A New Perspective on Osteogenesis Imperfecta: From Cellular Mechanisms to the Systemic Impact of Collagen Dysfunction

TL;DR

This paper explores how collagen defects in osteogenesis imperfecta cause cellular stress and multiorgan issues, suggesting new treatment approaches.

Contribution

The paper introduces an integrated view of collagen dysfunction linking cellular stress to systemic disease effects in osteogenesis imperfecta.

Findings

Collagen defects in OI cause endoplasmic reticulum stress and mitochondrial dysfunction.

Misfolded collagen leads to oxidative damage and inflammation, contributing to multisystemic disease.

Targeting proteostasis pathways may improve cell homeostasis and patient outcomes in OI.

Abstract

Osteogenesis imperfecta (OI) is a rare genetic disease caused by mutations in collagen type I, leading to defective protein folding and an impaired extracellular matrix structure and remodelling. Beyond skeletal fragility, these molecular defects trigger a network of intracellular stress responses with multiorgan implications: the accumulation of misfolded collagen can induce persistent endoplasmic reticulum stress, which can in turn compromise mitochondrial function and autophagy or lead to cell death activation, and it can even promote widespread redox imbalance and inflammation. The interplay between intracellular stress, widespread oxidative damage and inflammation not only underlies cellular dysfunction but also the multisystemic manifestations of osteogenesis imperfecta. Targeting these interconnected pathways may result in new insights for a better understanding of OI and possibly offer novel therapeutic strategies designed to restore proteostasis and improve cell homeostasis and overall patient outcomes, highlighting the need for an integrated understanding of the cellular and molecular mechanisms involved in the pathogenesis of this disease and their translation into patient-centred therapeutic interventions.

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