Decorin interacts with connective tissue growth factor (CTGF)/CCN2 by LRR12 inhibiting its biological activity

Area of Science:

• Biochemistry
• Cell Biology
• Molecular Medicine

Background:

• Fibrotic disorders involve excessive extracellular matrix accumulation, primarily driven by connective tissue growth factor (CTGF/CCN2).
• The regulatory mechanisms governing CTGF activity remain largely unknown, hindering therapeutic development for fibrotic diseases.

Purpose of the Study:

• To investigate the role of decorin in modulating the pro-fibrotic activity of CTGF.
• To elucidate the molecular interactions between decorin and CTGF.

Main Methods:

• Comparative analysis of CTGF sensitivity in decorin null and wild-type myoblasts.
• Biochemical assays including co-immunoprecipitation and in vitro interaction studies.
• Assessment of decorin's regulatory effect on CTGF-induced fibronectin and collagen III accumulation and actin stress fiber formation.

Main Results:

• Decorin null myoblasts exhibit heightened sensitivity to CTGF-induced fibronectin and collagen III accumulation.
• Exogenous decorin inhibits CTGF's pro-fibrotic activity and actin stress fiber induction.
• Decorin directly binds to CTGF with high affinity (Kd = 4.4 nM), requiring decorin's core protein and specifically its leucine-rich repeats (LRRs) 10-12.
• A peptide derived from LRR12 inhibits CTGF-decorin complex formation and CTGF activity.
• CTGF was found to induce decorin synthesis, indicating a potential autoregulatory feedback loop.

Conclusions:

• Decorin acts as a direct negative regulator of CTGF's pro-fibrotic functions.
• The interaction between decorin and CTGF is specific and mediated by decorin's LRR domain.
• CTGF-induced decorin synthesis suggests an intrinsic mechanism for controlling fibrotic processes.