장지선 (서울대학교) | 한빛사논문 > 한빛사

한빛사논문

조회540

장지선Ji Sun Jang

서울대학교

CV File 74 kb

Redox Biol., Volume 69, February 2024, 103023 | https://doi.org/10.1016/j.redox.2023.103023 PINK1 restrains periodontitis-induced bone loss by preventing osteoclast mitophagy impairment

Ji Sun Jang ^a,1, Seo Jin Hong ^a,1, Shenzheng Mo ^a, Min Kyung Kim ^a, Yong-Gun Kim ^b, Youngkyun Lee ^c, Hong-Hee Kim ^a

^aDepartment of Cell and Developmental Biology, Dental Research Institute, School of Dentistry, Seoul National University, Seoul, 03080, Republic of Korea

^bDepartment of Periodontology, School of Dentistry, Kyungpook National University, Daegu, 41940, Republic of Korea

^cDepartment of Biochemistry, School of Dentistry, Kyungpook National University, Daegu, 41940, Republic of Korea

¹These authors contributed equally to this article as co-first authors.

Corresponding author : Hong-Hee Kim

Abstract

The oral colonization of periodontal pathogens onto gingival tissues establishes hypoxic microenvironment, often disrupting periodontal homeostasis in conjunction with oxidative stress. The association between reactive oxygen species (ROS) and osteolytic periodontitis have been suggested by recent studies. PTEN-induced kinase 1 (PINK1), a mitochondrial serine/threonine kinase, is an essential protein for mitochondrial quality control as it protects cells from oxidative stress by promoting degradation of damaged mitochondria through mitophagy. However, the pathophysiological roles of PINK1 in osteoclast-mediated bone loss have not been explored. Here we aimed to determine whether PINK1 plays a role in the regulation of osteoclastogenesis and alveolar bone resorption associated with periodontitis. C57BL/6 wild type (WT) and Pink1 knockout (KO) mice were subjected to ligature-induced periodontitis (LIP), and alveolar bones were evaluated by μCT-analysis and tartrate-resistant acid phosphatase (TRAP) staining. The μCT-analysis showed that bone volume fraction and travecular thickness were lower in Pink1 KO compared to WT mice. The number of TRAP-positive osteoclasts was markedly increased in the periodontal tissues of Pink1 KO mice with LIP. The genetic silencing or deletion of Pink1 promoted excessive osteoclast differentiation and bone resorption in vitro, as respectively indicated by TRAP staining and resorption pits on dentin slices. PINK1 deficiency led to mitochondrial instabilities as indicated by confocal microscopy of mitochondrial ROS, mitochondrial oxygen consumption rate (OCR) analysis, and transmission electron microscopy (TEM). Consequently, a significant increase in Ca ²⁺-nuclear factor of activated T cells 1 (NFATc1) signaling was also found. On the other hand, restoration of mitophagy and autophagy by spermidine (SPD) treatment and the resolution of oxidative stress by N-acetyl-l-cysteine (NAC) treatment protected PINK1 deficiency-induced excessive generation of osteoclasts. Taken together, our findings demonstrate that PINK1 is essential for maintaining mitochondrial homeostasis during osteoclast differentiation. Therefore, targeting PINK1 may provide a novel therapeutic strategy for severe periodontitis with fulminant osteolysis.

논문정보

형식Research article
게재일2024년 02월 (BRIC 등록일 2024-01-08)
연구진국내 연구진
분야 생명과학 > 세포생물학

댓글 작성 로그인

CV 열람하기

연락처 보기