Osteogenesis imperfecta due to mutations in non-collagenous genes: lessons in the biology of bone formation

Abstract

Purpose of review: Osteogenesis imperfecta or 'brittle bone disease' has mainly been considered a bone disorder caused by collagen mutations. Within the last decade, however, a surge of genetic discoveries has created a new paradigm for osteogenesis imperfecta as a collagen-related disorder, where most cases are due to autosomal dominant type I collagen defects, while rare, mostly recessive, forms are due to defects in genes whose protein products interact with collagen protein. This review is both timely and relevant in outlining the genesis, development, and future of this paradigm shift in the understanding of osteogenesis imperfecta.

Recent findings: Bone-restricted interferon-induced transmembrane (IFITM)-like protein (BRIL) and pigment epithelium-derived factor (PEDF) defects cause types V and VI osteogenesis imperfecta via defective bone mineralization, while defects in cartilage-associated protein (CRTAP), prolyl 3-hydroxylase 1 (P3H1), and cyclophilin B (CYPB) cause types VII-IX osteogenesis imperfecta via defective collagen post-translational modification. Heat shock protein 47 (HSP47) and FK506-binding protein-65 (FKBP65) defects cause types X and XI osteogenesis imperfecta via aberrant collagen crosslinking, folding, and chaperoning, while defects in SP7 transcription factor, wingless-type MMTV integration site family member 1 (WNT1), trimeric intracellular cation channel type b (TRIC-B), and old astrocyte specifically induced substance (OASIS) disrupt osteoblast development. Finally, absence of the type I collagen C-propeptidase bone morphogenetic protein 1 (BMP1) causes type XII osteogenesis imperfecta due to altered collagen maturation/processing.

Summary: Identification of these multiple causative defects has provided crucial information for accurate genetic counseling, inspired a recently proposed functional grouping of osteogenesis imperfecta types by shared mechanism to simplify current nosology, and has prodded investigations into common pathways in osteogenesis imperfecta. Such investigations could yield critical information on cellular and bone tissue mechanisms and translate to new mechanistic insight into clinical therapies for patients.

Figure 1

Abnormal molecular mechanisms in OI types caused by defects in collagen-related molecules. Dark grey arrows and the text in blue boxes show the aberrant mechanism in most OI cases linked to defects in the specific protein. A) Green arrow shows the normal secretion of PEDF (and subsequent collagen binding) after transcription in response to effects of BRIL protein and a possible modulator. The novel OI proteins all affect osteoblast development: specifically, nuclear OSTERIX affects osteoblast differentiation genes, the trimeric TRIC-B channel affects intracellular Ca²⁺ signaling, the ER-stress transducer OASIS modulates Col1 transcription when nuclear, and WNT1 binds LRP5 to affect bone formation. B) Green arrows show the normal effect of the proteins on collagen. The ER resident complex of CRTAP/P3H1/CyPB 3-hydroxylates specific prolines on the α1(I) and α2(I) chains, while chaperones contribute to normal folding of the collagen trimer.