SeminarOsteogenesis imperfecta
Introduction
The identification of the first gene for recessive osteogenesis imperfecta in 20061, 2 initiated a burst of exciting new information about the genetics and mechanism of this bone dysplasia.3 Osteogenesis imperfecta, or brittle bone disease, is a fairly common rare disorder (one in 15–20 000 births). This generalised connective tissue disorder has major manifestations in bone, leading to skeletal fragility and substantial growth deficiency.4 Previously, osteogenesis imperfecta was known as an autosomal dominant disorder caused by mutations in COL1A1 and COL1A2, coding for the α1(I) and α2(I) chains of type I collagen, the most abundant protein of bone, skin, and tendon extracellular matrices. Although about 85–90% of cases are caused by structural or quantitative mutations in the collagen genes themselves, the disorder is now more fully understood as a predominantly collagen-related disorder.3, 5 Seven recessive forms are caused by defects in genes whose protein products interact with collagen for folding or post-translational modifications. Two other rare defects mainly affect bone mineralisation, but also decrease collagen production. Now, the most recently identified genes could open a new chapter, with primary defects in osteoblast differentiation. Each discovery revealed a protein or pathway whose crucial importance for bone development had not been appreciated (see Orgel and colleagues6 for a review on bone composition and collagen-extracellular proteins interaction). The exciting advances in rare forms of the disorder sparked renewed interest in classic osteogenesis imperfecta with collagen defects, revealing changes in bone cell metabolism and development, and initiating a new era for diagnosis and potential treatment.
The classification evolved with the new genetic discoveries. The 1979 Sillence classification7 divided osteogenesis imperfecta into four types, from mild to lethal, on the basis of clinical and radiographic features.8 Identification of collagen defects showed that mild Sillence type I was related to quantitative deficiency of structurally normal collagen, whereas lethal (type II), severe (type III), and moderate (type IV) forms had mutations altering collagen structure.4 A genetic classification incorporated a new type for each defective gene. To make this information user friendly for clinicians and patients and to establish a structure for future development, we propose to group the genetic types on the basis of altered intracellular or extracellular metabolic pathways.
Section snippets
Diagnosis
The initial diagnosis is largely based on clinical and radiographic findings.7, 8 Fractures from mild trauma, bowing deformities of long bones, and growth deficiency are the hallmark features. Dependent on age and severity, skeletal features can include macrocephaly, flat midface and triangular facies, dentinogenesis imperfecta, chest wall deformities such as pectus excavatum or carinatum, barrel chest, and scoliosis or kyphosis.3 Skeletal radiographs reveal generalised osteopenia, and some
Defects in collagen
Type I collagen is a heterotrimer, containing two α1(I) and one α2(I) chains. It is synthesised as a procollagen molecule, with N-terminal and C-terminal globular propeptides flanking the helical domain. The helical domains contain uninterrupted Gly-Xaa-Yaa triplets because the small glycine side chain fits in the internal helical space.
Procollagen chains assemble at their C-propeptides and fold toward the N-terminal. The unfolded chains are subjected to multiple post-translational
Processing defects
After secretion, procollagen molecules undergo an extracellular maturation process, in which the N-propeptides and C-propeptides are removed by specific proteases. After processing, the collagen helices are able to spontaneously assemble into fibrils in tissue, to be further stabilised by crosslinks. Mutations altering the propeptide cleavage sites cause interesting and specific variants of osteogenesis imperfecta.23
The N-propeptide cleavage site is encoded by exon 6 in both COL1A1 and COL1A2;
Defects in collagen post-translational modification and folding
Procollagen undergoes several post-translational modifications during synthesis, which are important for procollagen folding, secretion, and extracellular matrix assembly and are cell, site, and temporally regulated. Most of these crucial processing steps occur in the endoplasmic reticulum. The identification of a multiprotein complex13 has helped researchers to further understand rare osteogenesis imperfecta forms and to identify a mechanism by which mutations in different proteins can cause
Defects in collagen folding and crosslinking
Another rough endoplasmic reticulum-resident immunophilin is also crucial for normal collagen synthesis. The PPIase FKBP65 is encoded by FKBP10 (figure 3).56 As with CyPB, FKBP65 has both direct and indirect effects on procollagen through collagen modifying enzymes. Recessive defects in FKBP10 cause a continuum of three previously distinct recessive syndromes.
FKBP65 deficiency was first shown to cause recessive osteogenesis imperfecta (type XI), ranging from progressive deforming, with long
Defects in ossification and mineralisation
Types V and VI osteogenesis imperfecta share the distinction of causing primary defects in endochondral bone ossification or mineralisation. Dominantly inherited type V and recessively inherited type VI were delineated clinically, on the basis of phenotypic, radiographic, and histological features, and normal type I collagen post-translational modification.11, 12 Whole exome sequencing revealed causative mutations in the interferon-induced transmembrane protein 5 (IFITM5) for type V68, 69 and
Defects in osteoblast development
Three genes implicated in osteoblast differentiation have been associated with osteogenesis imperfecta phenotypes: WNT1 (type XV), CREB3L1 (type XVI), and SP7 (type XII). Defects in these genes either cause, or are expected to cause, a reduction in type I collagen expression. The reported data support early onset osteoporosis but are still accumulating for the cause of osteogenesis imperfecta. The relation of these gene defects to collagen might simply be quantitative, resulting in osteopenia
Osteogenesis imperfecta classification
Both clinical and genetic classifications have emerged to encompass the rare forms of osteogenesis imperfecta since most new genes do not have specific diagnostic features. In the clinical classification, the new forms of the disorder were merged into Sillence types I to IV by clinical severity. For example, type II osteogenesis imperfecta, the perinatal lethal form, included lethal collagen mutations and some CRTAP, LEPRE1, PPIB, SERPINH1, and SP7 mutations.98 Some clinical classifications
Medical management of osteogenesis imperfecta
Osteogenesis imperfecta is best managed by a multidisciplinary team. Physical rehabilitation by a therapist with experience of the disorder is arguably the most important contribution to function. The combination of fragile bones, weak muscle, and cycles of fracture and disuse creates substantial challenges for a patient to attain and maintain gross motor skills, especially walking.102 Physiotherapy and hydrotherapy focused on muscle strength and joint range of motion are crucial to maximise an
Present and prospective drug therapies
Bisphosphonates, antiresorptive drugs, which are synthetic analogues of pyrophosphate, are widely used to treat children with osteogenesis imperfecta. Bisphosphonates are deposited on the surface of bone, where their endocytosis by precursor or mature ostoclasts induces cell death (apoptosis). Thus, treatment aims to increase bone volume by counteracting the high turnover cellular status of bone in classic osteogenesis imperfecta. The new bone would still contain defective collagen in the
Orthopaedic surgery
Placement of an intramedullary telescoping rod in a long bone can stabilise a severe fracture, provide internal support for healing after correction of bone deformity, or interrupt fracture or disuse cycles.134 The Fassier–Duval rod aims to be minimally invasive, with a single entry point, and does not require arthrotomies.135 Correction of deformity with Fassier-Duval rods is associated with improved ambulation.135 Telescoping rods have a substantial incidence of migration, perhaps due to poor
Conclusions
An exciting series of discoveries has rapidly advanced understanding of osteogenesis imperfecta and has identified genes whose importance for bone development was not previously appreciated. Common themes have emerged for dominant and recessive forms, including collagen-related mechanisms, abnormal mineralisation, osteoblast signalling, endoplasmic reticulum-stress, and cell–cell and cell–matrix signalling. Rare osteogenesis imperfecta types are prompting investigators to re-examine old themes,
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