Expression of transforming growth factor-beta 1 in dystrophic patient muscles correlates with fibrosis. Pathogenetic role of a fibrogenic cytokine.

Duchenne muscular dystrophy is a fatal disorder characterized by progressive muscular weakness, wasting, and severe muscle contractures in later disease stages. Muscle biopsy reveals conspicuous myofiber degeneration and fibrosis substituting muscle tissue. We quantitatively determined mRNA of the potent fibrogenic cytokine transforming growth factor-beta 1 by quantitative PCR in 15 Duchenne muscular dystrophy, 13 Becker muscular dystrophy, 11 spinal muscular atrophy patients, and 16 controls. Higher transforming growth factor-beta 1 expression was greater in Duchenne muscular dystrophy patients than controls (P = 0.012) and Becker patients (P = 0.03). Fibrosis was significantly more prominent in Duchenne muscular dystrophy than Becker muscular dystrophy, spinal muscular atrophy, and controls. The proportion of connective tissue in muscle biopsies increased progressively with age in Duchenne muscular dystrophy patients, while transforming growth factor-beta 1 levels peaked at 2 and 6 yr of age. Transforming growth factor-beta 1 protein was also detected by immunocytochemistry and immunoblotting. Our findings suggest that transforming growth factor-beta 1 stimulates fibrosis in Duchenne muscular dystrophy. Expression of transforming growth factor-beta 1 in the early stages of Duchenne muscular dystrophy may be critical in initiating muscle fibrosis and antifibrosis treatment could slow progression of the disease, increasing the utility of gene therapy.

[1]  M. Sporn,et al.  Transforming growth factor type beta: rapid induction of fibrosis and angiogenesis in vivo and stimulation of collagen formation in vitro. , 1986, Proceedings of the National Academy of Sciences of the United States of America.

[2]  E. Ruoslahti,et al.  Antibodies against transforming growth factor-beta 1 suppress intimal hyperplasia in a rat model. , 1994, The Journal of clinical investigation.

[3]  G. Proetzel,et al.  Targeted disruption of the mouse transforming growth factor-β1 gene results in multifocal inflammatory disease , 1992, Nature.

[4]  M. Gebbia,et al.  Very small dystrophin molecule in a family with a mild form of Becker dystrophy , 1993, Neuromuscular Disorders.

[5]  T. Colby,et al.  Transforming growth factor beta 1 is present at sites of extracellular matrix gene expression in human pulmonary fibrosis. , 1991, Proceedings of the National Academy of Sciences of the United States of America.

[6]  Eric P. Hoffman,et al.  Dystrophin: The protein product of the duchenne muscular dystrophy locus , 1987, Cell.

[7]  W. Border,et al.  Transforming Growth Factor β in Tissue Fibrosis , 1994 .

[8]  E. Hoffman,et al.  Dystrophin-deficient myofibers are vulnerable to mast cell granule-induced necrosis , 1994, Neuromuscular Disorders.

[9]  S. Wahl,et al.  Antagonistic and agonistic effects of transforming growth factor-beta and IL-1 in rheumatoid synovium. , 1990, Journal of immunology.

[10]  V. Dubowitz,et al.  A role for collagen in the pathogenesis of muscular dystrophy? , 1980, Nature.

[11]  L. Kunkel,et al.  The molecular basis for Duchenne versus Becker muscular dystrophy: correlation of severity with type of deletion. , 1989, American journal of human genetics.

[12]  J. Massagué,et al.  The TGF-β family and its composite receptors , 1994 .

[13]  S. Friedman The Cellular Basis of Hepatic Fibrosis -- Mechanisms and Treatment Strategies , 1993 .

[14]  M. V. Doyle,et al.  Quantitation of mRNA by the polymerase chain reaction. , 1989, Proceedings of the National Academy of Sciences of the United States of America.

[15]  S. Galli New concepts about the mast cell , 1994 .

[16]  S. Wahl,et al.  Reversal of acute and chronic synovial inflammation by anti- transforming growth factor beta , 1993, The Journal of experimental medicine.

[17]  M. Suthanthiran,et al.  Differential regulation of transforming growth factor beta and interleukin 2 genes in human T cells: demonstration by usage of novel competitor DNA constructs in the quantitative polymerase chain reaction , 1991, The Journal of experimental medicine.

[18]  S. Wahl,et al.  Transforming growth factor beta 1 suppresses acute and chronic arthritis in experimental animals. , 1991, The Journal of clinical investigation.

[19]  J. Dasch,et al.  Monoclonal antibodies recognizing transforming growth factor-beta. Bioactivity neutralization and transforming growth factor beta 2 affinity purification. , 1989, Journal of immunology.

[20]  F. Cornelio,et al.  T‐Cell Infiltration in Polymyositis Is Characterized by Coexpression of Cytotoxic and T‐Cell‐Activating Cytokine Transcripts a , 1995, Annals of the New York Academy of Sciences.

[21]  D. Hyde,et al.  Effect of antibody to transforming growth factor beta on bleomycin induced accumulation of lung collagen in mice. , 1993, Thorax.

[22]  Cecil B. Day,et al.  Elevated basic fibroblast growth factor in the serum of patients with Duchenne muscular dystrophy , 1994, Annals of neurology.

[23]  J. Miller,et al.  Randomized, double-blind six-month trial of prednisone in Duchenne's muscular dystrophy. , 1989, The New England journal of medicine.

[24]  A. Engel,et al.  Monoclonal antibody analysis of mononuclear cells in myopathies. I: Quantitation of subsets according to diagnosis and sites of accumulation and demonstration and counts of muscle fibers invaded by T cells , 1984, Annals of neurology.

[25]  P. Jullien,et al.  Acidic cellular environments: Activation of latent tgf‐β and sensitization of cellular responses to tgf‐β and egf , 1989 .

[26]  E. Kovacs Fibrogenic cytokines: the role of immune mediators in the development of scar tissue. , 1991, Immunology today.

[27]  E. Hoffman,et al.  A role for mast cells in the progression of Duchenne muscular dystrophy? Correlations in dystrophin-deficient humans, dogs, and mice , 1994, Journal of the Neurological Sciences.