Xanthine Derivative KMUP-1 Attenuates Experimental Periodontitis by Reducing Osteoclast Differentiation and Inflammation

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Abstract

Periodontitis is an inflammatory disease of gum that may predispose to serious systemic complications such as diabetes and cardiovascular diseases. Activation of macrophages and osteoclasts around periodontal tissue can accelerate gum inflammation. In addition, alteration of cyclic nucleotide levels is associated with the severity of periodontitis. Our previous study has shown that KMUP-1, a xanthine derivative exhibiting phosphodiesterase inhibition and soluble guanylyl cyclase activation, can inhibit lipopolysaccharide (LPS)-induced inflammation and receptor activator of nuclear factor kappa-Β ligand (RANKL)-induced osteoclastogenesis. This study was aimed to investigate whether KMUP-1 could attenuate periodontitis both in vitro and in vivo. In vitro, the protective effect of KMUP-1 on inflammation and osteoclastogenesis was investigated in RANKL-primed RAW264.7 cells treated by Porphyromonas gingivalis LPS ( PgLPS). The results showed that KMUP-1 attenuated PgLPS-induced osteoclast differentiation as demonstrated by decreased TRAP-positive multinuclear cells and TRAP activity. This reduction of osteoclast differentiation by KMUP-1 was reversed by KT5823, a protein kinase G inhibitor. Similarly, pro-inflammatory cytokine levels induced by PgLPS were inhibited by KMUP-1 in a dose-dependent manner whereas reversed by KT5823. Mechanistically, suppression of MAPKs, PI3K/Akt, and NF-κB signaling pathways and decrease of c-Fos and NFATc1 expression in osteoclast precursors by KMUP-1 may mediate its protective effect. In vivo, two models of periodontitis in rats were induced by gingival injections of PgLPS and ligature placement around molar teeth, respectively. Our results showed that KMUP-1 inhibited alveolar bone loss in both rat models, and this effect mediated at least partly by reduced osteoclastogenesis. In conclusion, our study demonstrated the therapeutic potential of KMUP-1 on periodontitis through suppression of inflammation and osteoclast differentiation.

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Periodontitis: from microbial immune subversion to systemic inflammation.

George Hajishengallis (2015)

Periodontitis is a dysbiotic inflammatory disease with an adverse impact on systemic health. Recent studies have provided insights into the emergence and persistence of dysbiotic oral microbial communities that can mediate inflammatory pathology at local as well as distant sites. This Review discusses the mechanisms of microbial immune subversion that tip the balance from homeostasis to disease in oral or extra-oral sites.

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Modulation of osteoclast differentiation and function by the new members of the tumor necrosis factor receptor and ligand families.

T Suda, N Takahashi, N Udagawa … (1999)

Osteoblasts/stromal cells are essentially involved in osteoclast differentiation and function through cell-to-cell contact (Fig. 8). Although many attempts have been made to elucidate the mechanism of the so-called "microenvironment provided by osteoblasts/stromal cells," (5-8) it has remained an open question until OPG and its binding molecule were cloned. The serial discovery of the new members of the TNF receptor-ligand family members has confirmed the idea that osteoclast differentiation and function are regulated by osteoblasts/stromal cells. RANKL, which has also been called ODF, TRANCE, or OPGL, is a member of the TNF ligand family. Expression of RANKL mRNA in osteoblasts/stromal cells is up-regulated by osteotropic factors such as 1 alpha, 25(OH)2D3, PTH, and IL-11. Osteoclast precursors express RANK, a TNF receptor family member, recognize RANKL through cell-to-cell interaction with osteoblasts/stromal cells, and differentiate into pOCs in the presence of M-CSF. RANKL is also involved in the survival and fusion of pOCs and activation of mature osteoclasts. OPG, which has also been called OCIF or TR1, is a soluble receptor for RANKL and acts as a decoy receptor in the RANK-RANKL signaling system (Fig. 8). In conclusion, osteoblasts/stromal cells are involved in all of the processes of osteoclast development, such as differentiation, survival, fusion, and activation of osteoclasts (Fig. 8). Osteoblasts/stromal cells can now be replaced with RANKL and M-CSF in dealing with the whole life of osteoclasts. RANKL, RANK, and OPG are three key molecules that regulate osteoclast recruitment and function. Further studies on these key molecules will elucidate the molecular mechanism of the regulation of osteoclastic bone resorption. This line of studies will establish new ways to treat several metabolic bone diseases caused by abnormal osteoclast recruitment and functions such as osteopetrosis, osteoporosis, metastatic bone disease, Paget's disease, rheumatoid arthritis, and periodontal bone disease.

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Porphyromonas gingivalis: An Overview of Periodontopathic Pathogen below the Gum Line

Kah How, Keang Peng Song, Kok Gan Chan (2016)

Periodontal disease represents a group of oral inflammatory infections initiated by oral pathogens which exist as a complex biofilms on the tooth surface and cause destruction to tooth supporting tissues. The severity of this disease ranges from mild and reversible inflammation of the gingiva (gingivitis) to chronic destruction of connective tissues, the formation of periodontal pocket and ultimately result in loss of teeth. While human subgingival plaque harbors more than 500 bacterial species, considerable research has shown that Porphyromonas gingivalis, a Gram-negative anaerobic bacterium, is the major etiologic agent which contributes to chronic periodontitis. This black-pigmented bacterium produces a myriad of virulence factors that cause destruction to periodontal tissues either directly or indirectly by modulating the host inflammatory response. Here, this review provides an overview of P. gingivalis and how its virulence factors contribute to the pathogenesis with other microbiome consortium in oral cavity.

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Author and article information

Contributors

Cheng-Hsiang Kuo: URI : https://loop.frontiersin.org/people/1597541/overview

Jong-Hau Hsu: URI : https://loop.frontiersin.org/people/966236/overview

Chao-Han Lai: URI : https://loop.frontiersin.org/people/1570344/overview

Jwu-Lai Yeh: URI : https://loop.frontiersin.org/people/620907/overview

Journal

Journal ID (nlm-ta): Front Pharmacol

Journal ID (iso-abbrev): Front Pharmacol

Journal ID (publisher-id): Front. Pharmacol.

Title: Frontiers in Pharmacology

Publisher: Frontiers Media S.A.

ISSN (Electronic): 1663-9812

Publication date (Electronic): 28 April 2022

Publication date Collection: 2022

Volume: 13

Electronic Location Identifier: 821492

Affiliations

[1] ¹ International Center for Wound Repair and Regeneration , National Cheng Kung University , Tainan, Taiwan

[2] ² Graduate Institute of Medicine , College of Medicine , Kaohsiung Medical University , Kaohsiung, Taiwan

[3] ³ Department of Pediatrics , Kaohsiung Medical University Hospital , Kaohsiung, Taiwan

[4] ⁴ Department of Pediatrics , School of Medicine , Kaohsiung Medical University , Kaohsiung, Taiwan

[5] ⁵ School of Dentistry , College of Dental Medicine , Kaohsiung Medical University , Kaohsiung, Taiwan

[6] ⁶ Orthopaedic Research Center , College of Medicine , Kaohsiung Medical University , Kaohsiung, Taiwan

[7] ⁷ Department of Medical Research , Kaohsiung Medical University Hospital , Kaohsiung, Taiwan

[8] ⁸ Regenerative Medicine and Cell Therapy Research Center , Kaohsiung Medical University , Kaohsiung, Taiwan

[9] ⁹ Cardiovascular Research Center , National Cheng Kung University , Tainan, Taiwan

[10] ¹⁰ Department of Biochemistry and Molecular Biology , College of Medicine , National Cheng Kung University , Tainan, Taiwan

[11] ¹¹ Department of Surgery , National Cheng Kung University Hospital , College of Medicine , National Cheng Kung University , Tainan, Taiwan

[12] ¹² Department of Biostatistics , Vanderbilt University Medical Center , Nashville, TN, United States

[13] ¹³ Department of Pharmacology , School of Medicine , Kaohsiung Medical University , Kaohsiung, Taiwan

Author notes

Edited by: Tim Vanmierlo, University of Hasselt, Belgium

Reviewed by: Yun-Song Wang, Yunnan University, China

Melissa Schepers, University of Hasselt, Belgium

*Correspondence: Jwu-Lai Yeh, jwulai@ 123456kmu.edu.tw

This article was submitted to Inflammation Pharmacology, a section of the journal Frontiers in Pharmacology

Article

Publisher ID: 821492

DOI: 10.3389/fphar.2022.821492

PMC ID: 9097136

PubMed ID: 35571109

SO-VID: 32a9ddcc-a913-4132-8f08-499b7ff91bc0

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This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

History

Date received : 24 November 2021

Date accepted : 21 March 2022

Funding

Funded by: Ministry of Science and Technology, Taiwan , doi 10.13039/501100004663;

Funded by: Kaohsiung Medical University , doi 10.13039/501100004694;

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Xanthine Derivative KMUP-1 Attenuates Experimental Periodontitis by Reducing Osteoclast Differentiation and Inflammation

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Most cited references 58

Periodontitis: from microbial immune subversion to systemic inflammation.

Modulation of osteoclast differentiation and function by the new members of the tumor necrosis factor receptor and ligand families.

Porphyromonas gingivalis: An Overview of Periodontopathic Pathogen below the Gum Line

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