Osteogenesis imperfecta

Abstract

Osteogenesis imperfecta is a phenotypically and molecularly heterogeneous group of inherited connective tissue disorders that share similar skeletal abnormalities causing bone fragility and deformity. Previously, the disorder was thought to be an autosomal dominant bone dysplasia caused by defects in type I collagen, but in the past 10 years discoveries of novel (mainly recessive) causative genes have lent support to a predominantly collagen-related pathophysiology and have contributed to an improved understanding of normal bone development. Defects in proteins with very different functions, ranging from structural to enzymatic and from intracellular transport to chaperones, have been described in patients with osteogenesis imperfecta. Knowledge of the specific molecular basis of each form of the disorder will advance clinical diagnosis and potentially stimulate targeted therapeutic approaches. In this Seminar, together with diagnosis, management, and treatment, we describe the defects causing osteogenesis imperfecta and their mechanism and interrelations, and classify them into five groups on the basis of the metabolic pathway compromised, specifically those related to collagen synthesis, structure, and processing; post-translational modification; folding and cross-linking; mineralisation; and osteoblast differentiation.

Figure 1:. Mutations in specific positions along type I procollagen molecule cause distinct clinical phenotypes

Mutations affecting the helical region of the α chains and the C-propeptide domain cause classic osteogenesis imperfecta, including the osteogenesis imperfecta/Ehlers-Danlos syndrome variant, which is caused by substitutions in the N-anchor domain. Molecular defects in the N-propeptide cleavage site cause Ehlers-Danlos syndrome VII A/B and in the C-propeptide cleavage site cause high bone mass osteogenesis imperfecta. Hexagons represent sugar molecules linked to hydroxyl lysine residues. OH-=hydroxyl group linked to proline or lysine residues.

Figure 2:. Proteins involved in type I procollagen post-translational modification and folding in the endoplasmic reticulum

Prolyl 3-hydroxylase, cartilage associated protein, and cyclophilin B act as a trimeric complex for hydroxylation of the 3-carbon position of the α1(I)Pro986 and α2(I) Pro707 proline residues. Cyclophilin B also affects the activity of lysyl hydroxylase 1, which hydroxylates lysine residues in the helical region of type I procollagen. The regulation of calcium ion concentration in the endoplasmic reticulum is relevant to procollagen post-translational modification because of its role in modulating calreticulin interaction with cyclophilin B and with protein disulphide isomerase. Protein disulphide isomerase complexes with prolyl 4-hydroxylase to hydroxylate the 4-carbon position of proline residues located in the Y-position of the repetitive collagenic triplet (Gly-X-Y).

Figure 3:. Proteins affecting procollagen intracellular trafficking and extracellular crosslinking

Heat shock protein 47 is a specific collagen I chaperone, binding to the triple helical collagen domain in the endoplasmic reticulum, preventing aggregation, and facilitating its trafficking to the Golgi. An RDEL signal will then guide the return of heat shock protein 47 to the endoplasmic reticulum. FK506 binding protein 65 is a peptydyl prolyl cis-trans isomerase known to affect the activity of lysyl hydroxylase 2, the enzyme which hydroxylates lysine residues in the N-telopeptides and C-telopeptides that are crucial for crosslink formation in the extracellular matrix. The question marks refer to probable but not yet proven interactions.

Figure 4:. Proteins involved in mineralisation of the collagen extracellular matrix

The transmembrane protein-bone restricted interferon induced transmembrane protein-like—regulates the expression of pigment epithelium derived factor, an important collagen-binding protein regulating bone homoeostasis and osteoid mineralisation, which also has strong anti-angiogenic functions by an unknown mechanism. SERPINF1 is the gene for pigment epithelium derived factor. The question marks refer to the presence of other factors in this pathway, which are not yet discovered. The plus and minus signs refer to increased and decreased transcription of the SERPINF1 gene. S40L refers to the IFITM5 mutation Ser40Leu.