Novel function of TWEAK in inducing intervertebral disc degeneration.
The goal of this research was to examine the role of TWEAK in normal disc cells and to investigate its potential role in disc degeneration. We performed histological examinations of disc tissues and assessed the role of the novel cytokine TWEAK using murine organ disc culture. The expression of both TWEAK and its receptor, Fn14, in discs was confirmed by immunohistochemistry and quantitative real-time PCR. TWEAK induced disc cells to generate MMP-3 in a dose- and time-dependent manner. This induction was strongly inhibited in the presence of a neutralizing antibody to TWEAK or a chimeric Fn14/Fc fusion protein. In disc tissues derived from TNF-alpha receptor 1- or TNF-alpha receptor 2-deficient mice, recombinant TWEAK modestly induced MMP-3. In contrast, in disc cultures lacking TWEAK, tissues from wild-type mice or receptor-deficient mice failed to express MMP-3. Furthermore, aggrecan expression was potently abrogated in a time-dependent manner in the presence of recombinant TWEAK. This is the first report to confirm expression of TWEAK and its receptor Fn14 in murine intervertebral disc tissues. The data suggest that TWEAK plays a role in MMP-3 up-regulation and aggrecan down-regulation in disc tissues, resulting in proteoglycan degradation and promotion of disc degeneration.
Wako
Masanori
M
Department of Orthopaedic Surgery, Graduate School of Medicine and Engineering, University of Yamanashi.
Haro
Hirotaka
H
Ando
Takashi
T
Hatsushika
Kyosuke
K
Ohba
Tetsuro
T
Iwabuchi
Sadahiro
S
Nakao
Atsuhito
A
Hamada
Yoshiki
Y
D053674:Aggrecans / Q000378:metabolism; D000818:Animals; D019138:Antibodies, Blocking / Q000494:pharmacology; D000074049:Cytokine TWEAK; D004790:Enzyme Induction / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects; D020868:Gene Silencing; D007124:Immunoenzyme Techniques; D007403:Intervertebral Disc / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D007405:Intervertebral Disc Displacement; D019278:Matrix Metalloproteinase 3 / Q000096:biosynthesis; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018124:Receptors, Tumor Necrosis Factor / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000172:deficiency / Q000235:genetics; D011994:Recombinant Proteins / Q000494:pharmacology; D000074050:TWEAK Receptor; D048069:Tumor Necrosis Factors / Q000235:genetics / Q000276:immunology / Q000378:metabolism* / Q000494:pharmacology
D053674:Aggrecans; D019138:Antibodies, Blocking; D000074049:Cytokine TWEAK; D018124:Receptors, Tumor Necrosis Factor; D047888:Receptors, Tumor Necrosis Factor, Type I; D011994:Recombinant Proteins; D000074050:TWEAK Receptor; C469948:Tnfrh2 protein, mouse; C000613299:Tnfrsf12a protein, mouse; C506236:Tnfrsf1a protein, mouse; C491645:Tnfsf12 protein, mouse; D048069:Tumor Necrosis Factors; D019278:Matrix Metalloproteinase 3