Searchable abstracts of presentations at key conferences on calcified tissues

ba0005p82 | Bone Matrix | ECTS2016

CRISPR/Cas9-mediated IFITM5 gene editing demonstrates that BRIL (Ser40Leu) substitution suppresses PEDF-mediated activation of PPARγ

Kang Heeseog , Marini Joan

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 (...

ba0001pp500 | Other diseases of bone and mineral metabolism | ECTS2013

IFITM5 c.−14C>T mutation causes variable type V osteogenesis imperfecta phenotype and decreased COL1A1 expression but increased mineralization by cultured proband osteoblasts

Reich Adi , Bae Alison S , Barnes Aileen M , Cabral Wayne A , Chitayat David , Marini Joan C

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 ...

ba0002oc12 | Biology | ICCBH2013

Improvement of collagen synthesis in fibroblasts of Brtl model for osteogenesis imperfecta following lentiviral-shRNA-mediated down-expression of mutant Col1a1 allele

Trichet Valerie , Rousseau Julie , Gioia Roberta , Layrolle Pierre , Heymann Dominique , Rossi Antonio , Marini Joan , Forlino Antonella

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="...

ba0005oc6.5 | Development and differentiation (or Aging) | ECTS2016

Absence of cyclophilin A impairs endochondral bone formation by altering intracellular signaling pathways required for osteoblast maturation

Sargent Brandi , Ishikawa Masaki , Clevenger Charles , Yamada Yoshihiko , Cabral Wayne , Marini Joan

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...

ba0005p434 | Other diseases of bone and mineral metabolism | ECTS2016

Cyclophilin B deficiency is associated with defective differentiation of bone cell populations and bone hypermineralization

Cabral Wayne , Fratzl-Zelman Nadja , Blouin Stephane , Roschger Paul , Klaushofer Klaus , Marini Joan

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...

ba0003cc3 | (1) | ECTS2014

Absence of ER cation channel TMEM38B/TRIC-B causes recessive osteogenesis imperfecta by dysregulation of collagen post-translational modification

Cabral Wayne , Makareeva Elena , Ishikawa Masaki , Barnes Aileen , MaryAnn Weis , Lacbawan Felicitas , Eyre David , Yamada Yoshihiko , Leikin Sergey , Marini Joan

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...

ba0003pp17 | Bone biomechanics and quality | ECTS2014

Bone fragility and matrix hypermineralization is rescued in homozygous OI Brtl mice mutants

Fratzl-Zelman Nadja , Kozloff Kenneth M , Meganck Jeff , Reich Adi , Roschger Paul , Cabral Wayne , Klaushofer Klaus , Marini Joan

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...

ba0007oc21 | (1) | ICCBH2019

New mouse model with IFITM5 S42L for atypical type VI osteogenesis imperfecta

Guterman Ram Gali , Hedjazi Ghazal , Stephan Chris , Blouin Stephane , Roschger Paul , Klaushofer Klaus , Kozloff Ken , Fratzl-Zelman Nadja , Marini Joan

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...

ba0007oc22 | (1) | ICCBH2019

Bone tissue phenotyping reveals increased matrix mineralization, elevated osteocyte lacunar density and altered vascularity in a new OI mouse model carrying a leucine substitution for the BRIL p.Serine42 residue

Hedjazi Ghazal , Guterman-Ram Gali , Blouin Stephane , Roschger Paul , Klaushofer Klaus , Fratzl-Zelman Nadja , Marini Joan C

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...

ba0007oc21 | (1) | IMPE2023

New mouse model with IFITM5 S42L for atypical type VI osteogenesis imperfecta

Guterman Ram Gali , Hedjazi Ghazal , Stephan Chris , Blouin Stephane , Roschger Paul , Klaushofer Klaus , Kozloff Ken , Fratzl-Zelman Nadja , Marini Joan

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...