Increase in decorin and biglycan in Duchenne Muscular Dystrophy: role of fibroblasts as cell source of these proteoglycans in the disease

Abstract

Fibrosis is a common pathological feature observed in muscles of patients with Duchenne muscular dystrophy (DMD). Biglycan and decorin are small chondroitin/dermatan sulfate proteoglycans in the muscle extracellular matrix (ECM) that belong to the family of structurally related proteoglycans called small leucine-rich repeat proteins. Decorin is considered an anti-fibrotic agent, preventing the process by blocking TGF-β activity. There is no information about their expression in DMD patients. We found an increased amount of both proteoglycans in the ECM of skeletal muscle biopsies obtained from DMD patients. Both biglycan and decorin were augmented in the perimysium of muscle tissue, but only decorin increased in the endomysium as seen by immunohistochemical analyses. Fibroblasts were isolated from explants obtained from muscle of DMD patients and the incorporation of radioactive sulfate showed an increased synthesis of both decorin and biglycan in cultured fibroblasts compared to controls. The size of decorin and biglycan synthesized by DMD and control fibroblasts seems to be similar in size and anion charge. These findings show that decorin and biglycan are increased in DMD skeletal muscle and suggest that fibroblasts would be, at least, one source for these proteoglycans likely playing a role in the muscle response to dystrophic cell damage.

Altered production of extra-cellular matrix components by muscle-derived Duchenne muscular dystrophy fibroblasts before and after TGF-β1 treatment

“…We have revealed that both the digested core protein and the glycosylated form are of higher intensity in DMD fibroblast media than in control media. Fadic et al (2006) have also reported increased decorin (and also biglycan synthesis) in muscle-derived fibroblasts from a DMD patient compared with controls. Kuroda and Shinkai (1997) have detected higher levels of decorin transcripts in systemic sclerosis fibroblasts, and Westergren- Thorsson et al (2004) have reported increased levels of decorin secreted by primary fibroblasts derived from a fibrotic lung.…”

Novel regulatory mechanisms for the proteoglycans decorin and biglycan during muscle formation and muscular dystrophy

“…They bind several ECM and plasma membrane proteins during skeletal muscle differentiation, regulating myogenesis (Riquelme et al, 2001;Casar et al, 2004;Droguett et al, 2006;Mercado et al, 2006;Rafii et al, 2006;Cabello-Verrugio and Brandan, 2007). In recent years much interest has been given to the role of decorin in satellite cell myogenesis and muscle regeneration, for its ability to modulate myoblast responsiveness to members of the TGF-β family which in turns affect fibrosis, muscle differentiation and regeneration (Caceres et al, 2000;Riquelme et al, 2001;Sato et al, 2003;Fadic, 2005;McCroskery et al, 2005;Fadic et al, 2006;Cabello-Verrugio and Brandan, 2007).…”

Decorin Interacts with Connective Tissue Growth Factor (CTGF)/CCN2 by LRR12 Inhibiting Its Biological Activity

“…After 6 h, cells were infected with an adenovirus that contained human decorin whole sequence (38) using 500 plaque-forming units/cell in 4 ml of DMEM supplemented with 2% of heat-inactivated fetal bovine serum (38). After 90 min of incubation, standard growing medium was added, and the incubation was continued for 24 h. Cells were incubated with growing factors or radiolabeled with H 2 [ 35 S]SO 4 (23). Decorin and Deletion Mutants of Decorin-The wild type decorin and the mutants that lack different LRRs were generated by overlapping PCR starting from human decorin (NM_133593) cloned in pcDNA 3.1 (kindly donated by Elke Schönherr, Institute of Physiological Chemistry and Pathobiochemistry, Münster, Germany).…”

“…Duchenne muscular dystrophy is a disease caused by the absence of the protein dystrophin, which produces muscle weakness that leads to cycles of degeneration and regeneration of the muscle fibers, resulting in a decrease of muscle mass and an increase of connective tissue (21)(22)(23)(24). In this way, fibrotic scarring ensues, and the regeneration of muscle is precluded by this fibrotic scar.…”

“…In this way, fibrotic scarring ensues, and the regeneration of muscle is precluded by this fibrotic scar. Both TGF-␤ and CTGF are known to be overexpressed in this disease (23,25,26). Moreover, we have previously shown that myoblasts are able to participate in this fibrotic process because they are able not only to produce CTGF but also to respond to the growth factor by increasing ECM production and actin stress fiber formation (27).…”