Epigenetics and rheumatoid arthritis: the role of SENP1 in the regulation of MMP-1 expression.

Maciejewska-Rodrigues H, Karouzakis E, Strietholt S, Hemmatazad H, Neidhart M, Ospelt C, Gay RE, Michel BA, Pap T, Gay S, Jüngel A

Forschungsartikel (Zeitschrift) | Peer reviewed

Zusammenfassung

The aggressive phenotype of RA synovial fibroblasts (RASF) is characterised by the increased expression of matrix metalloproteinase (MMP)-1 as well as the small ubiquitin like modifier (SUMO)-1 and decreased expression of SUMO-specific protease SENP1. Since we showed an increased activity of acetyltransferases in this autoimmune disease, we wanted to analyze whether this affects the expression of MMP-1 and can be reversed by the reconstitution of SENP1. In RASF, the acetylation of histone H4 was significantly increased in the distal region of the MMP-1 promoter by 274 +/- 36% compared to OASF. Most interestingly, overexpression of SENP1 in RASF decreased acetylation specifically in this region by 51 +/- 0.5% and globally by 73 +/- 11%. Furthermore, the overexpression of SENP1 resulted in a downregulation of MMP-1 at both the mRNA (58 +/- 7%) and protein levels (28 +/- 6%), significantly reduced the invasiveness of RASF (from 34 +/- 9% to 2 +/- 2%) and led to an accumulation of histone deacetylase 4 (HDAC4) on the MMP-1 promoter (197 +/- 36%). Interestingly, SENP1 failed to modulate the expression of MMP-1 in the cells silenced for HDAC4. This is the first study linking the SUMOylation pathway and the production of MMP-1 to an epigenetic control mechanism mediated through histone acetylation which has a functional consequence for the invasiveness of RASF.

Details zur Publikation

FachzeitschriftJournal of Autoimmunity (J Autoimmun)
Jahrgang / Bandnr. / Volume35
Ausgabe / Heftnr. / Issue1
Seitenbereich15-22
StatusVeröffentlicht
Veröffentlichungsjahr2010
Sprache, in der die Publikation verfasst istEnglisch
DOI10.1016/j.jaut.2009.12.010
StichwörterHistones; Endopeptidases; RNA Small Interfering; Animals; Acetylation; Synovial Membrane; Repressor Proteins; Matrix Metalloproteinase 1. Dogs; Arthritis Rheumatoid; Fibroblasts; Humans; Neoplasm Invasiveness; Promoter Regions Genetic; Epigenesis Genetic; Cell Line; Transgenes; Histone Deacetylases; Cloning Molecular; Histones; Endopeptidases; RNA Small Interfering; Animals; Acetylation; Synovial Membrane; Repressor Proteins; Matrix Metalloproteinase 1. Dogs; Arthritis Rheumatoid; Fibroblasts; Humans; Neoplasm Invasiveness; Promoter Regions Genetic; Epigenesis Genetic; Cell Line; Transgenes; Histone Deacetylases; Cloning Molecular

Autor*innen der Universität Münster

Pap, Thomas
Institut für Muskuloskelettale Medizin (IMM)
Strietholt, Simon
Institut für Muskuloskelettale Medizin (IMM)