Collagen crosslinking: effect on structure, mechanics and fibrosis progression

Area of Science:

• Biochemistry
• Biophysics
• Cell Biology

Background:

• Biophysical properties of the extracellular matrix (ECM), including stiffness and fibrous structure, are critical regulators of fibrosis and chronic disease progression.
• ECM crosslinking, both enzymatic and non-enzymatic, profoundly alters these biophysical properties and subsequent cellular responses, driving disease pathogenesis.
• A comprehensive understanding of ECM crosslinking mechanisms is lacking but essential for identifying novel therapeutic strategies.

Purpose of the Study:

• To review the primary crosslinking mechanisms prevalent in chronic diseases such as fibrosis, cancer, and osteoarthritis.
• To consolidate current knowledge on the biochemical reactions, impacts on ECM properties, and cellular behavior alterations associated with ECM crosslinking.
• To explore potential pharmaceutical interventions and clinical studies targeting ECM crosslinking processes.

Main Methods:

• Literature review focusing on enzymatic and non-enzymatic crosslinking reactions in chronic diseases.
• Analysis of the effects of crosslinking on ECM biophysical properties (stiffness, viscoelasticity, structure).
• Investigation of cellular responses to altered ECM crosslinking and examination of disease models.

Main Results:

• Crosslinking reactions significantly modify ECM composition and biomechanical characteristics, influencing cell behavior and disease progression.
• Identified common crosslinking mechanisms across various chronic diseases, highlighting their pathological roles.
• Summarized existing and potential pharmaceutical interventions targeting ECM crosslinking, alongside relevant clinical data.

Conclusions:

• ECM crosslinking is a pivotal mechanism in chronic diseases, offering potential therapeutic targets.
• Limitations in current pharmaceutical development stem from a lack of systemic, multi-level investigations into crosslinking influences.
• Further research is needed to address unclarified questions regarding crosslinking mechanisms and overcome challenges in developing targeted therapeutics.