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

Cheng-Hsiang Kuo; Ban-Hua Zhang; Shang-En Huang; Jong-Hau Hsu; Yan-Hsiung Wang; Thi Tuyet Ngan Nguyen; Chao-Han Lai; Jwu-Lai Yeh

doi:10.3389/fphar.2022.821492

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

Front Pharmacol. 2022 Apr 28:13:821492. doi: 10.3389/fphar.2022.821492. eCollection 2022.

Authors

Cheng-Hsiang Kuo¹, Ban-Hua Zhang², Shang-En Huang², Jong-Hau Hsu^{2

3

4}, Yan-Hsiung Wang^{5

6

7

8}, Thi Tuyet Ngan Nguyen², Chao-Han Lai^{9

10

11

12}, Jwu-Lai Yeh^{2

7

13}

Affiliations

¹ International Center for Wound Repair and Regeneration, National Cheng Kung University, Tainan, Taiwan.
² Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
³ Department of Pediatrics, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan.
⁴ Department of Pediatrics, School of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
⁵ School of Dentistry, College of Dental Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
⁶ Orthopaedic Research Center, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
⁷ Department of Medical Research, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan.
⁸ Regenerative Medicine and Cell Therapy Research Center, Kaohsiung Medical University, Kaohsiung, Taiwan.
⁹ Cardiovascular Research Center, National Cheng Kung University, Tainan, Taiwan.
¹⁰ Department of Biochemistry and Molecular Biology, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
¹¹ Department of Surgery, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
¹² Department of Biostatistics, Vanderbilt University Medical Center, Nashville, TN, United States.
¹³ Department of Pharmacology, School of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.

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.

Keywords: Porphyromonas gingivalis; cGMP signalling; inflammation; lipopolysaccharide; osteoclastogenesis; xanthine derivative.