Abstract

Osteogenesis Imperfecta (OI) are inherited disordesr generating skeletal fragility. It is caused by mutations in one of the two genes encoding type I collagen (COL-1A1, COL1A2). Four subtypes of OI has been identified: Classic non-deforming OI with blue sclerae (Type I), perinatally lethal OI (Type II), progressively deforming OI (Type III) and common variable OI with normal sclerae (Type IV). Type IV comprises patients with phenotype intermediate to types I and III. More recently, other types of OI (V-XV) have been reported. Although they phenotypically resemble to types I-IV, they are not associated to type I collagen mutations. Dentinogenesis Imperfecta (DI), associated or not with OI, was classified in five types: Dentin Dysplasia types I and II (DD1 and DD2) and Dentinogenesis Imperfecta (DGI-types I-III). Cleavage of DSPP gives rise to three molecules susceptible to mutations, respectively dentin sialoprotein (DSP), Dentin Glycoprotein (DGP) and Dentin Phosphoprotein (DPP). Pharmacological treatments contribute to reduce adverse effects of OI, whereas cells and genes therapies still need improvements.

Keywords

Osteogenesis Imperfecta; Dentinogenesis Imperfecta; Dentin Dysplasia; Collagen Type I, Non-Collagenous Extracellular Matrix Proteins; Gene Coding Protein Mutations

Introduction

Classification OI and DI: Genes Mutations

Osteogenesis Imperfecta

Bone fragility is the hallmark clinical feature of Osteogenesis Imperfecta (OI) leading to recurrent fractures and skeletal deformities.

Patients may have blue sclera, hearing loss, Dentinogenesis Imperfecta (DI), growth deficiency, joint laxity, or any combination of these characteristics. Sillence et al., in 1979, proposed the first classification of Osteogenesis Imperfecta (OI) (Types I-IV) [1]. It was expanded later, with types V-VIII, due to causative genes and nowadays, gene mutations cause abnormal structures up to type XV [1-5]. These publications are characterized by early-onset recurrent fractures, bone deformity, significant reduction of bone density, short stature, and, in some patients, blue sclera, therefore the classification of OI was expanded [6,7].

Type II was subdivided in II-A, II-B, II-C. Type V and VI remain part of the revised classification [8]. Three recessive OI types arise from defects of the collagen prolyl 3-hydroxylation complex (CRTAP, P3H1, CyPB), which modifies the collagen α1(I)Pro986 residues. Complex dysfunction leads to delay the folding of the procollagen triple helix. OI diseases result from mutations of the genes that encode the chains of type I collagen (COLIAI or COLIA2) [9].

Dentinogenesis Imperfecta

The most usual classification system for Dentinogenesis Imperfecta (DI) was formulated by Shields, et al., in 1973, recognizing three types of DI (types I, II, and III) [10]. DI is a hereditary disorder in dentin formation that is characterized by abnormal dentine structure affecting either the primary or both the primary and secondary dentitions. Radiographically, teeth show short roots, bulbous crown with marked cervical constriction and pulpal obliterations. The primary teeth are more severely affected than the permanent. DI type 1 is associated with OI. The teeth of both dentitions are typically amber and translucent and show significant attrition.

In addition to mutations of the coding genes for type I collagen, the genes coding for Dentin Sialophosphoprotein (DSPP) may produce dentin alterations. Three fragments of the initial DSPP molecule constitute the Dentin Sialoprotein (DSP), Dentin Glycoprotein (DGP) and Dentin Phosphoprotein (DPP). They result from the cleavage by astracin and metalloproteases (MMP-2, MMP-9). Each of the three molecules may be mutated. DGP and DPP are encoded by the end of exon 5 of the DSPP coding gene. DPP initiates hydroxyapatite formation at low concentration and inhibits Hap growth at higher concentration.

Clinical features of OI

Homozygous aim mice are born with fractures or develop them at an early age. The generalized radiolucency, bowing of the long bones, fractures, and calluses, as evidence of healed fractures, are radiological hallmarks of human OI.

Type I: It is an autosomal dominant inheritance with blue sclera. Normal stature, with little or no deformity, early deafness and hearing loss in 50%. Dentinogenesis imperfecta is rare and may distinguish a subset. Type IB is characterized by the absence/presence of dentinogenesis imperfecta.

Type II: Is lethal in the perinatal period, associated with minimal calvarial mineralization, beaded ribs, compressed femurs, marked long bone deformit [l]. In II-A, wide (thin) ribs with fractures are frequent. Lethal perinatally, type II OI is later divided into three subtypes (A, B, and C OI type II). OI type IIA is caused by mutations of the COL1A1 and COL1A2 genes (17q21.31-q22 and 7q22.1 respectively).

Type III: It is a severe type of OI and cause progressively deforming bones. Sclerae have variable colors, often lighten with age. Dentinogenesis imperfecta is common, with hearing loss. The stature is short, progressively deforming, OI Type III affects about 1 in 15000 new-borns.

Type IV: Displays normal sclerae, mild to moderate bone deformity and variable short stature. Dentinogenesis imperfecta is common (opalescent teeth), and hearing loss occurs in some cases. Type IV has moderately deforming bones [9,11]. Type IV-A displays normal teeth, in contrast with type IV-B that engender a pathologic type I dentinogenesis Imperfecta. The mutations give rise to severe bone fragility in humans.

SPARC-null mice developed a progressive osteoporosis. Recessive mutations in SPARC are a cause of severe OI [12]. COL1A1, COL1A2, CRTAP and LEPRE1 are the genes implicated in these forms of OI. Based on the common classification, OI patients can be categorized into mild (Type I), perinatal lethal (Type II), progressively deforming (Type III), and moderately severe (Type IV) (Table 1).

The various types occur in approximately 1/15,000-20,000 births. Most OI cases have autosomal dominant inheritance. Over 1500 dominant mutations were found:

• Either with COL1A1 or COL1A2 genes, encoding the α-chains [α1(I) and α2(I)] of type I collagen
• They have also been identified closely with other genes mutations [13]

Table 1: Other genes mutations generating clinical manifestations.

Types VII-IX affect collagen folding and chaperone functions. They result from mutations of the SERPINH1 and FKBP10 gene. Collagen-associated proteins are implicated in collagen modification in OI: either in mineralization, or folding, crosslinking, and chaperoning (Fig. 1).

Figure 1: Dentinogenesis Imperfecta (DI) in a patient with OI Type III.

Dentinogenesis Imperfecta

Molecular genetics studies allow to discriminate only two major pathologies: Dentinogenesis Imperfecta (formerly DGI Shield type II, III and DD Shield type II) and dentin dysplasia (formerly DD Shield type I) corresponding to a radicular anomaly. DI is characterized by discoloration of the dentition, severe attrition of the teeth, bulbous crowns and early obliteration of the pulp in both deciduous and permanent dentitions. Pulp obliteration occurs soon after eruption or prior to tooth eruption. Primary dentition is more severely affected than the permanent dentition.

DI type 3 is characteristic of a tri-racial population from Maryland and Washington, DC, known as the Brandywine isolate. The clinical features are variable and resemble those seen in DI types 1 and 2, but the primary teeth show multiple pulp exposures and radiographically, they often manifest as a ‘shell’ teeth [15].

Histologically, the dentin is similarly affected in the three types of DI. A layer of normal mantle dentin with an irregular texture of dentinal matrix and an abnormal number and structure of dentin tubules has been reported. Consistently, there are atubular areas of dentin.

The strong association between OI and DI had induced different authors to propose another classification by making diagnosis of OI, depending on the presence of DI. DI has been classified into two major groups: Dentin Dysplasia (DD) type I and II and dentinogenesis imperfecta (DGI type I-III). It is obvious that mutations of DSPP produce DGI types II and DD-II [16].

The dental features of DI type 2 are similar to those of DI type 1 but without association of OI. The diseases have been classified into two major groups with subtypes (Table 2):

1. Dentin Dysplasia (DD) types I and II
2. Dentinogenesis Imperfecta (DGI) types I-III [16]

Genetic linkage studies have identified the critical loci for DD‐II, DGI‐II, and DGI‐II to human chromosome 4q21. Located within the common disease loci for these diseases there is a cluster of dentin/bone genes that includes a series of Small Integrin-Binding Ligand N-linked Glycoproteins (SIBLINGs), a family of genes coding Osteopontin (OPN), Bone Sialoprotein (BSP), Matrix Extracellular Phosphoglycoprotein (MEPE), Dentin Matrix Protein 1 (DMP1), and Dentin Sialophosphoprotein (DSPP). Only mutations of DSPP are associated with the pathogenesis of dentin diseases [16].

Table 2: Classification of Dentinogenesis Imperfecta.

Dentinogenesis Imperfecta (DI type I) is found more commonly in OI type III. DI type I is associated with mutations of the genes encoding type I collagen [17].

Dentin Dysplasia with Coronary Defects

All the three mutated molecules produced by DSPP cleavage are members of the SIBLINGS family, and implicated in tooth mineralization. Teeth are grey-blue or amber brown; and display opalescent discoloration. Bullous crown, because of cervical constriction, and partial obliteration of the pulp chamber are recognized in this phenotype. The teeth showed few and large dentinal tubules and atubular areas. Enamel chipping is also observed.

Dentin Dysplasia (type II and III) with Radicular Defects

This type affects only deciduous teeth. The pulp exhibits a large pulpal chamber, followed by thin root canals. Pulpstones are frequent (Fig. 2).

Figure 2: Reprint from: Waltimo et al., 1991, Waltimo 1996.

Treatment of Osteogenesis Imperfecta

Pharmacologic treatment (including bisphosphonates, synthetic analogues of pyrophosphate inhibit bone resorption). Deposited on the bone surface, they are ingested by osteoclasts, inducing apoptosis of the cells. Decreased osteoclastic activity is indicative by a reduction in serum levels of calcium, phosphate and alkaline phosphatase [18-20]. Alendronate demonstrated a reduction in the number of fractures and an increase in bone mineral density. Numerous cases of osteonecrosis of the jaw (namely in the mandibular and maxillary alveolar bone) have been reported to be due to a bisphosphonate treatment.

A family of drugs (Pamidronate, intraveinous disodium pamidonate, zoledronic acid, drugs inhibiting bone resorption by inducing osteoclast apoptosis) have been used sucessfullly. They are also indicated to treat or reduce the effects of OI [21].

For OI type 5, the treatment prompt to use of indomethacin, an anti-inflammatory COX-1 and COX-2 prostaglandin inhibitor, has been recommended. Oral risedronate (Actonel^®) seems also to cure OI and provide therapeutic beneficial effects.

Cell and Gene Therapies

The aim of this approach is to supply terminally differentiated osteoblasts. Osteoblasts arise from mesenchymal stem cells that reside in the bone marrow. The ability for bone to regenerate is attributed to quiescent stem cells that undergo proliferation and differentiation.

Since the transplanted cells are stem cells, they will self-renew and it is expected that they provide treatment for life. Gene therapy using a mutation-independent approach by targeting polymorphic sites within procollagen genes may be used in conjunction with collagen genes supplementation.

In addition, it is possible to overexpress the normal collagen gene in cells of the OI patients. The potential of collagen gene replacement as an approach for OI treatment was further evaluated by determining the ability of the bone marrow stromal cells to be transduced with collagen genes.

As a proof of concept, an adenoviral vector carrying the murine procollagen α2 (I) cDNA was used to transduce osteoprogenitor cells harvested from oim mice that are deficient in the pro α2 (I) collagen synthesis.

A combination of gene silencing and gene replacement approaches in stem cells will need to be developed for the treatment of OI patients mutations. This implies to take advantages of methods of cell delivery and methods aiming to increase efficiency of the mesenchymal stem cell engraftment [22,23].

Conclusion

All these approaches are efficient in addition to dental treatment performed under general analgesia. Cardiopulmonary complications should be taken into account because they are the major cause of morbidity.

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