Bone Collagen: New Clues to Its Mineralization Mechanism from Recessive Osteogenesis Imperfecta

Until 2006 the only mutations known to cause osteogenesis imperfecta (OI) were in the two genes coding for type I collagen chains. These dominant mutations affecting the expression or primary sequence of collagen α1(I) and α2(I) chains account for over 90 % of OI cases. Since then a growing list of mutant genes causing the 5–10 % of recessive cases has rapidly emerged. They include CRTAP, LEPRE1, and PPIB, which encode three proteins forming the prolyl 3-hydroxylase complex; PLOD2 and FKBP10, which encode, respectively, lysyl hydroxylase 2 and a foldase required for its activity in forming mature cross-links in bone collagen; SERPINH1, which encodes the collagen chaperone HSP47; SERPINF1, which encodes pigment epithelium-derived factor required for osteoid mineralization; and BMP1, which encodes the type I procollagen C-propeptidase. All cause fragile bone in infancy, which can include overmineralization or undermineralization defects as well as abnormal collagen posttranslational modifications. Consistently both dominant and recessive variants lead to abnormal cross-linking chemistry in bone collagen. These recent discoveries strengthen the potential for a common pathogenic mechanism of misassembled collagen fibrils. Of the new genes identified, eight encode proteins required for collagen posttranslational modification, chaperoning of newly synthesized collagen chains into native molecules, or transport through the endoplasmic reticulum and Golgi for polymerization, cross-linking, and mineralization. In reviewing these findings, we conclude that a common theme is emerging in the pathogenesis of brittle bone disease of mishandled collagen assembly with important insights on posttranslational features of bone collagen that have evolved to optimize it as a biomineral template.