Induction of COX‐2 Expression by Mechanical Tension Force in Human Periodontal Ligament Cells

Abstract

Occlusal trauma is caused by excessive occlusal forces and is associated with alveolar bone loss. In the periodontal ligament (PDL), which primarily receives the occlusal force, there is increased prostaglandin E (PGE2) synthesis in response to mechanical stress, and many studies have shown that PGE2 is involved in the pathogenesis of periodontal diseases. Recently, two isozymes of cyclooxygenase, COX-1 and COX-2, which are key enzymes in prostaglandin (PG) biosynthesis, were identified and COX-2 was induced following the activation of cells by a variety of proinflammatory agents. However, the biosynthetic pathway of mechanical stress-dependent PGE2 from PDL cells has not been well understood. When cyclic tension force was applied to human PDL cells (18% increase in surface area), PGE2 release to the culture medium increased in a time-dependent manner. As analyzed by semi-quantitative PCR, COX-2 mRNAs, while hardly detectable in controls, increased dramatically on day 3 and 5 in response to tension force. In contrast, COX-1 mRNAs detected in controls were not affected by tension force. By immunocytochemical staining, COX-2 protein was significantly increased by tension force around the unstained cell nucleus in a time-dependent manner. When NS-398, a selective COX-2 inhibitor, was added to the medium, PGE2 synthesis increased by tension force was completely inhibited. These results indicate that tension force induces COX-2 in human PDL cells and that this induction is responsible for the augmentation of PGE2 production stimulated by tension force. Since selective COX-2 inhibitors have less adverse effects compared with those of non-steroidal anti-inflammatory drugs, they may be of therapeutic benefit for treatment of periodontal disease accompanying traumatic occlusion.

Signaling by mechanical strain involves transcriptional regulation of proinflammatory genes in human periodontal ligament cells in vitro

“…In response to applied mechanical forces, osteoblast-like PDL cells perceive mechanical signals and respond to them via cellular events such as cell proliferation, differentiation, matrix catabolism, and matrix synthesis. 6,9,16,24,25 These events, in turn, are controlled by sequential synthesis of cytokines and growth factors that regulate bone resorption at compression sites and bone synthesis at tension sites. 9,14,16,23 It is well documented that compressive forces induce expression of proinflammatory mediators, and interleukin-β (IL-1β) has been implicated as one of the major cytokines synthesized in response to compressive forces exerted on the PDL.…”

“…9,14,16,23 It is well documented that compressive forces induce expression of proinflammatory mediators, and interleukin-β (IL-1β) has been implicated as one of the major cytokines synthesized in response to compressive forces exerted on the PDL. 4,13,14,16,23 IL-1β stimulates prostaglandin estradiol (PGE 2 ) synthesis, 9,16,19,[23][24][25]30 Nitric oxide (NO) production, 9,28,30 and secretion of proteases. 7,10,19 Simultaneously, IL-1β induces synthesis of matrix metalloproteinases (MMPs) to augment matrix degradation, 2,12,18 and also inhibits synthesis of tissue inhibitor of metalloprotease-II (TIMP-II), a potent suppressor of MMP activity.…”

“…2,9,10,22-25 IL-1β and PGE 2 are found at both tension and compression sides of the tooth. 9,13,[23][24][25] The presence of these bone-resorptive mediators in the PDL has raised the question as to how anabolic events like bone deposition occur at tension sites in an environment primed for catabolic processes.…”

“…20,21 In contrast, TENS of higher magnitude (12.5%-18% elongation) induces PGE 2 and IL-1β production in PDL cells in vitro. 15,[23][24][25]29 Based on the aforementioned observations, we speculated that intracellular signals generated by tensile strain antagonize the actions of proinflammatory signals and allow bone deposition despite the presence of inflammatory mediators in the PDL. Therefore, we examined the effects of TENS alone on PDL cells, as well as in the presence of IL-1β, to mimic inflammatory conditions.…”

IL‐1β induces COX2, MMP‐1, ‐3 and ‐13, ADAMTS‐4, IL‐1β and IL‐6 in human tendon cells

“…However, endogenous IL-1p could cause subtle MMP induction resulting in tendon fibroblast-mediated matrix destruction in a feedback loop. Mechanical stimulation induces IL-1 p and COX2 in periodontal ligament cells in vitro [41]. Inducible cytokines have been detected in osteoarthritic cartilage, another example of which is characterized by degenerative changes caused after episodes of injury [33].…”