Mechanical stretch enhances NF-kappaB-dependent gene expression and poly(ADP-ribose) synthesis in synovial cells.
Temporomandibular joint disorders (TMD) show complex symptoms associated with inflammation, pain and degeneration of the peripheral tissues including synovium. Although it is believed that excessive mechanical stress on synovium causes development of TMD, the molecular mechanism by which mechanical stress triggers TMD has still remained unclear. In order to examine the effect of mechanical stress on synoviocytes, rabbit synovial cells were cyclically stretched in vitro. The stretch efficiently increased the gene expressions of cyclooxygenase-2 (COX-2), inducible nitric oxide synthase (iNOS) and NF-kappaB responsive reporter gene constructs. The interruption of NF-kappaB activating pathway by inhibitors resulted in the abrogation of those expressions, indicating the pivotal role of NF-kappaB in the mechanical stretch-mediated COX-2 and iNOS expressions. In parallel, the stretch remarkably increased NO production and poly(ADP-ribose) (PAR) synthesis, suggesting that excessive amounts of NO causes DNA injury and in turn activates PAR synthesis by poly(ADP-ribose) polymerase (PARP). The inhibition of PAR synthesis by a PARP inhibitor or a radical scavenger enhanced the mechanical stretch-induced gene expressions in a NF-kappaB-independent manner, implying an involvement of PARP in the gene expression. Taken together, these results demonstrate that mechanical stress on synovial cells not only induces gene expressions of COX-2 and iNOS but also affects PAR synthesis.
Morisugi
Toshiaki
T
Department of Oral and Maxillofacial Surgery, Nara Medical University, Shijio-cho 840, Kashihara, Nara 634-8521, Japan. t_morisugi@hotmail.com
Tanaka
Yasuharu
Y
Kawakami
Tetsuji
T
Kirita
Tadaaki
T
D000111:Acetylcysteine / Q000494:pharmacology; D000818:Animals; D002478:Cells, Cultured; D003474:Curcumin / Q000494:pharmacology; D051546:Cyclooxygenase 2 / Q000235:genetics* / Q000378:metabolism; D016166:Free Radical Scavengers / Q000494:pharmacology; D005786:Gene Expression Regulation; D007546:Isoquinolines / Q000494:pharmacology; D007976:Leupeptins / Q000494:pharmacology; D016328:NF-kappa B / Q000378:metabolism*; D009569:Nitric Oxide / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000235:genetics* / Q000378:metabolism; D010880:Piperidines / Q000494:pharmacology; D011064:Poly Adenosine Diphosphate Ribose / Q000096:biosynthesis*; D011759:Pyrrolidines / Q000494:pharmacology; D011817:Rabbits; D013314:Stress, Mechanical; D013329:Structure-Activity Relationship; D013583:Synovial Membrane / Q000166:cytology* / Q000378:metabolism; D013859:Thiocarbamates / Q000494:pharmacology
D016166:Free Radical Scavengers; D007546:Isoquinolines; D007976:Leupeptins; D016328:NF-kappa B; D010880:Piperidines; D011759:Pyrrolidines; D013859:Thiocarbamates; C020972:pyrrolidine dithiocarbamic acid; D011064:Poly Adenosine Diphosphate Ribose; D009569:Nitric Oxide; C108729:3,4-dihydro-5-(4-(1-piperidinyl)butoxy)-1(2H)-isoquinolinone; D052247:Nitric Oxide Synthase Type II; D051546:Cyclooxygenase 2; D003474:Curcumin; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde; D000111:Acetylcysteine