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Year : 2019  |  Volume : 14  |  Issue : 3  |  Page : 268-271

Role of caspases in periodontal diseases


Department of Periodontics and Implantology, Sharad Pawar Dental College, Datta Meghe Institute of Medical Sciences (Deemed to be University), Wardha, Maharashtra, India

Date of Submission08-Jun-2019
Date of Decision10-Jul-2019
Date of Acceptance20-Aug-2019
Date of Web Publication2-May-2020

Correspondence Address:
Dr. Sudhindra Baliga
Department of Periodontics, Sharad Pawar Dental College, Datta Meghe Institute of Medical Sciences (Deemed to be University), Sawangi (Meghe), Wardha, Maharashtra
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jdmimsu.jdmimsu_39_19

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  Abstract 


Periodontitis is initiated by various Gram-negative bacteria characterized by the destruction of the periodontal tissue. Intracellular proteases, caspases that are the key mediators of apoptosis, are shown to involve in disease progression. The activation of caspase-3 and caspase-7 is considerably enhanced in the gingival tissue from patients with periodontitis. A considerable number of cells in the gingival epithelium and connective tissue revealed active caspases, whereas in healthy tissue, almost no caspase activation was observed. These results therefore suggest that caspase activation may be functionally involved in periodontitis-associated tissue damage.

Keywords: Aggressive periodontitis, caspase, chronic periodontitis, periodontal diseases Aggressive periodontitis, caspase, chronic periodontitis, periodontal diseases


How to cite this article:
Baliga V, Dhadse P, Ragit G, Lulla R, Baliga S, Nibudey A. Role of caspases in periodontal diseases. J Datta Meghe Inst Med Sci Univ 2019;14:268-71

How to cite this URL:
Baliga V, Dhadse P, Ragit G, Lulla R, Baliga S, Nibudey A. Role of caspases in periodontal diseases. J Datta Meghe Inst Med Sci Univ [serial online] 2019 [cited 2020 Sep 28];14:268-71. Available from: http://www.journaldmims.com/text.asp?2019/14/3/268/283588




  Introduction Top


Periodontitis, a common infectious disease, involves multiple factors in its initiation and progression. The most important initiating factor is various Gram-negative bacteria characterized by the destruction of the periodontal tissue, involving alveolar bone, cementum, periodontal ligament, and gingiva.[1] Although periodontopathogenic microorganisms are mainly responsible for direct pathological effects on the periodontal tissues, periodontal damage also seems to be inflicted by indirect mechanisms. Bacterial products act on the cellular constituents of the gingival tissues, activating cellular processes that induce the destruction of the connective tissue and bone. Immunohistochemical studies have established that the majority of mononuclear cells migrate toward the perivascular connective tissue to form an inflammatory infiltrate, which is mainly composed of neutrophils, T- and B-lymphocytes, and macrophages.[2]


  Apoptosis and Periodontitis Top


Several periodontal pathogens have been reported to induce cytotoxicity in a variety of cellular components of the periodontium. Short-chain carboxylic acids present in Porphyromonas gingivalis (Pg), Prevotella loescheii, and Fusobacterium nucleatum induce apoptosis in the T-cells and gingival keratinocytes.[3] Moreover, lipopolysaccharide, a common component of the cell wall of Gram-negative bacteria, stimulates butyric acid-induced apoptosis in the human peripheral blood mononuclear cells, also a toxin from Actinobacillus actinomycetemcomitans induces apoptosis in B-lymphocytes present in the periodontal tissue. All these data indicate that tissue destruction by apoptosis seems to play a relevant role in the pathogenesis of chronic adult periodontitis.[4]


  What Is Apoptosis Top


Programmed cell death or apoptosis is the process by which cells are induced to activate their own death or cell suicide. Apoptosis occurs in a wide variety of cell types and is recognized to have a major impact on the development of numerous systems. Histologically, the term apoptosis refers to the characteristic morphology of cells undergoing programmed cell death.[5] Apoptotic cells appear shrunken with extensive membrane, blebbing, and nuclear fragmentation. The final point in apoptosis involves the fragmentation of the cells into membrane-bound vesicles containing cellular remnants of protein and fragmented chromatin, referred to as apoptotic bodies. These membrane-bound vesicles are eventually phagocytosed by macrophages without the involvement of an inflammatory reaction.[6]


  Role of Caspase in Apoptosis Top


Recent studies demonstrate that apoptosis is essentially mediated by a family of cysteine proteases, called caspases, which can be divided into initiator and effector caspases. Initiator caspases, such as caspase-8 or -9, exert regulatory roles by activating downstream effector caspases, such as caspase-3, -6, or -7, which cleave various cellular substrates.[1]


  How Do Caspases Act? Top


Activation of caspases is achieved via two signaling pathways. The extrinsic death pathway involves the ligation of death receptors that leads to the recruitment of pro-caspase-8 into a death-inducing signaling complex. The intrinsic death pathway is initiated by the mitochondrial release of cytochrome c, a process that is inhibited by anti-apoptotic Bcl-2 proteins. When released, cytochrome c binds together with the apoptosis protease-activating factor-1 to procaspase-9 to form the apoptosome. Initiator caspases, such as caspase-8 or caspase-9, exert regulatory roles.[7]


  Role of Caspase in Periodontitis Top


Data fromin vitro cell cultures and a few reports of patient biopsies had suggested that apoptosis might play a role in periodontitis-associated gingival tissue damage. However, the relative contribution of apoptosis and the functional role of caspases in the periodontal tissue damage remained largely unknown. Studies demonstrated by immunoblot and substrate assays that caspase-3 and -7, two major effector caspases, are activated to a higher extent in the tissue homogenates from patients with chronic periodontitis than in healthy tissue. Furthermore, increased caspase activation was directly detectable in inflamed gingival biopsies.[7] A considerable number of cells in the gingival epithelium and connective tissue revealed active caspases, whereas in healthy tissue, almost no caspase activation was observed. These results therefore suggest that caspase activation may be functionally involved in periodontitis-associated tissue damage. Caspase-3 was observed in detectable levels in the gingival crevicular fluid (GCF) and not detected in the saliva and serum, which indicates that caspase-3 is activated and secreted locally by the mesenchymal cells, such as gingival and periodontal ligament fibroblasts and/or macrophages and neutrophils, into the GCF and not derived from systemic contribution or saliva contamination. Caspase-3 might have a shorter half-life that is easily captured in the GCF in which the cells are undergoing apoptosis rather than at distant sites in saliva or serum.[8]

Inflamed gingival fibroblasts from persons with adult periodontitis were highly susceptible to mitochondria- and caspase-dependent apoptosis induced by butyric acid, compared with healthy gingival fibroblasts. Activation of caspase involves butyric acid-induced apoptosis of inflamed gingival fibroblasts, death receptor-mediated signals, and stress-mediated signals. The butyric-acid-induced apoptosis of inflamed gingival fibroblasts was reduced by inhibitors of caspase-3/7, -6, -8, and -9. This suggests that caspase-3, -6, -7, -8, and -9 each play an essential role in the butyric-acidinduced apoptosis of inflamed gingival fibroblasts. Therefore, in the butyric-acid-induced apoptosis of inflamed gingival fibroblasts, death-receptor mediated and stress-mediated signals appear to cause caspase activation. However, because caspase inhibitors did not completely inhibit the inflamed gingival fibroblast apoptosis induced by butyric acid, factors other than caspases may also play an important role, together with caspases, in butyric-acid-induced apoptosis in inflamed gingival fibroblasts.[9]

Bantel et al. investigated the role of caspases, intracellular proteases that are the key mediators of apoptosis. They showed that activation of caspase-3 and caspase-7 is considerably enhanced in the gingival tissue from patients with periodontitis. They also demonstrated inin vitro experiments that various periodontopathic bacteria exert a direct growth-suppressing effect and moreover can trigger a host-mediated cytotoxic activity involving the CD95 death receptor. They suggested that caspase activation is a prominent feature in periodontitis-associated tissue injury.[1]

Using three independent markers, i.e., caspase-3 and -7 activation as well as poly(ADP-ribose)polymerase (PARP) cleavage, the results clearly show that caspase activation is found in the keratinocytes, basal cells, and connective tissue cells, cell types that are damaged in periodontitis. This finding is compatible with a study demonstrating that cells with p53 expression and DNA damage are mainly localized in the epithelium and connective tissue of periodontitis patients. The rate of cells showing caspase activation was considerably high with all three apoptotic markers, even though the cells often revealed no classical apoptotic alterations. This high number of cells with active caspases certainly exceeds the number of cells that can be usually detected by techniques measuring DNA fragmentation, which is a late event in apoptosis.[10] There are several possibilities to explain this finding. It is commonly assumed that activation of caspases results in apoptosis, although there is increasing evidence that within a cell, the extent of caspase activation may be restricted and not necessarily lead to cell death. More importantly is presumably the fact that caspase activation is a very early event in apoptosis. Cells in later stages might be rapidly phagocytosed by macrophages and therefore escape morphological detection.

Pg is a major etiologic agent for chronic periodontitis. Tissue destruction by Pg results partly from the induction of host inflammatory responses through TLR2 signaling. Studies examine the role of apoptosis-associated speck-like Apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC), an adaptor protein for inflammasome receptors, is essential for inducing caspase-1 activation Induction of interleukin (IL)-6, IL-8, IL-10, and tumor-necrosis-factor (TNF) also requires ASC, but this induction is not inhibited by IL-1 receptor antagonistor caspase-1 inhibitor. These results suggest a role for ASC in cytokine induction by Pg involving both caspase-1-dependent and -independent mechanisms.[11]

Behl et al., 2008 investigated how the acquired immune response could contribute to osteolytic lesions by injecting the periodontal pathogen Pgadjacent to calvarial bone with or without prior immunization against the bacterium. Knockdown of FOXO1 by siRNA significantly reduced cytokine-stimulated apoptosis, cleaved caspase-3/7 activity, and decreased mRNA levels of the proapoptotic genes, TNFα, FADD, caspase-3, -8, and -9. These results indicate that activation of the acquired immunity by a periodontal pathogen reduces the coupling of bone formation and resorption.[2]

Johnson and Wikle looked at gender differences in the inflammatory and apoptotic signaling molecules in both normal and diseased human gingiva by assessing caspase-3 expressions. According to their study, they found that females had the highest incidence of gingival apoptosis at sites of periodontal disease.[12]

Pradeep et al. showed that the GCF and serum concentration of caspase-3 proportionally increase with the progression of periodontal disease, that is, gingival inflammation, Probing pocket depth (PPD) and Clinical attachment level (CAL).[13]


  Role of Caspases in Aggressive Periodontitis Top


Bulut et al., 2006 investigated the clinical features and known indicators of apoptosis (p53, Bcl-2, caspase-3) in patients with generalized aggressive periodontitis (GAP). The expression of caspase-3, Bcl-2, and p53 was evaluated by immunohistochemistry. There were no significant differences between GAP and control group with respect to levels of caspase-3 and p53 expression (P > 0.05).[3]

Leukotoxin causes activation of caspase-1 and abundant secretion of bioactive IL-1β correlated with a high proportion of macrophages. The mononuclear leukocytes exposed to leukotoxin-deleted A. Actinomycetemcomitans or Pg at a ratio of 10 bacteria/leukocyte did not increase their content of cytosolic caspase-1.[14],[15],[16]

ATP upregulated p21WAF1/cip1, an inhibitor of cell-cycle progression, whereas ATPgS induced caspase-dependent apoptosis. Caspase-3/7 is a well-known key enzyme involved in many types of apoptotic cell death. When benzyloxycarbonyl-Val-Ala-Asp fluoromethyl ketone (50 mM), a pan-caspase inhibitor, 17 was added as a cotreatment, ATPgS-increased TUNEL activity was substantially blocked. Both ATP and ATPgS initially act to upregulate p21WAF1/cip1, but because of its ability to inhibit ecto-ATPase, only ATPgS could secondarily trigger caspase-dependent apoptosis through continued activation of the initial site of action or through secondary actions at other sites. It is also possible that another metabolite of ATPgS, thiophosphate, acts as a cytotoxic agent to activate those caspases, as shown in human leukemia HL-60 cells.[9]


  Conclusion Top


The mechanisms responsible for periodontal disease progression remain unclear. However, recent studies suggest that apoptosis or programmed cell death may be one mechanism underlying the pathophysiology of periodontal disease progression. During cell apoptosis, a sequential activation of cysteine proteases, called caspases, plays a central role in the execution phase of apoptosis. Caspase-3 is one of the key executor caspases that regulates a number of critical cellular substrates and when active has been easily detected in cells undergoing apoptosis. Eventually, the caspase cascade culminates in the cleavage of DNA into fragments, a hallmark of apoptosis. Immunoblot and substrate assays have shown that caspase-3 and -7, two major effector caspases, are activated to a higher extent in tissue homogenates from patients with chronic periodontitis. Furthermore, increased caspase activation was directly detectable in inflamed gingival biopsies. A considerable number of cells in the gingival epithelium and connective tissue revealed active caspases, whereas in healthy tissue, almost no caspase activation was observed. These results therefore suggest that caspase activation may be functionally involved in periodontitis-associated tissue damage. Thus, these apoptotic molecules may be helpful biomarkers of disease status at any point in time.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Bantel H, Beikler T, Flemmig TF, Schulze-Osthoff K. Caspase activation is involved in chronic periodontitis. FEBS Lett 2005;579:5559-64.  Back to cited text no. 1
    
2.
Behl Y, Siqueira M, Ortiz J, Li J, Desta T, Faibish D, et al. Activation of the acquired immune response reduces coupled bone formation in response to a periodontal pathogen. J Immunol 2008;181:8711-8.  Back to cited text no. 2
    
3.
Bulut S, Uslu H, Ozdemir BH, Bulut OE. Expression of caspase-3, p53 and Bcl-2 in generalized aggressive periodontitis. Head Face Med 2006;2:17.  Back to cited text no. 3
    
4.
Calenic B, Yaegaki K, Kozhuharova A, Imai T. Oral malodorous compound causes oxidative stress and p53-mediated programmed cell death in keratinocyte stem cells. J Periodontol 2010;81:1317-23.  Back to cited text no. 4
    
5.
Chae HJ, Chae SW, Kang JS, Bang BG, Cho SB, Park RK, et al. Dexamethasone suppresses tumor necrosis factor-alpha-induced apoptosis in osteoblasts: Possible role for ceramide. Endocrinology 2000;141:2904-13.  Back to cited text no. 5
    
6.
Cox SW, Rodriguez-Gonzalez EM, Booth V, Eley BM. Secretory leukocyte protease inhibitor and its potential interactions with elastase and cathepsin B in gingival crevicular fluid and saliva from patients with chronic periodontitis. J Periodontal Res 2006;41:477-85.  Back to cited text no. 6
    
7.
Page RC, Offenbacher S, Schroeder HE, Seymour GJ, Kornman KS. Advances in the pathogenesis of periodontitis: Summary of developments, clinical implications and future directions. Periodontol 2000 1997;14:216-48.  Back to cited text no. 7
    
8.
Abuhussein H, Bashutski JD, Dabiri D, Halubai S, Layher M, Klausner C, et al. The role of factors associated with apoptosis in assessing periodontal disease status. J Periodontol 2014;85:1086-95.  Back to cited text no. 8
    
9.
Kurita-Ochiai T, Seto S, Suzuki N, Yamamoto M, Otsuka K, Abe K, et al. Butyric acid induces apoptosis in inflamed fibroblasts. J Dent Res 2008;87:51-5.  Back to cited text no. 9
    
10.
Kawase T, Okuda K, Yoshie H. Extracellular ATP and ATPgammaS suppress the proliferation of human periodontal ligament cells by different mechanisms. J Periodontol 2007;78:748-56.  Back to cited text no. 10
    
11.
Silva GK, Costa RS, Silveira TN, Caetano BC, Horta CV, Gutierrez FR, et al. Apoptosis-associated speck-like protein containing a caspase recruitment domain inflammasomes mediate IL-1β response and host resistance to trypanosoma cruzi infection. J Immunol 2013;191:3373-83.  Back to cited text no. 11
    
12.
Johnson RB, Wikle JC. Sex differences in inflammatory and apoptotic signaling molecules in normal and diseased human gingiva. J Periodontol 2014;85:1612-9.  Back to cited text no. 12
    
13.
Pradeep AR, Suke DK, Prasad MV, Singh SP, Martande SS, Nagpal K, et al. Expression of key executioner of apoptosis caspase-3 in periodontal health and disease. J Investig Clin Dent 2016;7:174-9.  Back to cited text no. 13
    
14.
Kelk P, Johansson A, Claesson R, Hänström L, Kalfas S. Caspase 1 involvement in human monocyte lysis induced by actinobacillus actinomycetemcomitans leukotoxin. Infect Immun 2003;71:4448-55.  Back to cited text no. 14
    
15.
Ghangurde AA, Ganji KK, Bhongade ML, Sehdev B. Role of Chemically Modified Tetracyclines in the Management of Periodontal Diseases: A Review. Drug Res (Stuttg) 2017;67:258-65.  Back to cited text no. 15
    
16.
Shah N, Bhongade ML, Kriplani R. Current Status of Proinflammatory Cytokines in Periodontal Disease and During Periodontal Therapy. Data wydania: 2015. p. 1-90  Back to cited text no. 16
    




 

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Abstract
Introduction
Apoptosis and Pe...
What Is Apoptosis
Role of Caspase ...
How Do Caspases Act?
Role of Caspase ...
Role of Caspases...
Conclusion
References

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