{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T22:05:41Z","timestamp":1791324341020,"version":"4.3.1"},"reference-count":37,"publisher":"MDPI AG","issue":"21","license":[{"start":{"date-parts":[[2023,11,5]],"date-time":"2023-11-05T00:00:00Z","timestamp":1699142400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Japan Society for the Promotion of Science","award":["17H04417"],"award-info":[{"award-number":["17H04417"]}]},{"name":"Japan Society for the Promotion of Science","award":["20H03862"],"award-info":[{"award-number":["20H03862"]}]},{"name":"Japan Society for the Promotion of Science","award":["23H03077"],"award-info":[{"award-number":["23H03077"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Periodontal ligament-associated protein 1 (PLAP-1), also known as Asporin, is an extracellular matrix protein expressed in the periodontal ligament and plays a crucial role in periodontal tissue homeostasis. Our previous research demonstrated that PLAP-1 may inhibit TLR2\/4-mediated inflammatory responses, thereby exerting a protective function against periodontitis. However, the precise roles of PLAP-1 in the periodontal ligament (PDL) and its relationship to periodontitis have not been fully explored. In this study, we employed PLAP-1 knockout mice to investigate its roles and contributions to PDL tissue and function in a ligature-induced periodontitis model. Mandibular bone samples were collected from 10-week-old male C57BL\/6 (WT) and PLAP-1 knockout (KO) mice. These samples were analyzed through micro-computed tomography (\u03bcCT) scanning, hematoxylin and eosin (HE) staining, picrosirius red staining, and fluorescence immunostaining using antibodies targeting extracellular matrix proteins. Additionally, the structure of the PDL collagen fibrils was examined using transmission electron microscopy (TEM). We also conducted tooth extraction and ligature-induced periodontitis models using both wild-type and PLAP-1 KO mice. PLAP-1 KO mice did not exhibit any changes in alveolar bone resorption up to the age of 10 weeks, but they did display an enlarged PDL space, as confirmed by \u03bcCT and histological analyses. Fluorescence immunostaining revealed increased expression of extracellular matrix proteins, including Col3, BGN, and DCN, in the PDL tissues of PLAP-1 KO mice. TEM analysis demonstrated an increase in collagen diameter within the PDL of PLAP-1 KO mice. In line with these findings, the maximum stress required for tooth extraction was significantly lower in PLAP-1 KO mice in the tooth extraction model compared to WT mice (13.89 N \u00b1 1.34 and 16.51 N \u00b1 1.31, respectively). In the ligature-induced periodontitis model, PLAP-1 knockout resulted in highly severe alveolar bone resorption, with a higher number of collagen fiber bundle tears and significantly more osteoclasts in the periodontium. Our results demonstrate that mice lacking PLAP-1\/Asporin show alteration of periodontal ligament structures and acceleration of bone loss in periodontitis. This underscores the significant role of PLAP-1 in maintaining collagen fibrils in the PDL and suggests the potential of PLAP-1 as a therapeutic target for periodontal diseases.<\/jats:p>","DOI":"10.3390\/ijms242115989","type":"journal-article","created":{"date-parts":[[2023,11,5]],"date-time":"2023-11-05T07:35:06Z","timestamp":1699169706000},"page":"15989","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Mice Lacking PLAP-1\/Asporin Show Alteration of Periodontal Ligament Structures and Acceleration of Bone Loss in Periodontitis"],"prefix":"10.3390","volume":"24","author":[{"given":"Masaki","family":"Kinoshita","sequence":"first","affiliation":[{"name":"Department of Periodontology and Regenerative Dentistry, Osaka University Graduate School of Dentistry, Suita 565-0871, Osaka, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Satoru","family":"Yamada","sequence":"additional","affiliation":[{"name":"Department of Periodontology and Endodontolgy, Tohoku University Graduate School of Dentistry, Sendai 980-8575, Miyagi, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0330-0397","authenticated-orcid":false,"given":"Junichi","family":"Sasaki","sequence":"additional","affiliation":[{"name":"Department of Dental Biomaterials, Osaka University Graduate School of Dentistry, Suita 565-0871, Osaka, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0888-4050","authenticated-orcid":false,"given":"Shigeki","family":"Suzuki","sequence":"additional","affiliation":[{"name":"Department of Periodontology and Endodontolgy, Tohoku University Graduate School of Dentistry, Sendai 980-8575, Miyagi, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tetsuhiro","family":"Kajikawa","sequence":"additional","affiliation":[{"name":"Department of Periodontology and Endodontolgy, Tohoku University Graduate School of Dentistry, Sendai 980-8575, Miyagi, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tomoaki","family":"Iwayama","sequence":"additional","affiliation":[{"name":"Department of Periodontology and Regenerative Dentistry, Osaka University Graduate School of Dentistry, Suita 565-0871, Osaka, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chiharu","family":"Fujihara","sequence":"additional","affiliation":[{"name":"Department of Periodontology and Regenerative Dentistry, Osaka University Graduate School of Dentistry, Suita 565-0871, Osaka, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Satoshi","family":"Imazato","sequence":"additional","affiliation":[{"name":"Department of Dental Biomaterials, Osaka University Graduate School of Dentistry, Suita 565-0871, Osaka, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shinya","family":"Murakami","sequence":"additional","affiliation":[{"name":"Department of Periodontology and Regenerative Dentistry, Osaka University Graduate School of Dentistry, Suita 565-0871, Osaka, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,11,5]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"279","DOI":"10.1016\/S0378-1119(01)00683-7","article-title":"Expression profile of active genes in human periodontal ligament and isolation of PLAP-1, a novel SLRP family gene","volume":"275","author":"Yamada","year":"2001","journal-title":"Gene"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"12212","DOI":"10.1074\/jbc.M011290200","article-title":"Expression pattern and gene characterization of asporin. a newly discovered member of the leucine-rich repeat protein family","volume":"276","author":"Henry","year":"2001","journal-title":"J. Biol. Chem."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"23070","DOI":"10.1074\/jbc.M611181200","article-title":"PLAP-1\/asporin, a novel negative regulator of periodontal ligament mineralization","volume":"282","author":"Yamada","year":"2007","journal-title":"J. Biol. Chem."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"138","DOI":"10.1038\/ng1496","article-title":"An aspartic acid repeat polymorphism in asporin inhibits chondrogenesis and increases susceptibility to osteoarthritis","volume":"37","author":"Kizawa","year":"2005","journal-title":"Nat. Genet."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"20","DOI":"10.1111\/j.1600-0757.1997.tb00094.x","article-title":"The periodontal ligament: A unique, multifunctional connective tissue","volume":"13","author":"Beertsen","year":"1997","journal-title":"Periodontol. 2000"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"46","DOI":"10.12968\/denu.2004.31.1.46","article-title":"Periodontal ligament: Structural and clinical correlates","volume":"31","author":"Berkovitz","year":"2004","journal-title":"Dent. Update"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"248","DOI":"10.1016\/j.matbio.2010.01.001","article-title":"The role of small leucine-rich proteoglycans in collagen fibrillogenesis","volume":"29","author":"Kalamajski","year":"2010","journal-title":"Matrix Biol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"8888","DOI":"10.1074\/jbc.M806590200","article-title":"Genetic evidence for the coordinated regulation of collagen fibrillogenesis in the cornea by decorin and biglycan","volume":"284","author":"Zhang","year":"2009","journal-title":"J. Biol. Chem."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"20712","DOI":"10.1074\/jbc.270.35.20712","article-title":"Decorin-binding sites for collagen type I are mainly located in leucine-rich repeats 4-5","volume":"270","author":"Svensson","year":"1995","journal-title":"J. Biol. Chem."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"21801","DOI":"10.1074\/jbc.C000278200","article-title":"Decorin binds near the C terminus of type I collagen","volume":"275","author":"Keene","year":"2000","journal-title":"J. Biol. Chem."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1042\/BJ20090542","article-title":"Asporin competes with decorin for collagen binding, binds calcium and promotes osteoblast collagen mineralization","volume":"423","author":"Kalamajski","year":"2009","journal-title":"Biochem. J."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1111\/prd.12251","article-title":"Role of occlusion in periodontal disease","volume":"79","author":"Passanezi","year":"2019","journal-title":"Periodontol. 2000"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1902\/annals.1999.4.1.7","article-title":"Dental plaque-induced gingival diseases","volume":"4","author":"Mariotti","year":"1999","journal-title":"Ann. Periodontol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1706","DOI":"10.1177\/0022034515606859","article-title":"PLAP-1\/Asporin Regulates TLR2- and TLR4-induced Inflammatory Responses","volume":"94","author":"Yamaba","year":"2015","journal-title":"J. Dent. Res."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1417","DOI":"10.1177\/0022034515598507","article-title":"PLAP-1\/Asporin Positively Regulates FGF-2 Activity","volume":"94","author":"Awata","year":"2015","journal-title":"J. Dent. Res."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1914","DOI":"10.1002\/jbmr.2522","article-title":"Decreased Mechanical Strength and Collagen Content in SPARC-Null Periodontal Ligament Is Reversed by Inhibition of Transglutaminase Activity","volume":"30","author":"Rosset","year":"2015","journal-title":"J. Bone Miner. Res."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"R69","DOI":"10.1093\/hmg\/ddg085","article-title":"Normal and abnormal dental development","volume":"12","author":"Miletich","year":"2003","journal-title":"Hum. Mol. Genet."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"195","DOI":"10.1016\/0301-4622(88)87039-X","article-title":"The molecular and fibrillar structure of collagen and its relationship to the mechanical properties of connective tissue","volume":"29","author":"Parry","year":"1988","journal-title":"Biophys. Chem."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1180","DOI":"10.1359\/jbmr.2002.17.7.1180","article-title":"Phenotypic effects of biglycan deficiency are linked to collagen fibril abnormalities, are synergized by decorin deficiency, and mimic Ehlers-Danlos-like changes in bone and other connective tissues","volume":"17","author":"Corsi","year":"2002","journal-title":"J. Bone Miner. Res."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"214","DOI":"10.1115\/1.1449904","article-title":"Tensile mechanical properties of three-dimensional type I collagen extracellular matrices with varied microstructure","volume":"124","author":"Roeder","year":"2002","journal-title":"J. Biomech. Eng."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"249","DOI":"10.1023\/A:1025383913444","article-title":"The role of decorin in collagen fibrillogenesis and skin homeostasis","volume":"19","author":"Reed","year":"2002","journal-title":"Glycoconj. J."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"933","DOI":"10.1016\/j.joca.2015.02.011","article-title":"Asporin and osteoarthritis","volume":"23","author":"Xu","year":"2015","journal-title":"Osteoarthr. Cartil."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"32185","DOI":"10.1074\/jbc.M700522200","article-title":"Mechanisms for asporin function and regulation in articular cartilage","volume":"282","author":"Nakajima","year":"2007","journal-title":"J. Biol. Chem."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"196","DOI":"10.3109\/08977194.2011.595714","article-title":"TGF-\u03b2 signaling in fibrosis","volume":"29","author":"Biernacka","year":"2011","journal-title":"Growth Factors"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"76","DOI":"10.1016\/j.cbi.2018.07.008","article-title":"New insights into TGF-\u03b2\/Smad signaling in tissue fibrosis","volume":"292","author":"Hu","year":"2018","journal-title":"Chem. Biol. Interact."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"141","DOI":"10.3109\/10409239709108551","article-title":"The family of the small leucine-rich proteoglycans: Key regulators of matrix assembly and cellular growth","volume":"32","author":"Iozzo","year":"1997","journal-title":"Crit. Rev. Biochem. Mol. Biol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"6588","DOI":"10.1016\/S0021-9258(18)32453-0","article-title":"Proteoglycans of developing bone","volume":"258","author":"Fisher","year":"1983","journal-title":"J. Biol. Chem."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1061","DOI":"10.1590\/S0100-879X2003000800012","article-title":"Distribution of biglycan and decorin in rat dental tissue","volume":"36","author":"Santos","year":"2003","journal-title":"Braz. J. Med. Biol. Res."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1767","DOI":"10.1177\/00220345960750101001","article-title":"Human granulation-tissue fibroblasts show enhanced proteoglycan gene expression and altered response to TGF-beta 1","volume":"75","author":"Westermarck","year":"1996","journal-title":"J. Dent. Res."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"312","DOI":"10.1111\/j.1600-0765.2005.00800.x","article-title":"Distinctive localization and function for lumican, fibromodulin and decorin to regulate collagen fibril organization in periodontal tissues","volume":"40","author":"Matheson","year":"2005","journal-title":"J. Periodontal Res."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1869","DOI":"10.1038\/labinvest.3780197","article-title":"A role for decorin in the structural organization of periodontal ligament","volume":"80","author":"Strassburger","year":"2000","journal-title":"Lab. Investig."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"177","DOI":"10.1016\/j.archoralbio.2011.08.011","article-title":"Effects of biglycan on physico-chemical properties of ligament-mineralized tissue attachment sites","volume":"57","author":"Chiu","year":"2012","journal-title":"Arch. Oral. Biol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"107R","DOI":"10.1093\/glycob\/cwf065","article-title":"Mice deficient in small leucine-rich proteoglycans: Novel in vivo models for osteoporosis, osteoarthritis, Ehlers-Danlos syndrome, muscular dystrophy, and corneal diseases","volume":"12","author":"Ameye","year":"2002","journal-title":"Glycobiology"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1026","DOI":"10.1177\/0022034516645796","article-title":"Transcriptome Reveals Cathepsin K in Periodontal Ligament Differentiation","volume":"95","author":"Yamada","year":"2016","journal-title":"J. Dent. Res."},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Maccarana, M., Svensson, R.B., Knutsson, A., Giannopoulos, A., Pelkonen, M., Weis, M., Eyre, D., Warman, M., and Kalamajski, S. (2017). Asporin-deficient mice have tougher skin and altered skin glycosaminoglycan content and structure. PLoS ONE, 12.","DOI":"10.1371\/journal.pone.0184028"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"911","DOI":"10.1016\/S0092-8674(00)81069-7","article-title":"Fibroblast growth factor receptor 3 is a negative regulator of bone growth","volume":"84","author":"Deng","year":"1996","journal-title":"Cell"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1016\/j.jim.2013.05.002","article-title":"Optimization of the ligature-induced periodontitis model in mice","volume":"394","author":"Abe","year":"2013","journal-title":"J. Immunol. Methods"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/21\/15989\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T21:17:54Z","timestamp":1760131074000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/21\/15989"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,11,5]]},"references-count":37,"journal-issue":{"issue":"21","published-online":{"date-parts":[[2023,11]]}},"alternative-id":["ijms242115989"],"URL":"https:\/\/doi.org\/10.3390\/ijms242115989","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,11,5]]}}}