Intracellular and Extracellular Markers of Lethality in Osteogenesis Imperfecta: A Quantitative Proteomic Approach.

Luca Bini,Jean-Charles Sanchez,Roberta Besio,Chiara Carnemolla,Domitille Schvartz,Nadia Garibaldi,Antonella Forlino,Laura Bianchi

doi:10.3390/ijms22010429

Abstract

Osteogenesis imperfecta (OI) is a heritable disorder that mainly affects the skeleton. The inheritance is mostly autosomal dominant and associated to mutations in one of the two genes, COL1A1 and COL1A2, encoding for the type I collagen α chains. According to more than 1500 described mutation sites and to outcome spanning from very mild cases to perinatal-lethality, OI is characterized by a wide genotype/phenotype heterogeneity. In order to identify common affected molecular-pathways and disease biomarkers in OI probands with different mutations and lethal or surviving phenotypes, primary fibroblasts from dominant OI patients, carrying COL1A1 or COL1A2 defects, were investigated by applying a Tandem Mass Tag labeling-Liquid Chromatography-Tandem Mass Spectrometry (TMT LC-MS/MS) proteomics approach and bioinformatic tools for comparative protein-abundance profiling. While no difference in α1 or α2 abundance was detected among lethal (type II) and not-lethal (type III) OI patients, 17 proteins, with key effects on matrix structure and organization, cell signaling, and cell and tissue development and differentiation, were significantly different between type II and type III OI patients. Among them, some non–collagenous extracellular matrix (ECM) proteins (e.g., decorin and fibrillin-1) and proteins modulating cytoskeleton (e.g., nestin and palladin) directly correlate to the severity of the disease. Their defective presence may define proband-failure in balancing aberrances related to mutant collagen.

Highlights

Osteogenesis imperfecta (OI) is a clinically and genetically heterogeneous rare disease (1/10,000–15,000 live births) affecting mainly bone, but impairing extraskeletal tissues functionality [1]
No definitive therapy currently exists for this disease [11] and the comprehension of cellular and biochemical mechanisms that determine OI molecular aberrances is crucial in the attempt to improve its clinical management and innovative and more effective therapies development
En route for this ambitious goal, we attempted to ameliorate the understanding of OI affected molecular pathways and of their possible influence on the outcome of the disorder by identifying protein differences occurring among lethal OI type II and non-lethal OI type III patients, which carry glycine substitution at different positions along the α chains of collagen type I

Summary

Introduction

Osteogenesis imperfecta (OI) is a clinically and genetically heterogeneous rare disease (1/10,000–15,000 live births) affecting mainly bone, but impairing extraskeletal tissues functionality [1]. It is mainly inherited as an autosomal dominant disorder (80–85%). #120150) or COL1A2 (MIM #120160) genes, which encode the α1 and α2 chains of type I procollagen, respectively. COL1A1/COL1A2 mutations may cause quantitative (haploinsufficiency) or qualitative defects of the collagen type I. Dominant qualitative defects, causing chain sequence alteration and synthesis and secretion of abnormal procollagen molecules, result in a wide spectrum of phenotypes: from perinatal lethal type II to moderate type IV based on OI Sillence classification The mutant collagen is generally secreted by the cells and responsible for the assembly of an abnormal extracellular matrix (ECM), a fraction of the protein is retained in the endoplasmic reticulum (ER), causing cellular stress responsible for unfolded protein response, autophagy, and apoptosis activation

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