Update on the Genetics of Osteogenesis Imperfecta

Abstract

Osteogenesis imperfecta (OI) is a heterogeneous heritable skeletal dysplasia characterized by bone fragility and deformity, growth deficiency, and other secondary connective tissue defects. OI is now understood as a collagen-related disorder caused by defects of genes whose protein products interact with collagen for folding, post-translational modification, processing and trafficking, affecting bone mineralization and osteoblast differentiation. This review provides the latest updates on genetics of OI, including new developments in both dominant and rare OI forms, as well as the signaling pathways involved in OI pathophysiology. There is a special emphasis on discoveries of recessive mutations in TENT5A, MESD, KDELR2 and CCDC134 whose causality of OI types XIX, XX, XXI and XXI, respectively, is now established and expends the complexity of mechanisms underlying OI to overlap LRP5/6 and MAPK/ERK pathways. We also review in detail new discoveries connecting the known OI types to each other, which may underlie an eventual understanding of a final common pathway in OI cellular and bone biology.

Keywords: Bone mineralization; IFITM5/BRIL; MAPK/ERK; Mitochondria; Osteoblast differentiation; Osteogenesis imperfecta; PDEF; RIP/MBTPS2.

Fig. 1

Mechanisms and signaling pathways of OI. The two proα1(I) and one proα2(I) chains of the procollagen heterotrimer undergo post-translational modifications of proline and lysine residues by P4H and LH1, respectively, in the ER. During procollagen folding, the ER-residing prolyl 3-OH complex, consisting of P3H1, CRTAP, and PPIB, hydroxylates the P986 residue important for alignment of procollagen chains. HSP47, an ER chaperone, binds to procollagen triple helix to facilitate collagen folding and secretion. FKBP10, another ER chaperone, cooperate with HSP47 in procollagen trafficking from the ER to the Golgi. Another protein that functions closely with HSP47 is KDEL receptor 2, which has a role in intracellular recycling of ER-resident proteins through retrograde transport. Once the procollagen triple helix is secreted into extracellular space, N- and C-propeptides of procollagen are cleaved by ADAMTS-2 and BMP1 enzymes, respectively. Type I collagen is released and incorporated into extracellular matrix. An important regulator of collagen assembly is SPARC, which binds collagen as a matricellular glycoprotein. At the level of transcriptional regulation, Osterix/Sp7, a zinc finger transcriptional factor, interacts with RUNX2, which induces the expression of collagen genes. Intracellular calcium is important for collagen post-translational modification and metabolism. TRIC-B together with IP3R regulate calcium flux from the ER to cytoplasm. In addition, TRIC-B absence impacts the fusion and fission of mitochondria, affecting MFN2 and DRP1 regulators at the ER-mitochondria contact sites. Transmembrane transcriptional factor OASIS is transported from the ER to the Golgi membrane for RIP signaling. OASIS is cleaved by S1P and S2P in the Golgi and the released N-terminal end of OASIS translocates into the nucleus for transcription of genes important for extracellular matrix, such as collagens. Also affecting collagen expression and bone mineralization in osteoblasts is FAM46A, encoded by TENTA, which is involved in the polyadenylation of collagen transcripts and other proteins involved in bone mineralization. BRIL is an important regulator of bone mineralization and impacts SERPINF1 transcription in the nucleus. SERPINF1 encodes the PDEF protein, which binds collagen to activate its own anti-angiogenic function. Wnt signaling, important for bone development, is activated by binding of WNT1 ligand to the Frizzled and LRP5/6 receptors, which inhibits the degradation complex, consisting of Axin, APC, and GSK3, in order to stabilize β-catenin. β-catenin translocates to the nucleus to activate transcription of Wnt target genes. MESD, a chaperone residing in the ER, has a role in Wnt signaling by translocating LRP5/6 receptors, and is also a direct chaperone of pro-α1(I) in osteoblasts. BMP signaling is another important pathway for bone metabolism. BMP binds to BMP receptors and induces phosphorylation of SMAD 1/5/8. Together SMAD 1/5/8, FAM46A, and SMAD4 form a complex that further translocates to the nucleus to induce transcription of BMP target genes. Recently proposed OI-causing gene CCDC134 encodes a secretory protein CCDC134 that inhibits ERK and JNK phosphorylation of MAPK pathway, and impacts osteoblast expression of collagen and mineralization