| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
on Fas-Induced Apoptosis in Rheumatoid Arthritis Synovial Fibroblasts1
* Division of Experimental Rheumatology and Orthopedics, Institute of Microbiology, Institute of Experimental Internal Medicine, and Clinic of Orthopedic Surgery, Otto-von-Guericke University, Magdeburg, Germany; ¶ Division of Vascular and Connective Tissue Research, Gaubius Laboratory, Netherlands Central Organization for Applied Scientific Research Prevention and Health, Leiden, The Netherlands; || Department of Rheumatology, Leiden University Medical Center, Leiden, The Netherlands; and # Division of Molecular Medicine of Musculoskeletal Tissue, Department of Orthopaedic Surgery, University Munster, Munster, Germany
Apart from counteracting matrix metalloproteinases, tissue inhibitor of metalloproteinases-3 (TIMP-3) has proapoptotic properties. These features have been attributed to the inhibition of metalloproteinases involved in the shedding of cell surface receptors such as the TNFR. However, little is known about effects of TIMP-3 in cells that are not susceptible to apoptosis by TNF-
. In this study, we report that gene transfer of TIMP-3 into human rheumatoid arthritis synovial fibroblasts and MRC-5 human fetal lung fibroblasts facilitates apoptosis and completely reverses the apoptosis-inhibiting effects of TNF-. Although TNF- inhibits Fas/CD95-induced apoptosis in untransfected and mock-transfected cells, fibroblasts ectopically expressing TIMP-3 are sensitized most strongly to Fas/CD95-mediated cell death by TNF-. Neither synthetic MMP inhibitors nor glycosylated bioactive TIMP-3 are able to achieve these effects. Gene transfer of TIMP-3 inhibits the TNF--induced activation of NF-
B in rheumatoid arthritis synovial fibroblasts and reduces the up-regulation of soluble Fas/CD95 by TNF-, but has no effects on the cell surface expression of Fas. Collectively, our data demonstrate that intracellularly produced TIMP-3 not only induces apoptosis, but also modulates the apoptosis-inhibiting effects of TNF- in human rheumatoid arthritis synovial fibroblast-like cells. Thus, our findings may stimulate further studies on the therapeutic potential of gene transfer strategies with TIMP-3.
This article has been cited by other articles:
|
|
 |
|
  F. Li and T. E. Curry Jr. Regulation and Function of Tissue Inhibitor of Metalloproteinase (TIMP) 1 and TIMP3 in Periovulatory Rat Granulosa Cells Endocrinology, August 1, 2009; 150(8): 3903 - 3912. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Chetty, S. S. Lakka, P. Bhoopathi, S. Kunigal, R. Geiss, and J. S. Rao Tissue Inhibitor of Metalloproteinase 3 Suppresses Tumor Angiogenesis in Matrix Metalloproteinase 2-Down-regulated Lung Cancer Cancer Res., June 15, 2008; 68(12): 4736 - 4745. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Bukowska, L. Schild, G. Keilhoff, D. Hirte, M. Neumann, A. Gardemann, K. H. Neumann, F.-W. Rohl, C. Huth, A. Goette, et al. Mitochondrial Dysfunction and Redox Signaling in Atrial Tachyarrhythmia Experimental Biology and Medicine, May 1, 2008; 233(5): 558 - 574. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. L. Peng Fas (CD95)-related apoptosis and rheumatoid arthritis Rheumatology, January 1, 2006; 45(1): 26 - 30. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T Pap, I Meinecke, U Muller-Ladner, and S Gay Are fibroblasts involved in joint destruction? Ann Rheum Dis, November 1, 2005; 64(suppl_4): iv52 - iv54. [Full Text] [PDF]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
