Bone Abstracts

Osteogenesis imperfecta (OI) type VI is caused by recessive null mutations in SERPINF1, encoding pigment epithelium-derived factor (PEDF), an anti-angiogenic secretory glycoprotein. Dominant mutations in IFITM5, encoding BRIL (Bone Restricted Ifitm-Like), a transmembrane protein upregulated in osteoblasts during mineralization, cause either type V OI (c.-14C>T, addition of 5 amino acids on BRIL) or atypical type VI OI (...

Introduction: Osteogenesis imperfecta (OI) is a genetically heterogeneous disorder characterized by bone fragility. OI type V, with autosomal dominant inheritance, is characterized by ossification of the forearm interosseus membrane, radiodense metaphyseal bands, propensity for hyperplastic callus formation, and mesh-like lamellation on bone histology. Type V OI probands are reported to have white sclerae and normal teeth. Recent reports identified the cause of type V OI as a ...

Objectives: The Brtl mouse, a unique model for the autosomal dominant forms of osteogenesis imperfecta was used to prove the feasibility of a lentiviral-shRNA-based strategy to improve collagen quality by targeting the mutant Col1a1 allele at the point mutation responsible for the causative substitution Gly349Cys. The ability to specifically suppress the mutant allele should convert the moderate Brtl outcome to the mild one caused by quantitative defect.<p class="...

Using a CyPB-null mouse model, we previously demonstrated delayed folding, abnormal post-translational modification and altered crosslinking of type I collagen synthesized by osteoblasts. However, intracellular folding of collagen molecules was further delayed by CsA treatment of CyPB-null cells, suggesting involvement of additional PPIases in collagen folding. Since studies of CyPA functions in osteoblasts have not been reported, we investigated the role of this cytoplasmic P...

Deficiency of Cyclophilin B (CyPB) causes recessively inherited Type IX osteogenesis imperfecta, a moderately severe to lethal bone dysplasia. CyPB, encoded by PPIB, is an ER-resident peptidyl-prolyl cis-trans isomerase (PPIase) that catalyzes the rate-limiting step in collagen folding, and also functions as a component of the collagen prolyl 3-hydroxylation complex. We previously demonstrated in a Ppib−/− mouse model that CyPB PPIase activity r...

Recessive osteogenesis imperfecta (OI) is caused by mutations in genes encoding proteins involved in post-translational interactions with type I collagen. A founder mutation in a new gene responsible for recessive OI has recently been reported in Bedouins from Israel and Saudi Arabia, who have a homozygous deletion of TMEM38B exon 4 and surrounding intronic sequence. TMEM38B encodes TRIC-B, an integral ER membrane monovalent cation channel involved in Ca...

Classical osteogenesis imperfecta (OI) is caused by mutations in the two genes encoding type I collagen. OI is associated with low bone mass and abnormally high bone matrix mineralization. The Brtl/+ OI mouse is a knock-in model caused by a glycine substitution in one COL1A1 allele. Brtl/+ pups display 30% perinatal lethality; survivors have small size and brittle bone. Unexpectedly, homozygous Brtl/Brtl pups, producing only mutant collagen, have normal survival rates...

Objectives: Osteogenesis Imperfecta (OI) is a collagen-related disorder. Type V OI, caused by a recurrent dominant mutation in the plasma membrane protein IFITM5/BRIL, and type VI OI, caused by recessive null mutations in the anti-angiogenic factor PEDF, have distinct features. IFITM5 S40L, reported in six patients, causes severe dominant OI with phenotype and bone histology similar to type VI, rather than Type V, OI. Our objective is to understand the pathway connecting IFITM...

Objectives: A common feature of nearly all forms of osteogenesis imperfecta (OI) is a hypermineralized bone matrix. Null mutations in SERPINF1, encoding the potent antiangiogenic factor PEDF, lead to type VI OI with excessive osteoid formation, abnormal osteoblast-osteocyte development and increased matrix mineralization. Recently, atypical type VI OI has been delineated, caused by a loss-of-function mutation (p.S40L) in IFITM5 the causative gene for type V OI. The 6 cases rep...

Osteogenesis imperfecta (OI) type V is caused by a unique dominant mutation (c.−14C>T) in IFITM5, which encodes BRIL, a transmembrane ifitm-like protein most strongly expressed in osteoblasts, while type VI OI is caused by recessive null mutations in SERPINF1, encoding pigment epithelium-derived factor (PEDF). We identified a 25-year-old woman with severe OI, whose dermal fibroblasts and cultured osteoblasts displayed minimal secretion of PEDF, but ...