两种SIBLING家族蛋白在牙和牙源性肿瘤中的表达及意义
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摘要
属SIBLING蛋白家族成员的牙本质基质蛋白1 (DMP1)和牙本质涎磷蛋白(DSPP),是最早被认为具有牙本质特异性的细胞外基质蛋白。他们的生物学作用主要是是参与牙本质和骨等特异性矿化组织的的形成。但随后的研究发现,SIBLING家族成员可参与肿瘤发生过程。近年,Qin等发现DMP1是以非活性的全长形式合成,后被水解为两个具有活性的功能片段,即N-DMP1和C-DMP1。这两个蛋白片段不仅蛋白质结构和属性不同,而且在细胞和组织中分布不同,因此提示两者可能具有不同的生物学作用。DSPP,牙本质涎磷蛋白,经过类似于DMP1的水解活化过程后形成牙本质涎蛋白(DSP)和牙本质磷蛋白(DPP)。尽管DSPP与DMP1的氨基酸序列不同,但两者之间具有一些特殊关系。例如DSPP和DMP1都对矿化组织的形成起到重要的调节作用;蛋白质结构相似、经历相近的水解活化过程;在牙发育中的分布相似;DMP1可以调节DSPP基因的转录等。牙源性肿瘤主要发生在颌骨内,某些病损具有局部骨内浸润生长的特点,而另一些病损中可见到具有诊断意义的病理性钙化组织。但是,对于这两种SIBLING家族蛋白是否表达在牙源性肿瘤中并且是否参与病理性钙化的形成,尚无研究报道。所以我们设计了本实验。
本研究中我们利用抗C-DMP1、N-DMP1和DSP蛋白的特异性抗体,通过免疫组化技术,首次研究DMP1的不同活性部分以及DSPP在牙源性肿瘤中的表达情况,并探讨他们的表达意义。实验对象选取12例不同发育阶段的人牙胚组织和50例不同类型的牙源性肿瘤的组织切片。牙源性肿瘤中包括:实性成釉细胞瘤23例、牙源性角化囊性瘤14例、牙源性钙化囊性瘤10例、牙源性腺样瘤2例、成釉细胞纤维瘤1例。选用针对C’-末端部分DMP1、N’-末端部分DMP1及DSP的抗体试剂。免疫组化采用SABC法。染色后发现在正常发育的牙胚中和五种牙源性肿瘤中均可表达DMP1的不同活化形式以及DSP。并且C-DMP1和N-DMP1在组织和细胞中的表达部位明显不同,而DMP1和DSP表达结果较为相似。
对实验结果讨论分析后得到以下的结论:一、在正常发育的人牙胚组织中,C-DMP1和N-DMP1表达部位不同,而DMP1和DSP表达相似。这一结果不仅证明了抗体的特异性,而且也进一步证实了在正常牙齿硬组织形成和矿化过程中C-DMP1和N-DMP1可能起到不同的作用,而DMP1和DSP可能具有协同的作用;二、DMP1和DSPP在不同类型牙源性肿瘤中表达,提示它们均可能参与牙源性肿瘤不同的发展过程;三、DMP1不同活性部分和DSP均可表达在病理性钙化组织中,表明他们不仅对正常矿化组织的形成起到作用,而且也可参与牙源性肿瘤中病理性钙化的形成。而C-DMP1和N-DMP1在钙化结构中的表达部位不同,提示DMP1这两个不同的活化形式在病理过程中可能同样起到不同的生物学作用。DMP1与DSP在肿瘤细胞中和病理钙化组织中表达部位相似,提示两者病理条件下也可能具有协同作用。
The extracellular matrix (ECM) of bone and dentin contains a number of noncollagenous proteins (NCPs). One category of NCPs, the SIBLING (Small Integrin-Binding LIgand, N-linked Glycoprotein) family, includes bone sialoprotein (BSP), osteopontin (OPN), dentin matrix protein 1 (DMP1), dentin sialophospho-protein (DSPP), matrix extracellular phosphoglycoprotein (MEPE). Because these polyanionic SIBLING proteins are especially prominent in mineralized tissues and are secreted into the ECM during the formation and mineralization of these tissues, they probably play key biological roles in the mineralization of bone and dentin. At the same time, they are emerging as important players in many stages of cancer progression, including cancer cell adhesion and proliferation, invasion and extracellular matrix degradation, metastasis, complement evasion, microcalcification.
DMP1, dentin matrix protein 1, as predicted from its cDNA sequence, has unusually large numbers of acidic, phosphorylated domains, a property that would be consistent with a role in regulationof matrix mineralization. This purported biological function is supported by observations that transgenic MC3T3-E1 cells overexpressing DMP1 demonstrate higher levels of in vitro mineralization. Furthermore, recombinant DMP1 possesses calcium-binding ability under physiological conditions, suggesting that it could be a nucleator for apatite deposition in vitro. Recent findings from gene knockout mice further indicate a role for DMP1 in mineralization. These DMP1 deficient mice showed reduced levels of dentin along with increased predentin thickness, enlarged pulp chambers, the absence or delayed development of third molars and downregulation of DSPP. The expression of DMP1 in osteocytes was elevated by mechanical stress, suggesting that this molecule may be a key factor in the maintenance of mineralized tissue homeostasis. Recent protein chemistry data indicate that DMP is naturally present as processed fragments in bone or dentin, namely 37 K fragments from the NH2-terminal region and 57 K fragments from the COOH-terminal region. The data indicate that the proteolytic processing of rat DMP1 results from cleavage at the NH2-terminus of four aspartic acid residues in a manner very similar to that of DSPP. Recent studies found that the NH2-terminal and COOH-terminal fragments of DMP1 have different expression patterns which could reflect their potentially distinct roles in the biomineralization of dentin and bone matrices.
Sequencing of the DSPP cDNA indicates that its transcriptsencode a large protein that is proteolytically processed to form two smaller proteins: dentin phosphoprotein (DPP) and dentin sialoprotein (DSP), present as individual molecules in the ECM of dentin. DPP, the most abundant NCP in the ECM of dentin, is an important initiator and modulator for the formation and growth of hydroxyapatite (HA) crystals. While the functions of DSP are presently undefined, sequence data from DSP tryptic peptides, along with comparison to the cDNA-deduced amino acid sequence, showed that processing involves cleavage of two–X–Asp–bonds, similar to those identified in DMP1. The importance of DSPP in dentinogenesis is indicated by observations that mutations in the DSPP gene are associated with dentinogenesis imperfecta in humans and that DSPP gene knockout mice show hypomineralization of dentin, a phenotype similar to the dental manifestations in DMP1 knockout mice.
Although their overall amino acid sequences are dissimilar, DMP1 and DSPP exhibit many similarities: both have very acidic domains that are postulated to be the calciumbinding sites and numerous phosphorylation sites that could play a role in HA formation. Both are proteolytically processed (see above) in a similar fashion and both are critical for dentin mineralization. A close relationship between the two is further supported by the observation that DSPP gene and protein are downregulated in mice lacking the DMP1 gene. The present investigation was performed to test for similarities in the expression of DMP1 and DSPP in tooth development. We observed striking similarities in the distribution of these two molecules at later stages in the formation of rat first molars, suggesting that DMP1 and DSPP may play similar roles in dentinogenesis.
We have noticed that a variety of odontogenic tumours occurring in osseous tissues of the maxillofacial complex demonstrate various amounts of dystrophic calcific structure, and some also exhibit bone and or cementum differentiation. These calcifed products and their nature are of significant importance in accurate histological diagnosis. Aetiology is unknown for the majority of these pathological processes involving the jaws and related structures. To test the hypothesis that different DMP1 activities and DSP is expressed by odontogenic tumour cells, we used histological sections of a number of relatively common odontogenic cysts and tumours and performed immunohistochemical.
The experiment objects are 12 human tooth germs at different stages and 50 paraffinic specimens which diagnosis to Odontogenic Tumors. Normal human tooth germs set as positive control group, include 2 bud stage, 3 cap stage, 2 early bell stage and 3 late bell stage. Odontogenic tumors include 23 Ameloblastomas, 14 keratocystic odontogenic tumor, 10 calcifying cyctic odontogenic tumor, 2 adenomatoid odontogenic tumor and 1 amelobastic fibroma. All of them are rediagnosised by two clinical pathologists following 2005 WHO standard.
All the SIBLING antibodies used for this study were produced in the laboratory of Professor Chunlin Qin (Baylor College of Dentistry, U.S.) and have been previously published. The SIBLING monoclonal antibodies used were 8G10.3 for C-terminal fragment of DMP1, 2C12.3 for DSP. Their polyclonal counterparts 847 sera (affinity purified) and a-DSP sera (affinity purified), respectively, were used to validate corresponding monoclonal antibody results. Anti-N-terminal fragment DMP1 sera are polyclonal 859 sera. Immunohistochemical staining procedure was performed according to SABC method. Each specimen set negative and blank control group to eliminate non-specific stain. Tumor sample were subclassified with regarding ro similar semiquantitative scale by staining intensity and extent.
In the result, we find that C-DMP1 have apparent different distribution compare with N-DMP1 in tumor cell and pathologic calcification tissue. While, DSP stained location are similar with DMP1. (ⅰ) Human tooth germ. Three kinds of protein only detected in late bell stage, before that stage expression were negative or weak positive. In the dentin, NH2-terminal fragment localized to predentin, whereas the COOH-terminal fragment was mainly restricted to mineralized dentin. DSP expressed location similar to C-DMP1. Three form activity protein apparent at same dentingenetic cells, which include preodontoblasts, mature odontoblasts, preameloblasts and secretory ameloblast. However, C-DMP1 and DSP mainly observed in nuclei, while N-DMP1 primarily located in the cytoplasm surrounding the nuclei. (ⅱ)Ameloblastomas. C-DMP1 mainly located in nuclei of tumor cell in stroma and epithelium. DSP expressed in tumor cell nuclei and cytoplasm. But, N-DMP1 observed in cytoplasm of odontogenic tumor epithelium, as well as central cystic area. (ⅲ) Amelobastic Fibroma. C-DMP1, N-DMP1 and DSP expression pattern same as in secretory ameloblast. (ⅳ) Keratocystic Odontogenic Tumor. C-DMP1 positive cells were found throughout the lining cystic epithelium.N-DMP1 positive reaction could be observed in cell nuclei of basal layer, parabasal layer, and superficial para-keratinized layer of OKC. While, DSP immunostained cells were mainly located in the basal layers, and became weaken from deep to shallow layer. (ⅴ)Calcifying Cyctic Odontogenic Tumor, immunohistochemical staining of C-DMP1 was localized in the epithelial cells adjacent to the ghost cell nests. Cells not located in the vicinity of ghost cells showed no immunoreactivity. These features were similar with DSP expression. C-DMP1 and DSP also observed in ghost cell nuclei and their surrounding matrices. However, N-DMP1 could not emerge in nuclei but nonmineralized matrices. (ⅵ)Adenomatoid Odontogenic Tumor. In the epithelium cell, C-DMP1 was weak positive, and DSP was negative. Distinct strong positive C-DMP1 immunostaining was observed in acidophilia substance among epithelium cell. Either amyloid substance or dysplastic dentin-like hyaline material can observe C-DMP1 location. DSP express pattern similar to C-DMP1. N-DMP1 primarily locates in cytoplasm of epithelium and nonmineralized matrices surrounding osteodentin.
According to the observation of the results above all, we can conclude that:Ⅰ. In the human tooth germ, C-DMP1 immunolocalization is different with N-DMP1, it could indicate that them may play distinct roles in the biomineralization of dentin. The unique colocalization of DMP1 and DSPP in tooth development suggests that the two proteins play complementary and/or synergistic roles in formation of healthy teeth.
Ⅱ. Different kinds of odontogenic tumor could express DSP and variant activity DMP1 proteins indicate that the two SIBLING protein can also involve in odontogenic tumor progression.
Ⅲ. The NH2-terminal and COOH-terminal fragments of dentin matrix protein 1 have different expression patterns in dystrophic calcific structure, indicate that two fragments have different biological function in pathological processes, that same to result displayed in normal tissue. Dentin sialoprotein and similar localization compared with DMP1, indicate that two proteins may play complementary and/or synergistic roles in pathological condition, same to which displayed in healthy condition.
本研究中我们利用抗C-DMP1、N-DMP1和DSP蛋白的特异性抗体,通过免疫组化技术,首次研究DMP1的不同活性部分以及DSPP在牙源性肿瘤中的表达情况,并探讨他们的表达意义。实验对象选取12例不同发育阶段的人牙胚组织和50例不同类型的牙源性肿瘤的组织切片。牙源性肿瘤中包括:实性成釉细胞瘤23例、牙源性角化囊性瘤14例、牙源性钙化囊性瘤10例、牙源性腺样瘤2例、成釉细胞纤维瘤1例。选用针对C’-末端部分DMP1、N’-末端部分DMP1及DSP的抗体试剂。免疫组化采用SABC法。染色后发现在正常发育的牙胚中和五种牙源性肿瘤中均可表达DMP1的不同活化形式以及DSP。并且C-DMP1和N-DMP1在组织和细胞中的表达部位明显不同,而DMP1和DSP表达结果较为相似。
对实验结果讨论分析后得到以下的结论:一、在正常发育的人牙胚组织中,C-DMP1和N-DMP1表达部位不同,而DMP1和DSP表达相似。这一结果不仅证明了抗体的特异性,而且也进一步证实了在正常牙齿硬组织形成和矿化过程中C-DMP1和N-DMP1可能起到不同的作用,而DMP1和DSP可能具有协同的作用;二、DMP1和DSPP在不同类型牙源性肿瘤中表达,提示它们均可能参与牙源性肿瘤不同的发展过程;三、DMP1不同活性部分和DSP均可表达在病理性钙化组织中,表明他们不仅对正常矿化组织的形成起到作用,而且也可参与牙源性肿瘤中病理性钙化的形成。而C-DMP1和N-DMP1在钙化结构中的表达部位不同,提示DMP1这两个不同的活化形式在病理过程中可能同样起到不同的生物学作用。DMP1与DSP在肿瘤细胞中和病理钙化组织中表达部位相似,提示两者病理条件下也可能具有协同作用。
The extracellular matrix (ECM) of bone and dentin contains a number of noncollagenous proteins (NCPs). One category of NCPs, the SIBLING (Small Integrin-Binding LIgand, N-linked Glycoprotein) family, includes bone sialoprotein (BSP), osteopontin (OPN), dentin matrix protein 1 (DMP1), dentin sialophospho-protein (DSPP), matrix extracellular phosphoglycoprotein (MEPE). Because these polyanionic SIBLING proteins are especially prominent in mineralized tissues and are secreted into the ECM during the formation and mineralization of these tissues, they probably play key biological roles in the mineralization of bone and dentin. At the same time, they are emerging as important players in many stages of cancer progression, including cancer cell adhesion and proliferation, invasion and extracellular matrix degradation, metastasis, complement evasion, microcalcification.
DMP1, dentin matrix protein 1, as predicted from its cDNA sequence, has unusually large numbers of acidic, phosphorylated domains, a property that would be consistent with a role in regulationof matrix mineralization. This purported biological function is supported by observations that transgenic MC3T3-E1 cells overexpressing DMP1 demonstrate higher levels of in vitro mineralization. Furthermore, recombinant DMP1 possesses calcium-binding ability under physiological conditions, suggesting that it could be a nucleator for apatite deposition in vitro. Recent findings from gene knockout mice further indicate a role for DMP1 in mineralization. These DMP1 deficient mice showed reduced levels of dentin along with increased predentin thickness, enlarged pulp chambers, the absence or delayed development of third molars and downregulation of DSPP. The expression of DMP1 in osteocytes was elevated by mechanical stress, suggesting that this molecule may be a key factor in the maintenance of mineralized tissue homeostasis. Recent protein chemistry data indicate that DMP is naturally present as processed fragments in bone or dentin, namely 37 K fragments from the NH2-terminal region and 57 K fragments from the COOH-terminal region. The data indicate that the proteolytic processing of rat DMP1 results from cleavage at the NH2-terminus of four aspartic acid residues in a manner very similar to that of DSPP. Recent studies found that the NH2-terminal and COOH-terminal fragments of DMP1 have different expression patterns which could reflect their potentially distinct roles in the biomineralization of dentin and bone matrices.
Sequencing of the DSPP cDNA indicates that its transcriptsencode a large protein that is proteolytically processed to form two smaller proteins: dentin phosphoprotein (DPP) and dentin sialoprotein (DSP), present as individual molecules in the ECM of dentin. DPP, the most abundant NCP in the ECM of dentin, is an important initiator and modulator for the formation and growth of hydroxyapatite (HA) crystals. While the functions of DSP are presently undefined, sequence data from DSP tryptic peptides, along with comparison to the cDNA-deduced amino acid sequence, showed that processing involves cleavage of two–X–Asp–bonds, similar to those identified in DMP1. The importance of DSPP in dentinogenesis is indicated by observations that mutations in the DSPP gene are associated with dentinogenesis imperfecta in humans and that DSPP gene knockout mice show hypomineralization of dentin, a phenotype similar to the dental manifestations in DMP1 knockout mice.
Although their overall amino acid sequences are dissimilar, DMP1 and DSPP exhibit many similarities: both have very acidic domains that are postulated to be the calciumbinding sites and numerous phosphorylation sites that could play a role in HA formation. Both are proteolytically processed (see above) in a similar fashion and both are critical for dentin mineralization. A close relationship between the two is further supported by the observation that DSPP gene and protein are downregulated in mice lacking the DMP1 gene. The present investigation was performed to test for similarities in the expression of DMP1 and DSPP in tooth development. We observed striking similarities in the distribution of these two molecules at later stages in the formation of rat first molars, suggesting that DMP1 and DSPP may play similar roles in dentinogenesis.
We have noticed that a variety of odontogenic tumours occurring in osseous tissues of the maxillofacial complex demonstrate various amounts of dystrophic calcific structure, and some also exhibit bone and or cementum differentiation. These calcifed products and their nature are of significant importance in accurate histological diagnosis. Aetiology is unknown for the majority of these pathological processes involving the jaws and related structures. To test the hypothesis that different DMP1 activities and DSP is expressed by odontogenic tumour cells, we used histological sections of a number of relatively common odontogenic cysts and tumours and performed immunohistochemical.
The experiment objects are 12 human tooth germs at different stages and 50 paraffinic specimens which diagnosis to Odontogenic Tumors. Normal human tooth germs set as positive control group, include 2 bud stage, 3 cap stage, 2 early bell stage and 3 late bell stage. Odontogenic tumors include 23 Ameloblastomas, 14 keratocystic odontogenic tumor, 10 calcifying cyctic odontogenic tumor, 2 adenomatoid odontogenic tumor and 1 amelobastic fibroma. All of them are rediagnosised by two clinical pathologists following 2005 WHO standard.
All the SIBLING antibodies used for this study were produced in the laboratory of Professor Chunlin Qin (Baylor College of Dentistry, U.S.) and have been previously published. The SIBLING monoclonal antibodies used were 8G10.3 for C-terminal fragment of DMP1, 2C12.3 for DSP. Their polyclonal counterparts 847 sera (affinity purified) and a-DSP sera (affinity purified), respectively, were used to validate corresponding monoclonal antibody results. Anti-N-terminal fragment DMP1 sera are polyclonal 859 sera. Immunohistochemical staining procedure was performed according to SABC method. Each specimen set negative and blank control group to eliminate non-specific stain. Tumor sample were subclassified with regarding ro similar semiquantitative scale by staining intensity and extent.
In the result, we find that C-DMP1 have apparent different distribution compare with N-DMP1 in tumor cell and pathologic calcification tissue. While, DSP stained location are similar with DMP1. (ⅰ) Human tooth germ. Three kinds of protein only detected in late bell stage, before that stage expression were negative or weak positive. In the dentin, NH2-terminal fragment localized to predentin, whereas the COOH-terminal fragment was mainly restricted to mineralized dentin. DSP expressed location similar to C-DMP1. Three form activity protein apparent at same dentingenetic cells, which include preodontoblasts, mature odontoblasts, preameloblasts and secretory ameloblast. However, C-DMP1 and DSP mainly observed in nuclei, while N-DMP1 primarily located in the cytoplasm surrounding the nuclei. (ⅱ)Ameloblastomas. C-DMP1 mainly located in nuclei of tumor cell in stroma and epithelium. DSP expressed in tumor cell nuclei and cytoplasm. But, N-DMP1 observed in cytoplasm of odontogenic tumor epithelium, as well as central cystic area. (ⅲ) Amelobastic Fibroma. C-DMP1, N-DMP1 and DSP expression pattern same as in secretory ameloblast. (ⅳ) Keratocystic Odontogenic Tumor. C-DMP1 positive cells were found throughout the lining cystic epithelium.N-DMP1 positive reaction could be observed in cell nuclei of basal layer, parabasal layer, and superficial para-keratinized layer of OKC. While, DSP immunostained cells were mainly located in the basal layers, and became weaken from deep to shallow layer. (ⅴ)Calcifying Cyctic Odontogenic Tumor, immunohistochemical staining of C-DMP1 was localized in the epithelial cells adjacent to the ghost cell nests. Cells not located in the vicinity of ghost cells showed no immunoreactivity. These features were similar with DSP expression. C-DMP1 and DSP also observed in ghost cell nuclei and their surrounding matrices. However, N-DMP1 could not emerge in nuclei but nonmineralized matrices. (ⅵ)Adenomatoid Odontogenic Tumor. In the epithelium cell, C-DMP1 was weak positive, and DSP was negative. Distinct strong positive C-DMP1 immunostaining was observed in acidophilia substance among epithelium cell. Either amyloid substance or dysplastic dentin-like hyaline material can observe C-DMP1 location. DSP express pattern similar to C-DMP1. N-DMP1 primarily locates in cytoplasm of epithelium and nonmineralized matrices surrounding osteodentin.
According to the observation of the results above all, we can conclude that:Ⅰ. In the human tooth germ, C-DMP1 immunolocalization is different with N-DMP1, it could indicate that them may play distinct roles in the biomineralization of dentin. The unique colocalization of DMP1 and DSPP in tooth development suggests that the two proteins play complementary and/or synergistic roles in formation of healthy teeth.
Ⅱ. Different kinds of odontogenic tumor could express DSP and variant activity DMP1 proteins indicate that the two SIBLING protein can also involve in odontogenic tumor progression.
Ⅲ. The NH2-terminal and COOH-terminal fragments of dentin matrix protein 1 have different expression patterns in dystrophic calcific structure, indicate that two fragments have different biological function in pathological processes, that same to result displayed in normal tissue. Dentin sialoprotein and similar localization compared with DMP1, indicate that two proteins may play complementary and/or synergistic roles in pathological condition, same to which displayed in healthy condition.
引文
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