TWEAK in inclusion-body myositis muscle: possible pathogenic role of a cytokine inhibiting myogenesis.
Tumor necrosis factor-like weak inducer of apoptosis (TWEAK) and its receptor Fn14 exert pleiotropic effects, including regulation of myogenesis. Sporadic inclusion-body myositis (IBM) is the most common muscle disease of the elderly population and leads to severe disability. IBM mesoangioblasts, different from mesoangioblasts in other inflammatory myopathies, display a myogenic differentiation defect. The objective of the present study was to investigate TWEAK-Fn14 expression in IBM and other inflammatory myopathies and explore whether TWEAK modulation affects myogenesis in IBM mesoangioblasts. TWEAK, Fn14, and NF-κB expression was assessed by immunohistochemistry and Western blot in cell samples from both muscle biopsies and primary cultures. Mesoangioblasts isolated from samples of IBM, dermatomyositis, polymyositis, and control muscles were treated with recombinant human TWEAK, Fn14-Fc chimera, and anti-TWEAK antibody. TWEAK-RNA interference was performed in IBM and dermatomyositis mesoangioblasts. TWEAK levels in culture media were determined by enzyme-linked immunosorbent assay. In IBM muscle, we found increased TWEAK-Fn14 expression. Increased levels of TWEAK were found in differentiation medium from IBM mesoangioblasts. Moreover, TWEAK inhibited myogenic differentiation of mesoangioblasts. Consistent with this evidence, TWEAK inhibition by Fn14-Fc chimera or short interfering RNA induced myogenic differentiation of IBM mesoangioblasts. We provide evidence that TWEAK is a negative regulator of human mesoangioblast differentiation. Dysregulation of the TWEAK-Fn14 axis in IBM muscle may induce progressive muscle atrophy and reduce activation and differentiation of muscle precursor cells.
Department of Neurosciences, Institute of Neurology, Università Cattolica, Rome, Italy.
Roberta
R
Morosetti
Carla
C
Gliubizzi
Cristina
C
Sancricca
Aldobrando
A
Broccolini
Teresa
T
Gidaro
Matteo
M
Lucchini
Massimiliano
M
Mirabella
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001706:Biopsy; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D017077:Culture Media, Conditioned / Q000378:metabolism; D000074049:Cytokine TWEAK; D020868:Gene Silencing; D006801:Humans; D008875:Middle Aged; D024510:Muscle Development / Q000187:drug effects / Q000502:physiology*; D018482:Muscle, Skeletal / Q000378:metabolism / Q000473:pathology; D018979:Myositis, Inclusion Body / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D016328:NF-kappa B / Q000378:metabolism; D020286:Pericytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D017285:Polymyositis / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D018124:Receptors, Tumor Necrosis Factor / Q000378:metabolism; D011994:Recombinant Proteins / Q000494:pharmacology; D013234:Stem Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D000074050:TWEAK Receptor; D048069:Tumor Necrosis Factors / Q000378:metabolism* / Q000494:pharmacology / Q000502:physiology; D055815:Young Adult
D017077:Culture Media, Conditioned; D000074049:Cytokine TWEAK; D016328:NF-kappa B; D034741:RNA, Small Interfering; D018124:Receptors, Tumor Necrosis Factor; D011994:Recombinant Proteins; C000613297:TNFRSF12A protein, human; C109743:TNFSF12 protein, human; D000074050:TWEAK Receptor; D048069:Tumor Necrosis Factors