The importance of cyclooxigenase in dentistry: a narrative review

Abstract

Aim

Cyclooxygenase enzymes (COX) catalyze the conversion of arachidonic acid to prostaglandins and thromboxanes during pain and inflammation conditions. These enzymes have also been linked to several other conditions and diseases, and hence, in dentistry, it is crucial to identify the processes that increase the levels of these mediators. This paper aims to describe the significance of COX in dental practice through a narrative review.

Methods

Articles relating to COX upregulation published in English and Spanish over the last 51 years in databases such as EBSCO, Google Scholar, Science Direct, PubMed, and Web of Science; were analyzed.

Results

A total of 115 articles demonstrating the relationship between COX upregulation and multiple conditions and diseases of importance in prosthodontics, periodontics, oral pathology, orthodontics, and endodontics were included.

Conclusions

COX upregulation is related to inflammatory and malignant diseases in oral tissues, such as periodontitis, pulpitis, and oral cancer, nevertheless, its expression is advantageous in other fields of study such as orthodontics. Additionally, is well documented that dental materials provoke an undesired increase in COX expression, which could be a significant factor that directly affects pulpal health.

Prostaglandin-endoperoxide synthases; Dinoprostone; Periodontitis; Mouth neoplasms

Introduction

Cyclooxygenases are enzymes that regulate the production of prostanoids such as prostaglandins (PG) and thromboxanes which are potent lipid messengers synthesized from arachidonic acid. Cyclooxygenase-1 (COX-1), cyclooxygenase-2 (COX-2), and cyclooxygenase-3 (COX-3) are the three reported isoforms of this enzyme, all of which are encoded by distinct genes¹. Until recently, little was known about the function of the third isoform (COX-3)². COX-1 is constitutively expressed in many tissues and is indispensable for normal cell functioning, whereas COX-2 is an inducible enzyme³. Both are essential in various physiological and pathophysiological processes such as inflammation and cancer. In addition, these proteins are responsible for producing prostaglandin E2 (PGE2), an inflammatory mediator involved in an extensive range of effects such as vasodilation, potentiation of pain, and nociceptive responses⁴. The role of these enzymes in various oral disorders and pathologies has been widely studied. Increased COX-2 expression is associated with many conditions such as periodontitis, pulpitis, dental pain, and oral cancer.

This paper aims to provide an overview of the importance of cyclooxygenases in dentistry, the association of these enzymes with oral cavity pathologies and conditions, and the relevant aspects of their clinical implications.

Materials and methods

A literature search of the EBSCO, Google Scholar, Science Direct, PubMed and Web of Science databases for articles published in English and Spanish from 1971 to 2021 was performed. Search terms included: “Cyclooxygenase” and “Dentistry”, “COX-1” and “Dentistry”, “COX-2” and “Dentistry”.

Two hundred and thirteen duplicate studies were excluded from the articles retrieved. The search results were reviewed, the titles and abstracts were screened to remove studies outside the scope of this review, and 1962 articles were excluded. Then, the full text of all potentially eligible studies was obtained and further examined to exclude those that did not fulfill the inclusion criteria. In this step, 11 citations were removed. Ultimately, 115 studies were included, and the extracted information was organized in a spreadsheet (Excel, Microsoft Corporation, Redmond WA, USA) to facilitate analysis. A flow diagram of the literature is presented in Figure 1.

Figure 1
Flow diagram of the literature search and included studies

The inclusion criteria for the selection of articles were clinical case studies, review articles, and original articles with experimental studies, especially in humans and in vitro. Papers on perspectives and opinions, commentary articles, and book reviews were excluded.

Results

Cox in periodontitis progression

Understanding the mechanisms of COX expression in periodontal disease and its susceptibility to nonsteroidal anti-inflammatory drugs (NSAID’s), selective COX inhibitors, or other drugs could be important in the development of more effective treatments for periodontitis.

The gingival tissue of patients with the periodontal disease contains prostaglandins⁵, with exceptionally high levels of PGE2 in purulent exudates⁶. COX-2 overexpression in periodontal tissues is related to chronic periodontitis, bleeding index, inflammatory infiltrate, loss of connective tissue in the lamina propria, reduced clinical attachment, decrease radiographic alveolar bone mass, and inflammation⁷,⁸. In addition, high levels of PGE2 stimulate osteoclast bone resorption, and thereby promote the progression of periodontal disease⁹. These findings point to a link between COX, PGE2, and periodontitis, and the possibility that local production of these mediators contributes to the inflammatory changes seen in periodontal disease, particularly attachment loss mechanisms such as the breakdown of extracellular matrix and support structures as the disease progresses.

COX-2 expression is linked to the severity of periodontitis, and pharmacological suppression of this enzyme may have a beneficial effect on periodontitis progression. Consequently, some studies have focused on the use of NSAIDs or selective COX inhibitors for the treatment of periodontitis. Flurbiprofen, meclofenamate, naproxen, and ketoprofen were shown to suppress periodontitis-related COX activity in the human gingiva¹⁰, and celecoxib and rofecoxib inhibited PGE2 in gingival fibroblasts from patients with severe periodontitis¹¹. Moreover, nimesulide decreased PGE2 levels in the gingiva of patients with chronic periodontitis¹², and flurbiprofen reduced PGE2 expression in the crevicular fluid of patients with gingivitis¹³. The local reduction of PGE2, as well as positive outcomes in periodontal health, is attributed to the use of these anti-inflammatory drugs.

There are reports on how patients taking NSAIDs or COX-inhibitors, such as phenylbutazone, aspirin, etoricoxib, naproxen, ibuprofen, nimesulide, flurbiprofen, or meclofenamate, as a treatment for periodontal disease showed clinical improvement with decreased gingival index values, probing pocket depth, loss attachment, plaque index, gingival fluid volume, bleeding on probing, redness and bone loss¹²-¹⁹. Since the effectiveness of NSAIDs and COX-2 inhibitors on the inflammatory response of periodontal tissues can be clinically detected and may therefore help to avoid further disease progression, it can be considered COX-2 inhibition could be a helpful treatment for periodontal disease, with favorable clinical outcomes.

Because inflammatory mediator by-products synthesized by cyclooxygenase are responsible for periodontitis progression, this enzyme has potential use as a pharmaceutical target for treatment and as a biomarker of periodontal disease progression. NSAIDs or selective COX-2 inhibitors as adjuvants to traditional mechanical periodontal therapy may be a preferable option for a more effective treatment. Since the progression of periodontitis can be slowed by pharmacological modulation of COX-2 and PGE2 production, this mode of therapy could be regarded as a supplementary therapeutic option for periodontal disease; however, further research is required.

Cox association with cancer and precancerous lesions

Cancer lesions in the oral cavity can display aggressive behavior. Hence, identifying biomarkers that facilitate early diagnosis is key to developing more appropriate treatments options and improving the prognosis. There is evidence that COX-2 expression plays essential roles in cancerous and precancerous lesions in the head such as participating in malignant transformation, proliferation, cellular adhesion, immune surveillance, apoptosis, invasiveness, angiogenesis, metastasis, and tumor development²⁰,²¹. The increased energy demand of these malignant processes causes lipid metabolism disorders which in turn allow cancer cells to survive and proliferate. Consequently, aberrant levels of proteins and lipidic mediators associated with this pathway are linked to the risk or poor prognosis of a various malignancies²². Since COX-2 is an enzyme involved in lipid metabolism, any disruption in lipid synthesis, such as an increase in lipid utilization in cancer, will impact its upregulation.

The relationship between COX-2 expression and the progression of malignant and premalignant pathologies in the oral cavity can be understood by some common signaling pathways shared by growth factors²³. The findings of some studies suggested that COX-2 and PGE2 promote carcinogenesis and tumor recurrence in head and neck squamous cell carcinoma through cross-activation and the signaling loop of the epidermal growth factor receptor (EGFR), using a signaling pathway involving Akt activation²⁴,²⁵. This indicates that the EGF/AKT/COX-2/PGE2 signaling pathway may play an important role in the development and invasion of head and neck squamous cell carcinoma.

COX-2 overexpression has been linked to the severity or progression of various oral cancerous and precancerous lesions, including oral leucoplakia²⁶ and tongue squamous cell carcinoma²⁷. Additionally, COX-2 overexpression in the epithelium of oral lichen planus has been correlated with clinical severity, burning sensation, and pain symptoms²⁸. Moreover, COX-2 expression is significantly upregulated in radicular cysts, ameloblastomas, ameloblastic carcinomas, ameloblastic fibromas, and dentigerous cysts²⁹-³¹. COX-2 overexpression, which is involved in the carcinogenic process of these lesions, could be used as a possible indicator of the severity of malignancy of these conditions.

Information on COX-1 and its relationship with cancer is scarce. Nonetheless, there is evidence that benign salivary gland tumors, such as Whartin’s tumor, have high COX-1 and COX-2 protein expressions³². Additionally, COX-1 expression increases progressively from normal oral mucosa to hyperplasia, dysplasia, and finally, carcinoma. COX-2 is also expressed in hyperplasia, with maximum activation observed in dysplasia³³. Epidermal growth factor (EGF)-stimulated oral squamous cell carcinoma cell lines overexpressing COX-2 showed elevated PGE2 levels; however, COX-1 expression was unaffected²⁴. These results reveal an association between severity and increasing levels of cyclooxygenase expression, with COX-1 being linked to precancerous lesions and COX-2 overexpression being associated with cancerous lesions.

Understanding the molecular mechanisms of the relationship between cyclooxygenase and cancer is essential for the development of novel diagnostic biomarkers and therapeutic targets²². Excessive lipid levels promote cancer development by inducing an inflammatory response and upregulating multiple mediators³⁴. This results in unusual arachidonic acid metabolism, increasing COX-2/PGE2 activity and concentrations related to protumoral mechanisms, and poor outcome indicators in several types of cancer.

It is well known that early diagnosis is key to achieve a positive outcome in oral cancer. In this regard, COX-2 expression in cancerous and precancerous lesions in the oral cavity could be used as a prognostic biomarker; however, further research is needed. Additionally, COX-2 may represent a potential target for pharmacological approaches to manage these lesions.

Cox-related tissue destruction

As we delved further into the aforementioned topics, we found a common characteristic between the progression of periodontitis and cancerous lesions: an aggressive behavior characterized by destruction of the adjacent tissues. This contributes to bone degradation which in turn facilitates the spread of tumor or resorption of periodontal tissues.

It has been proposed that up-regulation of COX and PGE2 is associated with bone resorption in inflammatory conditions and space-occupying lesions⁹,³⁵. It promotes degradation, invasiveness and progression of the aforementioned pathologies in two ways: osteoclastic bone resorption and stimulation of other enzymes, such as matrix metalloproteinases (MMP), both of which involve a common endogenous pathway involving the receptor activator of NFkB ligand (RANKL)³⁶,³⁷.

For example, COX-2 and PGE2 mediate osteoclastogenesis, bone resorption, and upregulation of RANK, RANKL, and NFkB in a variety of cells and tissues, including dental pulp fibroblasts, periodontal ligament cells, gingival fibroblasts, and alveolar bone³⁷-⁴¹. These findings also support the hypothesis that decreasing PGE2 production by using COX-2 inhibitors may inhibit inflammatory bone resorption.

PGE2 increases RANKL expression in osteoblasts and fibroblasts, thereby enhancing osteoclastogenesis and bone resorption. A specific COX-2 inhibitor, NS-398, was shown to suppress this action, which can be reversed by adding exogenous PGE2 in vivo⁴². Furthermore, flurbiprofen prevents radiographic alveolar bone loss⁴³, while ketorolac rinse and orally-administered flurbiprofen was shown to reduce bone resorption and PGE2 levels in the gingival crevicular fluid of patients with periodontitis⁴⁴. In periodontal disease induced in rats, meloxicam prevented alveolar bone and cementum loss, along with a reduction in the number osteoclasts⁴⁵. These findings demonstrate the relevance of COX-2/PGE2 in bone resorption, as well as the efficacy of NSAIDs and selective COX-2 blockers drugs as potential treatments for periodontal disease.

It is critical to understand the mechanisms by which COX causes bone resorption. What other players, such as COX-regulated key enzymes, are involved in this phenomenon? MMPs are proteases involved in the physiological remodeling of extracellular matrix. An imbalance in the production and activity of these proteins could result in tissue destruction in the oral cavity⁴⁶. Increased levels of COX-2, MMP-1, MMP-3, and MMP-9 are associated with chronic periodontitis, and PGE2 could have a role in the degradation of extracellular matrix by inducing MMP production that can be downregulated by glucocorticoids⁴⁷,⁴⁸. The potential regulatory effects of arachidonic acid metabolites such as PGs on MMPs could cause tissue destruction in periodontitis development.

MMPs are involved in the deterioration of tissues during inflammatory responses. Under inflammatory conditions, the expression of MMP-1, MMP-3 and MMP-8 increased in gingival fibroblasts, and dexamethasone, celecoxib, and the COX-2 inhibitor NS-398 inhibited their expression⁴⁹-⁵¹. Furthermore, there is an association between PGE2 and MMP-8 overexpression in the crevicular fluid of patients with periodontitis, which could be reduced by meloxicam⁵²,⁵³. In addition, indomethacin significantly attenuates MMP-1 and MMP-8 upregulation in periodontal ligament cells⁵⁴.

Additionally, MMP-1, MMP-2, MMP-3, PGE2, and RANKL were overexpressed in odontogenic keratocyst fibroblasts under inflammatory conditions³⁶. Celecoxib reduced inflammatory-induced activation of COX-2, MMP-9, and NFkB in the rat alveolar bone³⁷. Conversely, COX-2 may exert anti-inflammatory effects in periodontal tissues through the downregulation of MMP-13 and MMP-14⁵¹,⁵⁵.

The interaction between COX and MMPs in tissue destruction is synergetic, where COX-2 initiates inflammation and promotes the activation of MMP, which subsequently triggers the tissue breakdown process, causing tissue damage and clinical inflammation. It is evident that COX-2 and PGE2 have regulatory effects on MMP expression and function, and that these effects can be affected by COX inhibitors.

Orthodonctic stimulation of COX

COX-related tissue destruction is present not only in pathological conditions or diseases, but can also be induced, in an advantageous way, for orthodontic purposes. Understanding the role of PGE2 in alveolar bone metabolism changes generated by orthodontic mechanical stress during tooth movement is essential to improve the comprehension of the bone biological response and its importance in orthodontics.

PGE2 is a proinflammatory mediator that is also one of the most effective osteoclast inducing agents (as previously stated); it is produced by a variety of cells in periodontal tissues. Therefore, it is essential to understand how the release of PGs in response to orthodontic mechanical stress promotes bone resorption and formation. Orthodontic tooth movement occurs as a result of therapeutic mechanical stress, causing bone remodeling that involves localized biochemical mediators, such as COX, which has been linked to the hyaline zone in the alveolar bone during orthodontic treatment⁵⁶,⁵⁷.

Periodontal ligament cells respond to mechanical stress by increasing the levels of PGE2, RANKL, bone resorptive activity, and osteoclastogenesis³⁹,⁵⁸. PGE2 is synthesized by osteoblasts and gingival fibroblasts exposed to mechanical stress⁵⁹,⁶⁰. In rats, compressive pressure was shown to prevent osteoblast differentiation and stimulate osteoclastic bone resorption via PGE2 production, which could be prevented by COX inhibition⁶¹,⁶². In contrast, the bone formation mechanism induced by orthodontic forces can also be stimulated through PGE2 synthesis. Osteoblastic cells exposed to compressive forces induce mineralization due to the increase in COX-2/PGE2 production⁶³. PGE2 levels could dictate the difference between bone resorption and formation in mechanical stress induced by orthodontic movements.

Some COX-related factors can improve orthodontic treatment outcomes. Mechanical vibration and local administration of PGE1 enhance alveolar bone resorption during orthodontic tooth movement via the cyclooxygenase pathway mechanism⁶⁴,⁶⁵. Other factors, such as the use of continuous light force or interrupted force do not show differences in PGE2 level changes in the gingiva; there is a sustained up-regulation in each kind of them⁶⁶.

Orthodontic treatment in the elderly is different because some of them are also treated for chronic inflammatory diseases and conditions, such as osteoporosis, which require pharmaceutical medications that could modify the outcomes of orthodontic treatment. There are reports that people over 35 years of age exhibit an increase in age-related COX-2 and PGE2 expression in periodontal ligament cells exposed to compressive force⁶⁷. The biphosphonate clodronate⁶⁸ and the COX inhibitor NS-398⁶⁹ reduced COX-2 and PGE2 synthesis overexpression in periodontal ligament fibroblasts exposed to mechanical stress. Furthermore, NSAIDs, such as etoricoxib, celecoxib, acetaminophen, rofecoxib, diclofenac, and aspirin inhibit orthodontic tooth movement in rats⁷⁰-⁷².

PGE2 modulation of bone metabolism may explain, at least in part, why optimal orthodontic force stimulates mineralization and bone resorption in an equilibrated way, resulting in the most effective tooth movement with fewer side effects, such as unwanted bone or root resorption.

Compression and tension stimulate bone metabolism through COX-2 induction, leading to increased PGE2 production and upregulation of RANKL expression, which is involved in the normal functioning of bone cells. PGs are helpful in clinical orthodontic treatment, and their manipulation may be the key to accelerating orthodontic tooth movement, whereas NSAIDs and selective COX-2 inhibitors could be considered for reducing pain and preventing undesired bone resorption.

Cox changes in pulpal and periapical disease

Changes in COX-2 production during pulpal inflammation can be used to predict disease prognosis and endodontic treatment outcomes. PGE2 levels rise throughout the transition from healthy pulp to reversible pulpitis, but decrease substantially when the pulpitis is irreversible⁷³. The increase in PGE2 levels occurs not only in inflamed pulp blood, irritated/painful pulpal tissues, and periapical lesions, but also in pulps of asymptomatic teeth with extensive restorations or cavities⁷⁴-⁷⁶. Its overexpression in irreversible pulpitis is caused by pulpal fibroblasts and macrophages⁷⁷. These studies suggest that PGE2 levels can be used to indicate the difference between symptomatic teeth with reversible and irreversible pulpitis when clinical endodontic diagnosis is in doubt; this measurement could be considered a parametrical value.

COX-2 triggered by endodontic pathogens and cytokines may play a role in the etiology of pulpal inflammation. Black-pigmented bacteria, IL-1β, IL-1α, TNF-α and TLR2 can upregulate COX-2 and PGE2 expression in pulp cells⁷⁸-⁸¹. In addition, lipopolysaccharide (LPS)-induced inflammation increased the expression of PGE2 membrane transporter proteins, microsomal PGE synthase, COX-2 dependent MMP-3, and PGE2 synthesis in rat dental pulp⁸²,⁸³.

PGE2 levels are lower in the pulp of patients taking NSAIDs⁷³. Indomethacin has been demonstrated to reduce PGE2 levels, vascular permeability, and periapical bone loss in rats with induced pulp inflammation⁸⁴,⁸⁵. Bradykinin and thrombin stimulate PGE2 production in dental-pulp fibroblasts, which can be inhibited by flurbiprofen, hydrocortisone, and dexamethasone⁸⁶. Moreover, meloxicam promotes proliferation, differentiation, and mineralization in LPS treated pulpal cells⁸⁷. Clinical trials are needed to evaluate whether NSAIDs and selective COX-2 inhibitors could be used to treat pulpitis and bone resorption in periapical lesions, decrease PGE2 levels, and promote the regeneration of dental pulp cells.

Regarding intracanal medication protocols, the addition of ciprofloxacin or chlorhexidine to calcium hydroxide was shown to be highly effective in lowering PGE2 levels⁸⁸,⁸⁹. In addition, there are some reports that, in rat pulps and pulpal cells, treatment with mineral trioxide aggregate (MTA) enhance the expression of PGE2 transporters and receptors in odontoblasts, endothelial cells, and nerve fibers, while also inducing the upregulation of COX-2 and PGE2 and activation of NFkB⁹⁰,⁹¹. Furthermore, the reparative dentinogenesis that occurs after MTA treatment involves mild inflammatory changes through COX-2/PGE2 and NFkB via a signaling pathway.

When immediate endodontic treatment is not possible for symptomatic pulpal diseases, the only option for temporary pain relief is to prescribe strong analgesics. However, pain associated with irreversible pulpitis is typically severe and difficult to tolerate. Therefore, it is necessary to consider other pharmacological therapies that could be used in such instances. Some reports have shown that intraosseous injection of the corticosteroid methylprednisolone decreases pulpal concentrations of PGE2, pain, and percussion pain in teeth with irreversible pulpitis while taking significantly fewer pain medications⁹²,⁹³. This therapy can be used temporarily alleviate the symptoms of irreversible pulpitis until definitive treatment can be perform.

PGE2 levels fluctuate during endodontic therapy. Spontaneous pain, sensitivity to percussion, pus, radiolucent area, sinus tract, and swelling, are significantly associated with high PGE2 concentrations in periapical exudates during root canal treatment⁹⁴,⁹⁵. PGE2 levels and the clinical manifestation of periapical periodontitis decreases markedly following endodontic therapy⁹⁶. These results suggest the central role of PGE2 in pulpitis and periapical diseases. However, concentrations of PGE2 in apical tissue fluid and postoperative pain were higher after the second endodontic treatment visit than after the first treatment visit, especially in teeth with large restorations and without pus discharge⁹⁵,⁹⁷. The reported increase in PGE2 could have resulted from periodontal ligament injuries related to canal instrumentation.

The proinflammatory function of PGE2 has been well documented; however, it has been described in in vitro experiments that through the augmentation of hepatocyte growth factor, a potent stimulator of regeneration, and the downregulation of MMP1⁹⁸,⁹⁹, PGE2 could exert a protective effect against dental pulp degeneration and inflammation.

PGE2 plays a key role in the pathogenesis of inflammatory pulpal diseases and may control disease manifestation and healing response following root canal therapy. COX-2 or PGE2 levels may help determine the severity of pulpal or periapical disease and treatment outcomes. As a therapeutic adjuvant, NSAIDs could be an excellent strategy to treat pulpal or periapical inflammation.

Dental materials and other substances that modulate COX expression

Some substances commonly used in dentistry that trigger cytotoxicity; which in turn could induce an inflammatory responses. For example, eugenol an endodontic obturation material, enhances COX-2 protein expression in human osteoblasts through the activation of NFkB, which can be inhibited by N-acetylcysteine¹⁰⁰. TEGDMA and BisGMA, both monomers of composite resin, induce the overexpression of COX-2 and PGE2 in dental pulp cells¹⁰¹,¹⁰². Dental bonding agents induce COX-2 overexpression in gingival fibroblasts¹⁰³. Tannin fluoride suppresses COX-2 and PGE2 expression induced by glass ionomer cement in dental pulp cells¹⁰⁴.

Other substances that are not frequently used in dentistry can modulate COX/PGE2 expression. For example, the substance emdogain (EMD), which is composed of enamel matrix proteins, elicits a proliferative response of periodontal ligament fibroblast through COX-2 upregulation, which can be inhibited by celecoxib¹⁰⁵. Retinoids inhibit both basal expression and EGF-mediated induction of COX-2 transcription and PGE2 production in squamous carcinoma cells; however, they do not affect levels of COX-1 expression¹⁰⁶. Pilocarpine reduces COX-2 dependent PGE2, and MMP-3 production in LPS-induced dental pulp inflammation in rats⁸². PGE2 levels in incisors exposed to dentinal injury increased moderately, whereas intradentinal administration of endotoxins or capsaicin resulted in a highly significant increase¹⁰⁷. Cyclosporine A reduces the expression of COX-2 in rat gingival fibroblasts¹⁰⁸. Multiple materials used in dentistry have been shown to increase COX expression, although further research is needed to fully understand these correlations.

Discussion

The effect of COX in conditions such as inflammation and pain has been extensively studied in dentistry¹⁰⁹; however, this enzyme also has a significant association with oral diseases, as discussed in this review. For this reason, we focus on other less well-known COX implications in dentistry that may have potential significance.

Since the majority of consultations in dentistry are related to pain¹¹⁰-¹¹⁴, dentists are well trained to treat it primarily with COX inhibitors¹¹⁵. However, it is necessary to understand how to modulate and interpret COX levels for the treatment of diseases related to COX upregulation. This may hold the key to complementary and preventive care of various oral disorders.

There are limitations in using COX inhibition as a treatment for many diseases or conditions such as those that are not pain-related, that are relevant in prosthodontics, periodontics, oral pathology, orthodontics, and endodontics. Therefore, this topic requires more exploration and research, especially regarding its clinical applications.

Conclusions

In many oral disorders, COX expression may hold the key to fundamental knowledge of disease processes and could be used to develop novel diagnostic and therapeutic procedures for multiple oral diseases (Figure 2). Although the exact role of COX in various conditions is not fully understood, it is clear that its upregulation is related to inflammatory and malignant diseases in oral tissues, such as periodontitis, pulpitis, and oral cancer, nevertheless, its expression is advantageous in other fields of study such as orthodontics.

Figure 2
Cyclooxygenase and their importance in dentistry

We suggest using COX levels to track periodontal disease progression, endodontic prognosis, differential diagnosis, and detection of periodontal ligament injury. In addition, this enzyme could be employed as a biomarker for early detection, prognosis, and progression of oral cancer. Finally, COX inhibition with drugs such as traditional NSAIDs or selective COX-2 inhibitors could provide an option for combining drug therapy and conventional treatments for periodontitis, pulpitis, and probably oral cancer.

COX-mediated bone resorption is one of the multiple factors involved in orthodontic tooth movement; its levels could be used for prognosis treatment and its utilization for tooth movement enhancement or inhibition to reduce bone and root resorption. Additionally, is well documented that dental materials provoke an undesired increase in COX expression, which could be a significant factor that directly affects pulpal health. Therefore, considering different materials could contribute to decreasing these complications and improving outcomes.

Although the importance of COX in dentistry is widely studied, there is a need for further research to understand its modulation from a clinical perspective and to identify substances other than NSAIDs and COX-2 selective inhibitors that can modulate COX levels in the oral cavity.

References

• ¹
  Hanna VS, Hafez EAA. Synopsis of arachidonic acid metabolism: A review. J Adv Res. 2018 Mar 13:11:23-32. doi: 10.1016/j.jare.2018.03.005.
• ²
  Smith WL, Murphy RC. The eicosanoids: cyclooxygenase, lipoxygenase and epoxygenase pathways. biochemistry of lipids, lipoproteins and membranes. 6. ed. Elsevier; 2015. p.259-96. doi: 10.1016/B978-0-444-63438-2.00009-2.
• ³
  Dubois RN, Abramson SB, Crofford L, Gupta RA, Simon LS, Van De Putte LB, et al. Cyclooxygenase in biology and disease. FASEB J. 1998 Sep;12(12):1063-73.
• ⁴
  Simmons DL, Botting RM, Hla T. Cyclooxygenase isozymes: the biology of prostaglandin synthesis and inhibition. Pharmacol Rev. 2004 Sep;56(3):387-437. doi: 10.1124/pr.56.3.3.
• ⁵
  El Attar TM, Lin HS. Relative conversion of arachidonic acid through lipoxygenase and cyclooxygenase pathways by homogenates of diseased periodontal tissues. J Oral Pathol. 1983 Feb;12(1):7-10. doi: 10.1111/j.1600-0714.1983.tb00311.x.
  » https://doi.org/10.1111/j.1600-0714.1983.tb00311.x
• ⁶
  Goodson JM, Dewhirst FE, Brunetti A. Prostaglandin E2 levels and human periodontal disease. Prostaglandins. 1974 Apr;6(1):81-5. doi: 10.1016/s0090-6980(74)80043-2.
• ⁷
  Zhang F, Engebretson SP, Morton RS, Cavanaugh PF Jr, Subbaramaiah K, Dannenberg AJ. The overexpression of cyclo-oxygenase-2 in chronic periodontitis. J Am Dent Assoc. 2003 Jul;134(7):861-7. doi: 10.14219/jada.archive.2003.0284.
  » https://doi.org/10.14219/jada.archive.2003.0284
• ⁸
  Mesa F, Aguilar M, Galindo-Moreno P, Bravo M, O’Valle F. Cyclooxygenase-2 expression in gingival biopsies from periodontal patients is correlated with connective tissue loss. J Periodontol. 2012 Dec;83(12):1538-45. doi: 10.1902/jop.2012.110561.
  » https://doi.org/10.1902/jop.2012.110561
• ⁹
  Offenbacher S, Heasman PA, Collins JG. Modulation of host PGE2 secretion as a determinant of periodontal disease expression. J Periodontol. 1993 May;64 Suppl 5S:432-44. doi: 10.1902/jop.1993.64.5s.432.
  » https://doi.org/10.1902/jop.1993.64.5s.432
• ¹⁰
  Offenbacher S, Odle BM, Green MD, Mayambala CS, Smith MA, Fritz ME, et al. Inhibition of human periodontal prostaglandin E2 synthesis with selected agents. Agents Actions. 1990 Mar;29(3-4):232-8. doi: 10.1007/BF01966452.
• ¹¹
  Tipton DA, Flynn JC, Stein SH, Dabbous MK. Cyclooxygenase-2 Inhibitors Decrease Interleukin-1β-Stimulated Prostaglandin E2 and IL-6 Production by Human Gingival Fibroblasts. J Periodontol. 2003 Dec;74(12):1754-63. doi: 10.1902/jop.2003.74.12.1754.
  » https://doi.org/10.1902/jop.2003.74.12.1754
• ¹²
  Vardar S, Baylas H, Huseyinov A. Effects of selective cyclooxygenase-2 inhibition on gingival tissue levels of prostaglandin E2 and prostaglandin F2alpha and clinical parameters of chronic periodontitis. J Periodontol. 2003 Jan;74(1):57-63. doi: 10.1902/jop.2003.74.1.57.
  » https://doi.org/10.1902/jop.2003.74.1.57
• ¹³
  Heasman PA, Offenbacher S, Collins JG, Edwards G, Seymour RA. Flurbiprofen in the prevention and treatment of experimental gingivitis. J Clin Periodontol. 1993 Nov;20(10):732-8. doi: 10.1111/j.1600-051x.1993.tb00699.x.
• ¹⁴
  Waite IM, Saxton CA, Young A, Wagg BJ, Corbett M. The periodontal status of subjects receiving non-steroidal anti-inflammatory drugs. J Periodontal Res. 1981 Jan;16(1):100-8. doi: 10.1111/j.1600-0765.1981.tb00953.x..
• ¹⁵
  Taiyeb Ali TB, Waite IM. The effect of systemic ibuprofen on gingival inflammation in humans. J Clin Periodontol. 1993 Nov;20(10):723-8. doi: 10.1111/j.1600-051x.1993.tb00697.x.
• ¹⁶
  Reddy MS, Palcanis KG, Barnett ML, Haigh S, Charles CH, Jeffcoat MK. Efficacy of meclofenamate sodium (Meclomen) in the treatment of rapidly progressive periodontitis. J Clin Periodontol. 1993 Oct;20(9):635-40. doi: 10.1111/j.1600-051x.1993.tb00708.x.
• ¹⁷
  Sekino S, Ramberg P, Lindhe J. The effect of systemic administration of ibuprofen in the experimental gingivitis model. J Clin Periodontol. 2005 Feb;32(2):182-7. doi: 10.1111/j.1600-051X.2005.00671.x.
• ¹⁸
  Aras H, Cağlayan F, Güncü GN, Berberoğlu A, Kilinç K. Effect of systemically administered naproxen sodium on clinical parameters and myeloperoxidase and elastase-like activity levels in gingival crevicular fluid. J Periodontol. 2007 May;78(5):868-73. doi: 10.1902/jop.2007.060412.
  » https://doi.org/10.1902/jop.2007.060412
• ¹⁹
  Vlad C, Vlad DC, Bucur A, Popescu R, Dumitraşcu V. Beneficial effects of selective cyclooxigenase-2 inhibitor etoricoxib in periodontitis. Ann Romanian Soc Cell Biol. 2012 Jan;17(1):211-6.
• ²⁰
  Cao Y, Prescott SM. Many actions of cyclooxygenase-2 in cellular dynamics and in cancer. J Cell Physiol. 2002 Mar;190(3):279-86. doi: 10.1002/jcp.10068.
• ²¹
  Mendes RA, Carvalho JF, Waal Iv. An overview on the expression of cyclooxygenase-2 in tumors of the head and neck. Oral Oncol. 2009 Oct;45(10):e124-8. doi: 10.1016/j.oraloncology.2009.03.016.
• ²²
  Long J, Zhang CJ, Zhu N, Du K, Yin YF, Tan X, Liao DF, Qin L. Lipid metabolism and carcinogenesis, cancer development. Am J Cancer Res. 2018 May 1;8(5):778-791.
• ²³
  Chandrasekharan NV, Simmons DL. The cyclooxygenases. Genome Biol. 2004;5(9):241. doi: 10.1186/gb-2004-5-9-241.
  » https://doi.org/10.1186/gb-2004-5-9-241.
• ²⁴
  Husvik C, Khuu C, Bryne M, Halstensen TS. PGE2 production in oral cancer cell lines is COX-2-dependent. J Dent Res. 2009 Feb;88(2):164-9. doi: 10.1177/0022034508329519.
  » https://doi.org/10.1177/0022034508329519
• ²⁵
  Yang CC, Tu HF, Wu CH, Chang HC, Chiang WF, Shih NC, et al. Up-regulation of HB-EGF by the COX-2/PGE2 signaling associates with the cisplatin resistance and tumor recurrence of advanced HNSCC. Oral Oncol. 2016 May;56:54-61. doi: 10.1016/j.oraloncology.2016.03.010.
• ²⁶
  Sinanoglu A, Soluk-Tekkesin M, Olgac V. Cyclooxygenase-2 and Ki67 Expression in Oral Leukoplakia: a Clinicopathological Study. J Oral Maxillofac Res. 2015 Jun;6(2):e3. doi: 10.5037/jomr.2015.6203.
• ²⁷
  Renkonen J, Wolff H, Paavonen T. Expression of cyclo-oxygenase-2 in human tongue carcinoma and its precursor lesions. Virchows Arch. 2002 Jun;440(6):594-7. doi: 10.1007/s00428-002-0616-y.
• ²⁸
  Chankong T, Chotjumlong P, Sastraruji T, Pongsiriwet S, Iamaroon A, Krisanaprakornkit S. Increased cyclooxygenase 2 expression in association with oral lichen planus severity. J Dent Sci. 2016 Sep;11(3):238-44. doi: 10.1016/j.jds.2015.12.002.
  » https://doi.org/10.1016/j.jds.2015.12.002
• ²⁹
  Tsai CH, Huang FM, Yang LC, Chou MY, Chang YC. Immunohistochemical localization of cyclooxygenase-2 in radicular cysts. Int Endod J. 2002 Oct;35(10):854-8. doi: 10.1046/j.1365-2591.2002.00584.x.
• ³⁰
  Alsaegh MA, Miyashita H, Taniguchi T, Zhu SR. Odontogenic epithelial proliferation is correlated with COX-2 expression in dentigerous cyst and ameloblastoma. Exp Ther Med. 2017 Jan;13(1):247-53. doi: 10.3892/etm.2016.3939.
• ³¹
  Sánchez-Romero C, Mosqueda-Taylor A, Delgado-Azañero W, Paes de Almedia O, Bologna-Molina R. Comparison of fatty acid synthase and cyclooxygenase-2 immunoexpression in embryonal, benign, and malignant odontogenic tissues. Oral Surg Oral Med Oral Pathol Oral Radiol. 2019 Apr;127(4):309-17. doi: 10.1016/j.oooo.2018.12.020.
• ³²
  Lipari L, Mauro A, Gallina S, Tortorici S, Buscemi M, Tete S, et al. Expression of gelatinases (MMP-2, MMP-9) and cyclooxygenases (COX-1, COX-2) in some benign salivary gland tumors. Int J Immunopathol Pharmacol. 2012 Jan-Mar;25(1):107-15. doi: 10.1177/039463201202500113.
• ³³
  Mauro A, Lipari L, Leone A, Tortorici S, Burruano F, Provenzano S, et al. Expression of cyclooxygenase-1 and cyclooxygenase-2 in normal and pathological human oral mucosa. Folia Histochem Cytobiol. 2010 Dec;48(4):555-63. doi: 10.2478/v10042-010-0066-3.
  » https://doi.org/10.2478/v10042-010-0066-3
• ³⁴
  Omabe M, Ezeani M, Omabe KN. Lipid metabolism and cancer progression: The missing target in metastatic cancer treatment. J Appl Biomed. 2014;13(1):47–59. doi: 10.1016/j.jab.2014.09.004.
  » https://doi.org/10.1016/j.jab.2014.09.004
• ³⁵
  Harris M, Jenkins MV, Bennett A, Wills MR. Prostaglandin production and bone resorption by dental cysts. Nature. 1973 Sep;245(5422):213-5. doi: 10.1038/245213a0.
• ³⁶
  Oka S, Kubota Y, Yamashiro T, Ogata S, Ninomiya T, Ito S, et al. Effects of positive pressure in odontogenic keratocysts. J Dent Res. 2005 Oct;84(10):913-8. doi: 10.1177/154405910508401008.
• ³⁷
  Ribeiro-Santos FR, Silva GGD, Petean IBF, Arnez MFM, Silva LABD, Faccioli LH, et al. Periapical bone response to bacterial lipopolysaccharide is shifted upon cyclooxygenase blockage. J Appl Oral Sci. 2019 Jun 3;27:e20180641. doi: 10.1590/1678-7757-2018-0641.
  » https://doi.org/10.1590/1678-7757-2018-0641
• ³⁸
  Nakao S, Ogata Y, Shimizu-Sasaki E, Yamazaki M, Furuyama S, Sugiya H. Activation of NFkappaB is necessary for IL-1beta-induced cyclooxygenase-2 (COX-2) expression in human gingival fibroblasts. Mol Cell Biochem. 2000 Jun;209(1-2):113-8. doi: 10.1023/a:1007155525020.
• ³⁹
  Kanzaki H, Chiba M, Shimizu Y, Mitani H. Periodontal ligament cells under mechanical stress induce osteoclastogenesis by receptor activator of nuclear factor kappaB ligand up-regulation via prostaglandin E2 synthesis. J Bone Miner Res. 2002 Feb;17(2):210-20. doi: 10.1359/jbmr.2002.17.2.210.
• ⁴⁰
  Kojima T, Yamaguchi M, Kasai K. Substance P stimulates release of RANKL via COX-2 expression in human dental pulp cells. Inflamm Res. 2006 Feb;55(2):78-84. doi: 10.1007/s00011-005-0013-5.
• ⁴¹
  Coon D, Gulati A, Cowan C, He J. The role of cyclooxygenase-2 (COX-2) in inflammatory bone resorption. J Endod. 2007 Apr;33(4):432-6. doi: 10.1016/j.joen.2006.12.001.
• ⁴²
  Lader CS, Flanagan AM. Prostaglandin E2, interleukin 1alpha, and tumor necrosis factor-alpha increase human osteoclast formation and bone resorption in vitro. Endocrinology. 1998 Jul;139(7):3157-64. doi: 10.1210/endo.139.7.6085.
• ⁴³
  Williams RC, Jeffcoat MK, Howell TH, Rolla A, Stubbs D, Teoh KW, et al. Altering the progression of human alveolar bone loss with the non-steroidal anti-inflammatory drug flurbiprofen. J Periodontol. 1989 Sep;60(9):485-90. doi: 10.1902/jop.1989.60.9.485.
• ⁴⁴
  Jeffcoat MK, Reddy MS, Haigh S, Buchanan W, Doyle MJ, Meredith MP, et al. A comparison of topical ketorolac, systemic flurbiprofen, and placebo for the inhibition of bone loss in adult periodontitis. J Periodontol. 1995 May;66(5):329-38. doi: 10.1902/jop.1995.66.5.329.
• ⁴⁵
  Bezerra MM, de Lima V, Alencar VB, Vieira IB, Brito GA, Ribeiro RA, et al. Selective cyclooxygenase-2 inhibition prevents alveolar bone loss in experimental periodontitis in rats. J Periodontol. 2000 Jun;71(6):1009-14. doi: 10.1902/jop.2000.71.6.1009.
• ⁴⁶
  Sorsa T, Tjäderhane L, Salo T. Matrix metalloproteinases (MMPs) in oral diseases. Oral Dis. 2004 Nov;10(6):311-8. doi: 10.1111/j.1601-0825.2004.01038.x.
• ⁴⁷
  Birkedal-Hansen H. Role of cytokines and inflammatory mediators in tissue destruction. J Periodontal Res. 1993 Nov;28(6 Pt 2):500-10. doi: 10.1111/j.1600-0765.1993.tb02113.x.
• ⁴⁸
  Li G, Yue Y, Tian Y, Li JL, Wang M, Liang H, et al. Association of matrix metalloproteinase (MMP)-1, 3, 9, interleukin (IL)-2, 8 and cyclooxygenase (COX)-2 gene polymorphisms with chronic periodontitis in a Chinese population. Cytokine. 2012 Nov;60(2):552-60. doi: 10.1016/j.cyto.2012.06.239.
  » https://doi.org/10.1016/j.cyto.2012.06.239
• ⁴⁹
  Domeij H, Yucel-Lindberg T, Modéer T. Signal pathways involved in the production of MMP-1 and MMP-3 in human gingival fibroblasts. Eur J Oral Sci. 2002 Aug;110(4):302-6. doi: 10.1034/j.1600-0722.2002.21247.x.
• ⁵⁰
  Sakaki H, Matsumiya T, Kusumi A, Imaizumi T, Satoh H, Yoshida H, et al. Interleukin-1beta induces matrix metalloproteinase-1 expression in cultured human gingival fibroblasts: role of cyclooxygenase-2 and prostaglandin E2. Oral Dis. 2004 Mar;10(2):87-93. doi: 10.1046/j.1354-523x.2003.00982.x.
• ⁵¹
  Vardar-Sengul S, Buduneli E, Turkoglu O, Buduneli N, Atilla G, Wahlgren J, et al. The effects of selective COX-2 inhibitor/celecoxib and omega-3 fatty acid on matrix metalloproteinases, TIMP-1, and laminin-5gamma2-chain immunolocalization in experimental periodontitis. J Periodontol. 2008 Oct;79(10):1934-41. doi: 10.1902/jop.2008.080001.
• ⁵²
  Söder B. Neutrophil elastase activity, levels of prostaglandin E2, and matrix metalloproteinase-8 in refractory periodontitis sites in smokers and non-smokers. Acta Odontol Scand. 1999 Apr;57(2):77-82. doi: 10.1080/000163599428940.
• ⁵³
  Buduneli N, Vardar S, Atilla G, Sorsa T, Luoto H, Baylas H. Gingival crevicular fluid matrix metalloproteinase-8 levels following adjunctive use of meloxicam and initial phase of periodontal therapy. J Periodontol. 2002 Jan;73(1):103-9. doi: 10.1902/jop.2002.73.1.103.
• ⁵⁴
  Guan SM, Shu L, Fu SM, Liu B, Xu XL, Wu JZ. Prevotella intermedia upregulates MMP-1 and MMP-8 expression in human periodontal ligament cells. FEMS Microbiol Lett. 2009 Oct;299(2):214-22. doi: 10.1111/j.1574-6968.2009.01748.x.
• ⁵⁵
  Noguchi K, Ruwanpura SM, Yan M, Yoshida N, Ishikawa I. Down-regulation of interleukin-1alpha-induced matrix metalloproteinase-13 expression via EP1 receptors by prostaglandin E2 in human periodontal ligament cells. Oral Microbiol Immunol. 2005 Feb;20(1):56-9. doi: 10.1111/j.1399-302X.2004.00187.x.
• ⁵⁶
  Roberts WE, Goodwin WC Jr, Heiner SR. Cellular response to orthodontic force. Dent Clin North Am. 1981 Jan;25(1):3-17.
• ⁵⁷
  Lilja E, Björnestedt T, Lindskog S. Cellular enzyme activity associated with tissue degradation following orthodontic tooth movement in man. Scand J Dent Res. 1983 Oct;91(5):381-90. doi: 10.1111/j.1600-0722.1983.tb00834.x.
• ⁵⁸
  Saito M, Saito S, Ngan PW, Shanfeld J, Davidovitch Z. Interleukin 1 beta and prostaglandin E are involved in the response of periodontal cells to mechanical stress in vivo and in vitro. Am J Orthod Dentofacial Orthop. 1991 Mar;99(3):226-40. doi: 10.1016/0889-5406(91)70005-H.
• ⁵⁹
  Ngan PW, Crock B, Varghese J, Lanese R, Shanfeld J, Davidovitch Z. Immunohistochemical assessment of the effect of chemical and mechanical stimuli on cAMP and prostaglandin E levels in human gingival fibroblasts in vitro. Arch Oral Biol. 1988;33(3):163-74. doi: 10.1016/0003-9969(88)90041-6.
  » https://doi.org/10.1016/0003-9969(88)90041-6
• ⁶⁰
  Sanuki R, Mitsui N, Suzuki N, Koyama Y, Yamaguchi A, Isokawa K, et al. Effect of compressive force on the production of prostaglandin E(2) and its receptors in osteoblastic Saos-2 cells. Connect Tissue Res. 2007;48(5):246-53. doi: 10.1080/03008200701541775.
• ⁶¹
  Yamasaki K, Miura F, Suda T. Prostaglandin as a mediator of bone resorption induced by experimental tooth movement in rats. J Dent Res. 1980 Oct;59(10):1635-42. doi: 10.1177/00220345800590101301.
  » https://doi.org/10.1177/00220345800590101301
• ⁶²
  Imamura K, Ozawa H, Hiraide T, Takahashi N, Shibasaki Y, Fukuhara T, et al. Continuously applied compressive pressure induces bone resorption by a mechanism involving prostaglandin E2 synthesis. J Cell Physiol. 1990 Aug;144(2):222-8. doi: 10.1002/jcp.1041440207.
• ⁶³
  Mitsui N, Suzuki N, Maeno M, Mayahara K, Yanagisawa M, Otsuka K, et al. Optimal compressive force induces bone formation via increasing bone sialoprotein and prostaglandin E(2) production appropriately. Life Sci. 2005 Nov;77(25):3168-82. doi: 10.1016/j.lfs.2005.03.037.
• ⁶⁴
  Yamasaki K, Shibata Y, Imai S, Tani Y, Shibasaki Y, Fukuhara T. Clinical application of prostaglandin E1 (PGE1) upon orthodontic tooth movement. Am J Orthod. 1984 Jun;85(6):508-18. doi: 10.1016/0002-9416(84)90091-5.
  » https://doi.org/10.1016/0002-9416(84)90091-5
• ⁶⁵
  Phusuntornsakul P, Jitpukdeebodintra S, Pavasant P, Leethanakul C. Vibration enhances PGE2, IL-6, and IL-8 expression in compressed hPDL cells via cyclooxygenase pathway. J Periodontol. 2018 Sep;89(9):1131-41. doi: 10.1002/JPER.17-0653.
• ⁶⁶
  Lee KJ, Park YC, Yu HS, Choi SH, Yoo YJ. Effects of continuous and interrupted orthodontic force on interleukin-1beta and prostaglandin E2 production in gingival crevicular fluid. Am J Orthod Dentofacial Orthop. 2004 Feb;125(2):168-77. doi: 10.1016/j.ajodo.2003.03.006.
• ⁶⁷
  Mayahara K, Kobayashi Y, Takimoto K, Suzuki N, Mitsui N, Shimizu N. Aging stimulates cyclooxygenase-2 expression and prostaglandin E2 production in human periodontal ligament cells after the application of compressive force. J Periodontal Res. 2007 Feb;42(1):8-14. doi: 10.1111/j.1600-0765.2006.00885.x.
• ⁶⁸
  Grimm S, Wolff E, Walter C, Pabst AM, Mundethu A, Jacobs C, et al. Influence of clodronate and compressive force on IL-1ß-stimulated human periodontal ligament fibroblasts. Clin Oral Investig. 2020 Jan;24(1):343-50. doi: 10.1007/s00784-019-02930-z.
• ⁶⁹
  Shimizu N, Ozawa Y, Yamaguchi M, Goseki T, Ohzeki K, Abiko Y. Induction of COX-2 expression by mechanical tension force in human periodontal ligament cells. J Periodontol. 1998 Jun;69(6):670-7. doi: 10.1902/jop.1998.69.6.670.
  » https://doi.org/10.1902/jop.1998.69.6.670
• ⁷⁰
  de Carlos F, Cobo J, Díaz-Esnal B, Arguelles J, Vijande M, Costales M. Orthodontic tooth movement after inhibition of cyclooxygenase-2. Am J Orthod Dentofacial Orthop. 2006 Mar;129(3):402-6. doi: 10.1016/j.ajodo.2005.11.020.
  » https://doi.org/10.1016/j.ajodo.2005.11.020
• ⁷¹
  Fang J, Li Y, Zhang K, Zhao Z, Mei L. Escaping the Adverse Impacts of NSAIDs on Tooth Movement During Orthodontics: Current Evidence Based on a Meta-Analysis. Medicine (Baltimore). 2016 Apr;95(16):e3256. doi: 10.1097/MD.0000000000003256.
• ⁷²
  Kirschneck C, Küchler EC, Wahlmann U, Proff P, Schröder A. Effects of the highly COX-2-selective analgesic NSAID etoricoxib on the rate of orthodontic tooth movement and cranial growth. Ann Anat. 2018 Nov;220:21-8. doi: 10.1016/j.aanat.2018.07.001.
• ⁷³
  Petrini M, Ferrante M, Ciavarelli L, Brunetti L, Vacca M, Spoto G. Prostaglandin E2 to diagnose between reversible and irreversible pulpitis. Int J Immunopathol Pharmacol. 2012 Jan-Mar;25(1):157-63. doi: 10.1177/039463201202500118.
• ⁷⁴
  Cohen JS, Reader A, Fertel R, Beck M, Meyers WJ. A radioimmunoassay determination of the concentrations of prostaglandins E2 and F2alpha in painful and asymptomatic human dental pulps. J Endod. 1985 Aug;11(8):330-5. doi: 10.1016/s0099-2399(85)80039-x.
• ⁷⁵
  McNicholas S, Torabinejad M, Blankenship J, Bakland L. The concentration of prostaglandin E2 in human periradicular lesions. J Endod. 1991 Mar;17(3):97-100. doi: 10.1016/S0099-2399(06)81737-1.
• ⁷⁶
  Nakanishi T, Matsuo T, Ebisu S. Quantitative analysis of immunoglobulins and inflammatory factors in human pulpal blood from exposed pulps. J Endod. 1995 Mar;21(3):131-6. doi: 10.1016/s0099-2399(06)80438-3.
• ⁷⁷
  Nakanishi T, Shimizu H, Hosokawa Y, Matsuo T. An immunohistological study on cyclooxygenase-2 in human dental pulp. J Endod. 2001 Jun;27(6):385-8. doi: 10.1097/00004770-200106000-00003.
• ⁷⁸
  Lin SK, Kuo MY, Wang JS, Lee JJ, Wang CC, Huang S, et al. Differential regulation of interleukin-6 and inducible cyclooxygenase gene expression by cytokines through prostaglandin-dependent and -independent mechanisms in human dental pulp fibroblasts. J Endod. 2002 Mar;28(3):197-201. doi: 10.1097/00004770-200203000-00013.
• ⁷⁹
  Chang YC, Tsai CH, Yang SH, Liu CM, Chou MY. Induction of cyclooxygenase-2 mRNA and protein expression in human gingival fibroblasts stimulated with nicotine. J Periodontal Res. 2003 Oct;38(5):496-501. doi: 10.1034/j.1600-0765.2003.00681.x.
• ⁸⁰
  Chang MC, Chen YJ, Tai TF, Tai MR, Li MY, Tsai YL, et al. Cytokine-induced prostaglandin E2 production and cyclooxygenase-2 expression in dental pulp cells: downstream calcium signalling via activation of prostaglandin EP receptor. Int Endod J. 2006 Oct;39(10):819-26. doi: 10.1111/j.1365-2591.2006.01156.x.
• ⁸¹
  Park C, Lee SY, Kim HJ, Park K, Kim JS, Lee SJ. Synergy of TLR2 and H1R on Cox-2 Activation in Pulpal Cells. J Dent Res. 2010 Feb;89(2):180-5. doi: 10.1177/0022034509354720.
• ⁸²
  De Couto Pita A, Borda E, Ganzinelli S, Passafaro D, Sterin-Borda L. Cholinoceptor modulation on nitric oxide regulates prostaglandin E(2) and metalloproteinase-3 production in experimentally induced inflammation of rat dental pulp. J Endod. 2009 Apr;35(4):529-36. doi: 10.1016/j.joen.2009.01.004.
• ⁸³
  Ohkura N, Shigetani Y, Yoshiba N, Yoshiba K, Okiji T. Prostaglandin transporting protein-mediated prostaglandin E2 transport in lipopolysaccharide-inflamed rat dental pulp. J Endod. 2014 Aug;40(8):1112-7. doi: 10.1016/j.joen.2013.12.024.
• ⁸⁴
  Okiji T, Morita I, Sunada I, Murota S. Involvement of arachidonic acid metabolites in increases in vascular permeability in experimental dental pulpal inflammation in the rat. Arch Oral Biol. 1989;34(7):523-8. doi: 10.1016/0003-9969(89)90090-3.
  » https://doi.org/10.1016/0003-9969(89)90090-3
• ⁸⁵
  Oguntebi BR, Barker BF, Anderson DM, Sakumura J. The effect of indomethacin on experimental dental periapical lesions in rats. J Endod. 1989 Mar;15(3):117-21. doi: 10.1016/S0099-2399(89)80131-1.
• ⁸⁶
  Sundqvist G, Rosenquist JB, Lerner UH. Effects of bradykinin and thrombin on prostaglandin formation, cell proliferation and collagen biosynthesis in human dental-pulp fibroblasts. Arch Oral Biol. 1995 Mar;40(3):247-56. doi: 10.1016/0003-9969(95)98813-e.
• ⁸⁷
  Li JY, Wang SN, Dong YM. [Anti-inflammatory and repaired effects of non-steroidal anti-inflammatory drugs on human dental pulp cells]. Beijing Da Xue Xue Bao Yi Xue Ban. 2020 Feb;52(1):24-9. Chinese. doi: 10.19723/j.issn.1671-167X.2020.01.004.
• ⁸⁸
  Martinho FC, Gomes CC, Nascimento GG, Gomes APM, Leite FRM. Clinical comparison of the effectiveness of 7- and 14-day intracanal medications in root canal disinfection and inflammatory cytokines. Clin Oral Investig. 2018 Jan;22(1):523-530. doi: 10.1007/s00784-017-2143-x.
• ⁸⁹
  Karataş E, Uluköylü E, Albayrak M, Bayır Y. Effect of calcium hydroxide alone or in combination with ibuprofen and ciprofloxacin on postoperative pain and periapical prostaglandin E2 level: a randomized clinical study. Prostaglandins Other Lipid Mediat. 2021 Apr;153:106525. doi: 10.1016/j.prostaglandins.2020.106525.
  » https://doi.org/10.1016/j.prostaglandins.2020.106525
• ⁹⁰
  Minamikawa H, Deyama Y, Nakamura K, Yoshimura Y, Kaga M, Suzuki K, et al. Effect of mineral trioxide aggregate on rat clonal dental pulp cells: expression of cyclooxygenase-2 mRNA and inflammation-related protein via nuclear factor kappa B signaling system. J Endod. 2009 Jun;35(6):843-6. doi: 10.1016/j.joen.2009.03.008.
• ⁹¹
  Ohkura N, Edanami N, Takeuchi R, Tohma A, Ohkura M, Yoshiba N, et al. Effects of pulpotomy using mineral trioxide aggregate on prostaglandin transporter and receptors in rat molars. Sci Rep. 2017 Jul;7(1):6870. doi: 10.1038/s41598-017-07167-y.
  » https://doi.org/10.1038/s41598-017-07167-y
• ⁹²
  Gallatin E, Reader A, Nist R, Beck M. Pain reduction in untreated irreversible pulpitis using an intraosseous injection of Depo-Medrol. J Endod. 2000 Nov;26(11):633-8. doi: 10.1097/00004770-200011000-00001.
• ⁹³
  Isett J, Reader A, Gallatin E, Beck M, Padgett D. Effect of an intraosseous injection of depo-medrol on pulpal concentrations of PGE2 and IL-8 in untreated irreversible pulpitis. J Endod. 2003 Apr;29(4):268-71. doi: 10.1097/00004770-200304000-00010.
• ⁹⁴
  Takayama S, Miki Y, Shimauchi H, Okada H. Relationship between prostaglandin E2 concentrations in periapical exudates from root canals and clinical findings of periapical periodontitis. J Endod. 1996 Dec;22(12):677-80. doi: 10.1016/s0099-2399(96)80063-x.
• ⁹⁵
  Alptekin NO, Ari H, Haliloglu S, Alptekin T, Serpek B, Ataoglu T. The effect of endodontic therapy on periapical exudate neutrophil elastase and prostaglandin-E2 levels. J Endod. 2005 Nov;31(11):791-5. doi: 10.1097/01.don.0000158010.43884.59.
• ⁹⁶
  Shimauchi H, Takayama S, Miki Y, Okada H. The change of periapical exudate prostaglandin E2 levels during root canal treatment. J Endod. 1997 Dec;23(12):755-8. doi: 10.1016/s0099-2399(97)80350-0.
• ⁹⁷
  Grga D, Dzeletović B, Damjanov M, Hajduković-Dragojlović L. Prostaglandin E2 in apical tissue fluid and postoperative pain in intact and teeth with large restorations in two endodontic treatment visits. Srp Arh Celok Lek. 2013 Jan-Feb;141(1-2):17-21. doi: 10.2298/sarh1302017g.
  » https://doi.org/10.2298/sarh1302017g
• ⁹⁸
  Ohnishi T, Suwa M, Oyama T, Arakaki N, Torii M, Daikuhara Y. Prostaglandin E2 predominantly induces production of hepatocyte growth factor/scatter factor in human dental pulp in acute inflammation. J Dent Res. 2000 Feb;79(2):748-55. doi: 10.1177/00220345000790020801.
• ⁹⁹
  Lin SK, Wang CC, Huang S, Lee JJ, Chiang CP, Lan WH, et al. Induction of dental pulp fibroblast matrix metalloproteinase-1 and tissue inhibitor of metalloproteinase-1 gene expression by interleukin-1alpha and tumor necrosis factor-alpha through a prostaglandin-dependent pathway. J Endod. 2001 Mar;27(3):185-9. doi: 10.1097/00004770-200103000-00012.
• ¹⁰⁰
  Lee YY, Yang SF, Ho WH, Lee YH, Hung SL. Eugenol modulates cyclooxygenase-2 expression through the activation of nuclear factor kappa B in human osteoblasts. J Endod. 2007 Oct;33(10):1177-82. doi: 10.1016/j.joen.2007.05.011.
  » https://doi.org/10.1016/j.joen.2007.05.011
• ¹⁰¹
  Chang MC, Lin LD, Chan CP, Chang HH, Chen LI, Lin HJ, et al. The effect of BisGMA on cyclooxygenase-2 expression, PGE2 production and cytotoxicity via reactive oxygen species- and MEK/ERK-dependent and -independent pathways. Biomaterials. 2009 Sep;30(25):4070-7. doi: 10.1016/j.biomaterials.2009.04.034.
• ¹⁰²
  Chang HH, Chang MC, Huang GF, Wang YL, Chan CP, Wang TM, et al. Effect of triethylene glycol dimethacrylate on the cytotoxicity, cyclooxygenase-2 expression and prostanoids production in human dental pulp cells. Int Endod J. 2012 Sep;45(9):848-58. doi: 10.1111/j.1365-2591.2012.02042.x.
• ¹⁰³
  Huang FM, Chang YC. Induction of cyclooxygenase-2 mRNA and protein expression by dentin bonding agents in human gingival fibroblasts. J Biomed Mater Res B Appl Biomater. 2004 Aug;70(2):297-302. doi: 10.1002/jbm.b.30045.
• ¹⁰⁴
  Nakamura K, Deyama Y, Yoshimura Y, Hashimoto M, Kaga M, Suzuki K, Yawaka Y. Tannin-fluoride preparation attenuates prostaglandin E2 production by dental pulp cells. Mol Med Rep. 2011 Jul-Aug;4(4):641-4. doi: 10.3892/mmr.2011.476.
• ¹⁰⁵
  Khedmat S, Seyedabadi M, Ghahremani MH, Ostad SN. Cyclooxygenase 2 plays a role in Emdogain-induced proliferation. J Periodontal Res. 2011 Feb;46(1):67-73. doi: 10.1111/j.1600-0765.2010.01313.x.
• ¹⁰⁶
  Mestre JR, Subbaramaiah K, Sacks PG, Schantz SP, Tanabe T, Inoue H, et al. Retinoids suppress epidermal growth factor-induced transcription of cyclooxygenase-2 in human oral squamous carcinoma cells. Cancer Res. 1997 Jul 15;57(14):2890-5.
• ¹⁰⁷
  Chidiac JJ, Hawwa N, Baliki M, Safieh-Garabedian B, Rifai K, Jabbur SJ, et al. A perfusion technique for the determination of pro-inflammatory mediators induced by intradental application of irritants. J Pharmacol Toxicol Methods. 2001 Nov-Dec;46(3):125-30. doi: 10.1016/s1056-8719(02)00164-8.
• ¹⁰⁸
  Chiang CY, Chen YT, Hung FM, Tu HP, Fu MM, Fu E. Cyclosporin-A inhibits the expression of cyclooxygenase-2 in gingiva. J Periodontal Res. 2007 Oct;42(5):443-9. doi: 10.1111/j.1600-0765.2006.00967.x.
• ¹⁰⁹
  Hargreaves K, Abbott PV. Drugs for pain management in dentistry. Aust Dent J. 2005 Dec;50(4 Suppl 2):S14-22. doi: 10.1111/j.1834-7819.2005.tb00378.x.
• ¹¹⁰
  Sindet-Pedersen S, Petersen JK, Götzsche PC. Incidence of pain conditions in dental practice in a Danish county. Community Dent Oral Epidemiol. 1985 Aug;13(4):244-6. doi: 10.1111/j.1600-0528.1985.tb01914.x.
• ¹¹¹
  Lacerda JT, Simionato EM, Peres KG, Peres MA, Traebert J, Marcenes W. [Dental pain as the reason for visiting a dentist in a Brazilian adult population]. Rev Saude Publica. 2004 Jun;38(3):453-8. Portuguese. doi: 10.1590/s0034-89102004000300017.
• ¹¹²
  Cohen LA, Bonito AJ, Akin DR, Manski RJ, Macek MD, Edwards RR, et al. Toothache pain: a comparison of visits to physicians, emergency departments and dentists. J Am Dent Assoc. 2008 Sep;139(9):1205-16. doi: 10.14219/jada.archive.2008.0336.
  » https://doi.org/10.14219/jada.archive.2008.0336
• ¹¹³
  Horst OV, Cunha-Cruz J, Zhou L, Manning W, Mancl L, DeRouen TA. Prevalence of pain in the orofacial regions in patients visiting general dentists in the Northwest Practice-based REsearch Collaborative in Evidence-based DENTistry research network. J Am Dent Assoc. 2015 Oct;146(10):721-8.e3. doi: 10.1016/j.adaj.2015.04.001. Erratum in: J Am Dent Assoc. 2015 Dec;146(12):874.
  » https://doi.org/10.1016/j.adaj.2015.04.001
• ¹¹⁴
  Rambabu T, Koneru S. Reasons for use and nonuse of dental services among people visiting a dental hospital in urban India: A descriptive study. J Educ Health Promot. 2018 Aug 2;7:99. doi: 10.4103/jehp.jehp_193_17.
• ¹¹⁵
  Pergolizzi JV, Magnusson P, LeQuang JA, Gharibo C, Varrassi G. The pharmacological management of dental pain. Expert Opin Pharmacother. 2020 Apr;21(5):591-601. doi: 10.1080/14656566.2020.1718651.

• Data availability
  Datasets related to this article will be available upon request to the corresponding author.

Edited by

Editor: Altair A. Del Bel Cury

Data availability

Data availability

Datasets related to this article will be available upon request to the corresponding author.

Publication Dates

• Publication in this collection
  22 Mar 2024
• Date of issue
  2024

History

• Received
  7 Oct 2022
• Accepted
  20 Jan 2023