone and subperiosteal mesenchymal cells of the fracture site, suggesting that FGFR3 is directly involved in the regulation. In the process of bone regeneration, the effect of FGFR3 on the bone formation of osteoblasts in the process of bone regeneration is similar to that of FG The role of FR3 in the reconstruction of the adult bone is similar, according to which the function of FGFR3 functional enhancement point mutation (FGFR3 K644E, Oc-cre) and the FGFR3 functional enhancement point mutation (FGFR3-(G369C/ +) The two genes of the mouse were knocked into the mouse model to study the object, and the physiological and pathological changes (bone injury) were discussed. GFR3 pair to Direct regulatory effects of osteocytes and bone formation. Part 1: Osteoblastic specificity Effect of the expression of FGFR3 with functional enhancement point mutation on bone formation in adult mice 1. The expression of FGFR3 in the osteoblast-specific expression was enhanced. Point mutation (FGFR3 K644E, The morphology of Oc-cre (Oc-cre) mouse's body length, tail length, body weight, etc. A.2. The development of the growth plate of the tibial growth plate of the newly-born mouse was observed by using the red solid green staining. Changes of bone mineral density and bone structure in adult mice were observed by X-ray film and Micro-CT.4. The structure and mineralization of the bone trabecula of the tibia were observed by HE staining and calcium-green-green double-scale experiment. The content of serum calcium and phosphorus was determined. Affected by bone metabolism; quantitative P CR detection of osteoblast differentiation marker gene Cbfa1, OC, OP, Chol 1. The expression changes of 1a1 and so on.5. The mouse's skull osteoblast was isolated and cultured, the growth curve was determined and the osteogenic induction was performed. The bone formation-related genes Cbfa1, OC, OP, Co were detected by the staining of alkaline phosphatase and the red staining of the bone. l1a1 and FGFR1, FGFR2, and BMPRIA The expression of TRAP was used to study the differentiation and mineralization of the osteoblast. To observe the formation and activity of osteoclast in the tibia. The second part: the function of FGFR3 enhances the damage to the cortical bone of the tibia. Effect of the repair process 1. Establishment of a FGFR3 function-enhancing mouse (FGF 3 ~ (G369C/ +)) tibial cortical defect model.2. The bone regeneration was observed by HE staining and micro-CT reconstruction. 3. Quantitation PC R. Detection of the Osteoblastic Differentiation-related Genes Cbfa1, OC, O in the New Bone Tissue Changes of mRNA level in P, Col1a1, etc. The main results are as follows: 1.FGFR3 K644E, Oc-cre mouse bone formation The body size decreased 1. The size of the FGFR3 K644E and Oc-cre mice became smaller and weight loss in the adult mice.2. The growth of the growth plate of the long bone in the new mice was not abnormal.2. The bone mass of FGFR3 K644E and Oc-cre mice increased, and the bone formation increased the X-ray film to show the increase of the radial density of the femur in the Oc-cre mice, and the micro-CT scan showed F. GFR3K644E, Oc-cre mice BV/ TV, trabecular number (Tb. N) and the thickness of the bone trabecula (Tb. Th) increased significantly; the HE staining of FGFR3 K644E In the Oc-cre mice, the bone trabecula of the dry and bone parts of the mouse was significantly increased, the growth and the increase of the bone trabecula were increased. 2-month-old FGFR3 K644E, Oc-cre mouse osteoblast differentiation enhancement, mineralization disorder 1)2-month-old FGFR3 K644E, Oc-cre mouse tibia bone tissue Up-regulation of expression of Cbfa1, OP and Col1a1 in bone cell differentiation marker genes, and Table The results showed that the bone mineralizing ability of FGFR3 K644E and Oc-cre mice was weakened, and the serum calcium and phosphorus content in the body was normal, suggesting that the bone mineralization disorder did not affect the whole body calcium and phosphorus level. The expression of alkaline phosphatase after osteoinductive culture is increased, and the formation of calcium nodules is reduced; and the osteoblast differentiation marker gene Cbfa1, OP, OC, Co The expression of l1a1 was up-regulated, indicating that the osteoblast differentiation was enhanced and the mineralization decreased.3) The expression of FGFR3 K644E, Oc-cre osteogenic related genes FGFR1, FGFR2 and BMPRIA was down-regulated. show F GFR3K644E, Oc-cre mouse tibial unit bone trabecula area No significant difference was found between the number of osteoclasts and wild mice, suggesting that the number and function of osteoclast in FGFR3 K644E and Oc-cre mice did not change significantly. Micro-CT scan and reconstruction of locally-born bone tissue after bone-cortical injury in FR3-(G369C/ +) mice Analysis and HE staining showed that the number and volume of local new bone tissue in FGFR3-(G369C/ +) mice increased significantly, and the expression of Cbfa1, OP and so on in new bone tissue was up-regulated, suggesting that the differentiation of osteoblasts was enhanced. reconstruction and analysis and HE staining showed a new lamellar bone in both wild-type and FGFR3-(G369C/ +) mice at the 21-day post-injury, but FGFR3-(G36 9 C/ +) The thickness of the new bone cortex of the mice is less than that of the wild mice. The expression of FGFR3 functional enhancement point mutant mice was small, but the growth plate There was no obvious abnormality in the cartilage, suggesting that the osteogenic abnormality could play a role in the body type of the ACH dwarf.2. The osteoblast-specific expression of the FGFR3 function The increase of the bone formation in the formation of the enhanced point mutant mice leads to an increase in bone mass.
【学位授予单位】：第三军医大学
【学位级别】：硕士
【学位授予年份】：2011
【分类号】：R363
【共引文献】
相关期刊论文 前8条
1 周锐;苏楠;李灿;陈思宇;谢杨丽;陈林;;小鼠胫骨骨皮质损伤修复过程中成纤维生长因子受体的表达[J];第三军医大学学报;2011年10期
2 吴莉萍;凌均h，
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