Altered cytoskeletal organization characterized lethal but not surviving Brtl+/- mice: insight on phenotypic variability in osteogenesis imperfecta

被引：30

作者：

Bianchi, Laura ^{[1
]}

Gagliardi, Assunta ^{[1
]}

Maruelli, Silvia ^{[2
]}

Besio, Roberta ^{[2
]}

Landi, Claudia ^{[1
]}

Gioia, Roberta ^{[2
]}

Kozloff, Kenneth M. ^{[3
]}

Khoury, Basma M. ^{[3
]}

Coucke, Paul J. ^{[4
]}

Symoens, Sofie ^{[4
]}

Marini, Joan C. ^{[5
]}

Rossi, Antonio ^{[2
]}

Bini, Luca ^{[1
]}

Forlino, Antonella ^{[2
]}

机构：

[1] Univ Siena, Dept Life Sci, Funct Prote Lab, I-53100 Siena, Italy

[2] Univ Pavia, Biochem Unit, Dept Mol Med, I-27100 Pavia, Italy

[3] Univ Michigan, Dept Orthopaed Surg, Orthopaed Res Labs, Ann Arbor, MI 48109 USA

[4] Univ Ghent, Ctr Med Genet, B-9000 Ghent, Belgium

[5] NICHD, Bone & Extracellular Matrix Branch, NIH, Bethesda, MD USA

来源：

HUMAN MOLECULAR GENETICS | 2015年 / 24卷 / 21期

关键词：

MURINE MODEL; MOUSE MODEL; I COLLAGEN; INTERMEDIATE-FILAMENTS; INTEGRIN RECEPTORS; CELL-SHAPE; OSTEOBLAST; ACTIN; PROTEINS; DIFFERENTIATION;

D O I：

10.1093/hmg/ddv328

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Osteogenesis imperfecta (OI) is a heritable bone disease with dominant and recessive transmission. It is characterized by a wide spectrum of clinical outcomes ranging from very mild to lethal in the perinatal period. The intra- and inter-familiar OI phenotypic variability in the presence of an identical molecular defect is still puzzling to the research field. We used the OI murine model Brtl(+/-) to investigate the molecular basis of OI phenotypic variability. Brtl(+/-) resembles classical dominant OI and shows either a moderately severe or a lethal outcome associated with the same Gly349Cys substitution in the alpha 1 chain of type I collagen. A systems biology approach was used. We took advantage of proteomic pathway analysis to functionally link proteins differentially expressed in bone and skin of Brtl(+/-) mice with different outcomes to define possible phenotype modulators. The skin/bone and bone/skin hybrid networks highlighted three focal proteins: vimentin, stathmin and cofilin-1, belonging to or involved in cytoskeletal organization. Abnormal cytoskeleton was indeed demonstrated by immunohistochemistry to occur only in tissues from Brtl(+/-) lethal mice. The aberrant cytoskeleton affected osteoblast proliferation, collagen deposition, integrin and TGF-beta signaling with impairment of bone structural properties. Finally, aberrant cytoskeletal assembly was detected in fibroblasts obtained from lethal, but not from non-lethal, OI patients carrying an identical glycine substitution. Our data demonstrated that compromised cytoskeletal assembly impaired both cell signaling and cellular trafficking in mutant lethal mice, altering bone properties. These results point to the cytoskeleton as a phenotypic modulator and potential novel target for OI treatment.

引用

页码：6118 / 6133

页数：16

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