Odontoblast Dysfunction in Osteogenesis Imperfecta: An LM,SEM, and Ultrastructural Study

The inherited dentin defect dentinogenesis imperfecta (DI), while clinically obvious in osteogenesis imperfecta (OI) Types IB and IC, II, III, and IVB, is now thought to be present in all children with OI, in a continuum from minimal to severe dentin pathology. This collaborative study further clarifies the structural and ultrastructural dentin changes in the teeth of OI children with clinically obvious DI, and attempts to explain these in terms of odontoblast dysfunction. Collaborative studies were carried out in Melbourne, Australia, and Strasbourg, France, using light and polarized-light microscopy, scanning and transmission electron microscopy (SEM, TEM), selected-area diffraction (SAD), and x-ray spectroscopy (EDX). These showed structurally normal enamel (but containing long and broad lamellae) and a normally scalloped dentino-enamel junction (DEJ), but severe pathologic changes in the dentin. An initial narrow band of normal-appearing dentin tubules (including the mantle layer) ceased abruptly and was replaced by a wavelike laminar zone parallel to the DEJ with occluded tubules. Multiple parallel channels of 5-10 &#119 m diameter were present at right angles to the DEJ indenting this zone, some terminating in retro-curved "processes." The abnormal dentin containing these channels almost completely occluded the pulp chamber. The structural and ultrastructural changes seen can be explained on the basis of the collagen defect in OI resulting in odontoblast dysfunction, which produces a distinct phenotype and one that is different from that in bone.     

Odontoblast dysfunction in osteogenesis imperfecta: an LM,SEM, and ultrastructural study

The inherited dentin defect dentinogenesis imperfecta (DI), while clinically obvious in osteogenesis imperfecta (OI) Types IB and IC, II, III, and IVB, is now thought to be present in all children with OI, in a continuum from minimal to severe dentin pathology. This collaborative study further clarifies the structural and ultrastructural dentin changes in the teeth of OI children with clinically obvious DI, and attempts to explain these in terms of odontoblast dysfunction. Collaborative studies were carried out in Melbourne, Australia, and Strasbourg, France, using light and polarized-light microscopy, scanning and transmission electron microscopy (SEM, TEM), selected-area diffraction (SAD), and x-ray spectroscopy (EDX). These showed structurally normal enamel (but containing long and broad lamellae) and a normally scalloped dentino-enamel junction (DEJ), but severe pathologic changes in the dentin. An initial narrow band of normal-appearing dentin tubules (including the mantle layer) ceased abruptly and was replaced by a wavelike laminar zone parallel to the DEJ with occluded tubules. Multiple parallel channels of 5-10 microns diameter were present at right angles to the DEJ indenting this zone, some terminating in retro-curved "processes." The abnormal dentin containing these channels almost completely occluded the pulp chamber. The structural and ultrastructural changes seen can be explained on the basis of the collagen defect in OI resulting in odontoblast dysfunction, which produces a distinct phenotype and one that is different from that in bone.     

Disorders of human dentin

Dentin, the most abundant tissue in teeth, is produced by odontoblasts, which differentiate from mesenchymal cells of the dental papilla. Dentinogenesis is a highly controlled process that results in the conversion of unmineralized predentin to mineralized dentin. By weight, 70% of the dentin matrix is mineralized, while the organic phase accounts for 20% and water constitutes the remaining 10%. Type I collagen is the primary component (>85%) of the organic portion of dentin. The non-collagenous part of the organic matrix is composed of various proteins, with dentin phosphoprotein predominating, accounting for about 50% of the non-collagenous part. Dentin defects are broadly classified into two major types: dentinogenesis imperfectas (DIs, types I-III) and dentin dysplasias (DDs, types I and II). To date, mutations in DSPP have been found to underlie the dentin disorders DI types II and III and DD type II. With the elucidation of the underlying genetic mechanisms has come the realization that the clinical characteristics associated with DSPP mutations appear to represent a continuum of phenotypes. Thus, these disorders should likely be called DSPP-associated dentin defects, with DD type II representing the mild end of the phenotypic spectrum and DI type III representing the severe end.     

牙本质唾液酸焦磷酸蛋白和牙本质

在牙本质,两个编码I型胶原蛋白基因的突变会导致成骨发育不全。除了胶原蛋白,在牙本质还有一定数量的非胶原蛋白。在牙本质非胶原蛋白编码的基因中,只有牙本质唾液酸焦磷酸蛋白(dentin sialophosphoprotein,DSPP)的突变引起遗传性牙齿畸形。DSPP的突变会引起牙本质发育不全(dentinogenesis imperfecta,DGI)Ⅰ型、Ⅱ型和牙本质发育异常(dentin dysplasia,DD)Ⅱ型。DSPP由成牙质细胞表达并分泌。分泌之后,DSPP由多个细胞外蛋白酶酶切成小片。DSPP被蛋白酶酶切为三个主要部分:牙本质涎蛋白(dentin sialoprotein,DSP),牙本质糖蛋白(dentin glycoprotein,DGP)和牙本质磷蛋白(dentin phosphoprotein,DPP)。本文就这三种蛋白的最新进展进行回顾。     

Popcorn calcification in osteogenesis imperfecta: incidence, progression, and molecular correlation

Osteogenesis imperfecta (OI) is a heritable disorder characterized by osteoporosis and increased susceptibility to fracture. All children with severe OI have extreme short stature and some have "popcorn" calcifications, areas of disorganized hyperdense lines in the metaphysis and epiphysis around the growth plate on lower limb radiographs. Popcorn calcifications were noted on radiographs of two children with non-lethal type VIII OI, a recessive form caused by P3H1 deficiency. To determine the incidence, progression, and molecular correlations of popcorn calcifications, we retrospectively examined serial lower limb radiographs of 45 children with type III or IV OI and known dominant mutations in type I collagen. Popcorn calcifications were present in 13 of 25 type III (52%), but only 2 of 20 type IV (10%), OI children. The mean age of onset was 7.0 years, with a range of 4-14 years. All children with popcorn calcifications had this finding in their distal femora, and most also had calcifications in proximal tibiae. While unilateral popcorn calcification contributes to femoral growth deficiency and leg length discrepancy, severe linear growth deficiency, and metaphyseal flare do not differ significantly between type III OI patients with and without popcorn calcifications. The type I collagen mutations associated with popcorn calcifications occur equally in both COL1A1 and COL1A2, and have no preferential location along the chains. These data demonstrate that popcorn calcifications are a frequent feature of severe OI, but do not distinguish cases with defects in collagen structure (primarily dominant type III OI) or modification (recessive type VIII OI).     

OIM and related animal models of osteogenesis imperfecta

Osteogenesis imperfecta (OI) is characterized by fragile bones, skeletal deformity, and growth retardation. This heritable disorder of connective tissue is the result of mutations affecting the COL1A1 and COL1A2 genes of type I collagen. Progress in OI research has been limited because of dependence on human fibroblast and osteoblast specimens and the absence of a naturally occurring animal model for this genetic disorder. Recent technology in molecular biology has led to the development of transgenic models of OI based on site directed mutagenesis of type I collagen genes. OIM is a naturally occurring model which incorporates both the phenotypic and biochemical defects of moderate to severe osteogenesis imperfecta. This powerful tool permits the development of models based on different type I collagen mutations. The collagen type I mutation in OIM is a C propeptide deletion which impairs the production of normal pro-alpha2(I). Tissues in OIM contain only [pro-alpha1(I)]3 homotrimer. Thus, although several animal models are now available for research in osteogenesis imperfecta few are viable or fully mimic human disease disorders. OIM duplicates the phenotype and biochemistry of human disease and has a normal life span.     

Lethal osteogenesis imperfecta associated with 46,XY,inv(7)(p13q22) karyotype.

An infant who died of complications of osteogenesis imperfecta (OI) at 22 days of age had a 46,XY,inv(7)(p13q22) karyotype. His mother carried the same inversion. One breakpoint of the inversion was within the region of the gene for alpha 2(I) procollagen. The product of this gene is a component of type I collagen, the principal collagen synthesised by osteoblasts. Karyotypic abnormalities involving type I collagen gene sites have not previously been reported in association with OI.     

Isolated dentinogenesis imperfecta and dentin dysplasia: revision of the classification

Dentinogenesis imperfecta is an autosomal dominant disease characterized by severe hypomineralization of dentin and altered dentin structure. Dentin extra cellular matrix is composed of 90% of collagen type I and 10% of non-collagenous proteins among which dentin sialoprotein (DSP), dentin glycoprotein (DGP) and dentin phosphoprotein (DPP) are crucial in dentinogenesis. These proteins are encoded by a single gene: dentin sialophosphoprotein (DSPP) and undergo several post-translational modifications such as glycosylation and phosphorylation to contribute and to control mineralization. Human mutations of this DSPP gene are responsible for three isolated dentinal diseases classified by Shield in 1973: type II and III dentinogenesis imperfecta and type II dentin dysplasia. Shield classification was based on clinical phenotypes observed in patient. Genetics results show now that these three diseases are a severity variation of the same pathology. So this review aims to revise and to propose a new classification of the isolated forms of DI to simplify diagnosis for practitioners.     

A novel <Emphasis Type="Italic">DSPP</Emphasis>mutation is associated with type II dentinogenesis Imperfecta in a chinese family

Background  

Hereditary defects of tooth dentin are classified into two main groups: dentin dysplasia (DD) (types I and II) and dentinogenesis imperfecta (DGI) (types I, II, and III). Type II DGI is one of the most common tooth defects with an autosomal dominant mode of inheritance. One disease-causing gene, the dentin sialophosphoprotein (DSPP) gene, has been reported for type II DGI.     

Osteogenesis imperfecta lethal in infancy: Case report and scanning electron microscopic studies of the deciduous teeth

Radiologic evaluation of the skeleton and scanning electron microscopic studies of the teeth were performed on an infant boy with a lethal osteogenesis imperfecta (OI) syndrome who died at 10 mo of pneumonia. The skeletal findings included ribs that were focally expanded by fracture calluses, flat vertebral bodies, and wide limb bones. On fractured tooth surfaces, the enamel and dentin were normal as was the dentin calcification front. Although microscopic abnormalities have been noted in teeth from previously reported infants with lethal OI, a few studies also report infants with normal teeth. These differences in dental findings may indicate heterogeneity in OI lethal in infancy. Results of our study indicate that, until the primary biochemical defects in the OI syndromes are elucidated, examination of teeth from other infants with lethal OI and detailed evaluation of other clinical and skeletal features will aid in delineating heterogeneity and variation in expression in lethal OI.     

Comparative studies of osteoblast and fibroblast type I collagen in a patient with osteogenesis imperfecta type IV.

The expression of type I collagen has been compared in fibroblast and osteoblast cultures of a patient with moderately severe osteogenesis imperfecta (OI) type IV, with respect to control cells. Electrophoretic analysis of type I collagen showed that both OI osteoblasts and fibroblasts synthesized normal chains and chains with delayed migration. However, the osteoblasts contained a higher proportion of abnormal chains than fibroblasts from the proband. Pulse-chase experiments showed that the trimers containing abnormal chains were cleared more rapidly from osteoblasts than fibroblasts. Moreover, the collagen secreted by OI osteoblasts had thermal stability 1 degrees C higher than collagen secreted by OI fibroblasts. These results suggest that the abnormal collagen in osteoblasts may be more resistant to intra- and extracellular degradation and may thus have better survival than in fibroblasts. This finding could have implications for understanding the clinical phenotype of OI.     

Osteoporosis and Familial Idiopathic Scoliosis: Association with an Abnormal Alpha 2(I) Collagen

A positive family history is considered a risk factor for osteoporosis (OP) although the genetic or biochemical basis for this relationship remains undefined. Various mutations affecting normal synthesis of type I collagen have been reported in osteogenesis imperfecta (OI), a heritable disorder of connective tissue. Family A, in which the proband and a daughter are afflicted with OP and idiopathic scoliosis was examined for defects in collagen metabolism. Dermal fibroblast cultures were established to investigate de novo collagen synthesis. SDS-PAGE revealed an abnormally migrating alpha 2(I) chain and procollagen in two generations. Examination of the kinetics of type I collagen pC & N-propeptide processing demonstrated a rate 2x control in the proband. The phenotype family A is not OI. It shares features with families B & C, having familial clustering of OP. However, collagen synthesis was not abnormal in family B & C. These data suggest that in family A the alpha 2(I) structural defect may be related to defective skeletal matrix formation.     

Osteoporosis and familial idiopathic scoliosis: association with an abnormal alpha 2(I) collagen

A positive family history is considered a risk factor for osteoporosis (OP) although the genetic or biochemical basis for this relationship remains undefined. Various mutations affecting normal synthesis of type I collagen have been reported in osteogenesis imperfecta (OI), a heritable disorder of connective tissue. Family A, in which the proband and a daughter are afflicted with OP and idiopathic scoliosis was examined for defects in collagen metabolism. Dermal fibroblast cultures were established to investigate de novo collagen synthesis. SDS-PAGE revealed an abnormally migrating alpha 2(I) chain and procollagen in two generations. Examination of the kinetics of type I collagen pC & N-propeptide processing demonstrated a rate 2x control in the proband. The phenotype family A is not OI. It shares features with families B & C, having familial clustering of OP. However, collagen synthesis was not abnormal in family B & C. These data suggest that in family A the alpha 2(I) structural defect may be related to defective skeletal matrix formation.     

Osteogenesis imperfecta: clinical, biochemical and molecular findings

Mutations in COL1A1 and COL1A2 genes, encoding the alpha1 and alpha2 chain of type I collagen, respectively, are responsible for the vast majority of cases of osteogenesis imperfecta (OI) (95% of patients with a definite clinical diagnosis). We have investigated 22 OI patients, representing a heterogeneous phenotypic range, at the biochemical and molecular level. A causal mutation in either type I collagen gene was identified in 20 of them: no recurrent mutation was found in unrelated subjects; 15 out of 20 mutations had not been reported previously. In two patients, we could not find any causative mutation in either type I collagen gene, after extensive genomic DNA sequencing. Failure of COL1A1/COL1A2 mutation screening may be due, in a few cases, to further clinical heterogeneity, i.e. additional non-collagenous disease loci are presumably involved in OI types beyond the traditional Sillence's classification.     

Osteogenesis imperfecta at the beginning of bone and joint decade

Osteogenesis imperfecta (OI), or brittle bone disease, is a heritable disorder characterized by increased bone fragility. Four different types of the disease are commonly distinguished, ranging from a mild condition (type I) to a lethal one (type II). Types III and IV are the severe forms surviving the neonatal period. In most cases, there is a reduction in the production of normal type I collagen or the synthesis of abnormal collagen as a result of mutations in the type I collagen genes. These classic forms of OI are described in this review. There are instances, however, where alterations in bone matrix components, other than type I collagen, are the basic abnormalities of the OI. Recently, three such discrete types have been identified by histomorphometric evaluation (types V and VI) and linkage analysis (Rhizomelic OI). They provide evidence for the as yet poorly understood complexity of the phenotype-genotype correlation in OI. We also discuss bisphosphonates treatment as well as fracture management and surgical correction of deformities observed in the patients with OI. However, ultimately, strengthening bone in OI will involve steps to correct the underlying genetic mutations that are responsible for this disorder. Thus, we also describe different genetic therapeutic approaches that have been tested either on OI cells or on available OI murine models.     

Dental Structural Diseases Mapping to Human Chromosome 4q21

Genetic diseases affecting tooth structure have been classified by the tissue affected enamel versus dentin, and their pattern of inheritance autosomal dominant, autosomal recessive, or X-linked. Advances in molecular genetics and the Human Genome Project have provided substantial progress regarding the identification of genes involved in the pathogenesis of human diseases. These include dental diseases affecting enamel and dentin formation: amelogenesis imperfecta (AI), dentinogenesis imperfecta (DGI) types II and III, and dentin dysplasia (DD) type II. Linkage studies using large informative families have provided insight identifying two proximal gene clusters on human chromosome 4q21 that contain the critical loci for five dental structural diseases. Studies related to the autosomal dominant forms of AI, representing ~85% of all cases, have established linkage to 4q21 for two forms: local hypoplastic and smooth hypoplastic AI. Two enamel matrix proteins, ameloblastin and enamelin, have been mapped within the critical regions for these diseases. Located more toward the telomere is another cluster containing loci for three dentin diseases: DGI type II, type III, and DD type II. Located within an overlapping segment of these diseases is a dentin/bone gene cluster that contains osteopontin, bone sialoprotein, matrix extracellular phosphoglycoprotein also known as osteoblast/osteocyte factor 45 or osteoregulin, dentin matrix protein 1, and dentin sialophosphoprotein. Continuing molecular genetic studies will facilitate the identification of novel tooth matrix proteins within these two tooth matrix gene clusters as well as the identification of additional autosomal dominant AI loci.     

常染色体隐性遗传性成骨不全症的分子遗传学研究进展

成骨不全症(osteogenesis imperfecta,OI)又称脆骨症,由于遗传缺陷而引起Ⅰ型胶原结构或功能异常,表现为全身骨骼等结缔组织异常.临床特点是多发性骨折,同时可伴有巨头畸形、蓝巩膜、耳聋、牙齿改变和脊柱后侧凸等.成骨不全症不仪临床表型变异度大,而且遗传异质性高,以常染色体显件或隐性遗传方式传递,本文就常染色体隐性遗传性成骨不全症的分子遗传学研究进展加以综述.     

Dental structural diseases mapping to human chromosome 4q21

Genetic diseases affecting tooth structure have been classified by the tissue affected enamel versus dentin, and their pattern of inheritance autosomal dominant, autosomal recessive, or X-linked. Advances in molecular genetics and the Human Genome Project have provided substantial progress regarding the identification of genes involved in the pathogenesis of human diseases. These include dental diseases affecting enamel and dentin formation: amelogenesis imperfecta (AI), dentinogenesis imperfecta (DGI) types II and III, and dentin dysplasia (DD) type II. Linkage studies using large informative families have provided insight identifying two proximal gene clusters on human chromosome 4q21 that contain the critical loci for five dental structural diseases. Studies related to the autosomal dominant forms of AI, representing approximately 85% of all cases, have established linkage to 4q21 for two forms: local hypoplastic and smooth hypoplastic AI. Two enamel matrix proteins, ameloblastin and enamelin, have been mapped within the critical regions for these diseases. Located more toward the telomere is another cluster containing loci for three dentin diseases: DGI type II, type III, and DD type II. Located within an overlapping segment of these diseases is a dentin/bone gene cluster that contains osteopontin, bone sialoprotein, matrix extracellular phosphoglycoprotein also known as osteoblast/osteocyte factor 45 or osteoregulin, dentin matrix protein 1, and dentin sialophosphoprotein. Continuing molecular genetic studies will facilitate the identification of novel tooth matrix proteins within these two tooth matrix gene clusters as well as the identification of additional autosomal dominant AI loci.     

常染色体隐性遗传性成骨不全症的分子遗传学研究进展

成骨不全症(osteogenesis imperfecta,OI)又称脆骨症,由于遗传缺陷而引起Ⅰ型胶原结构或功能异常,表现为全身骨骼等结缔组织异常.临床特点是多发性骨折,同时可伴有巨头畸形、蓝巩膜、耳聋、牙齿改变和脊柱后侧凸等.成骨不全症不仪临床表型变异度大,而且遗传异质性高,以常染色体显件或隐性遗传方式传递,本文就常染色体隐性遗传性成骨不全症的分子遗传学研究进展加以综述.