Soluble RANKL Cleaved from Activated Lymphocytes by TNF-α-Converting Enzyme Contributes to Osteoclastogenesis in Periodontitis.
Host immune responses play a key role in promoting bone resorption in periodontitis via receptor activator of NF-κB ligand (RANKL)-dependent osteoclastogenesis. Both membrane-bound RANKL (mRANKL) expressed on lymphocytes and soluble RANKL (sRANKL) are found in periodontal lesions. However, the underlying mechanism and cellular source of sRANKL release and its biological role in periodontitis are unclear. TNF-α-converting enzyme (TACE) is reported to cleave the following: 1) precursor TNF-α with release of mature, soluble TNF-α and 2) mRANKL with release of sRANKL. Both soluble TNF-α and sRANKL are found in the periodontitis lesion, leading to the hypothesis that TACE expressed on lymphocytes is engaged in RANKL shedding and that the resulting sRANKL induces osteoclastogenesis. In the current study, upon stimulating PBLs with mitogens in vitro, RANKL expression, sRANKL secretion, and TACE expression were all upregulated. Among the four putative mRANKL sheddases examined in neutralization assays, TACE was the only functional sheddase able to cleave mRANKL expressed on PBL. Moreover, PBL culture supernatant stimulated with mitogens in the presence of anti-TACE Ab or anti-RANKL Ab showed a marked reduction of osteoclastogenesis from osteoclast precursors, indicating that TACE-mediated sRANKL may possess sufficient osteoclastogenic activity. According to double-color confocal microscopy, B cells expressed a more pronounced level of RANKL and TACE expression than T cells or monocytes in periodontally diseased gingiva. Conditioned medium of patients' gingival lymphocyte culture increased in vitro osteoclastogenic activity, which was suppressed by the addition of anti-TACE Ab and anti-RANKL Ab. Therefore, TACE-mediated cleavage of sRANKL from activated lymphocytes, especially B cells, can promote osteoclastogenesis in periodontitis.
Department of Orthodontics, School of Dental Medicine, Tsurumi University, Yokohama, Kanagawa 230-8501, Japan.
Hiroyuki
H
Kanzaki
Division of Oral Rehabilitation, Department of Dental Science, Faculty of Dental Science, Kyushu University, Fukuoka 812-8582, Japan.
Seicho
S
Makihira
College of Dentistry Biosciences, The Ohio State University, Columbus, OH 43210.
Maiko
M
Suzuki
Department of Orthodontics, Tokyo Dental College, Tokyo 101-0061, Japan.
Takenobu
T
Ishii
Department of Immunology and Infectious Diseases, Forsyth Institute, Cambridge, MA 02142.
Alexandru
0000-0001-9612-4726
A
Movila
Birmingham Dental School and Hospital, Birmingham B5 7EG, United Kingdom.
Josefine
J
Hirschfeld
Department of Oral Basic and Clinical Science, King Abdulaziz University Faculty of Dentistry, Jeddah 21481, Saudi Arabia; and.
Hani
H
Mawardi
Department of Stomatology, Shengjing Hospital of China Medical University, Heping, Shenyang 110004, Liaoning Province, China.
Xiaoping
X
Lin
Department of Immunology and Infectious Diseases, Forsyth Institute, Cambridge, MA 02142.
Xiaozhe
X
Han
Department of Immunology and Infectious Diseases, Forsyth Institute, Cambridge, MA 02142.
Martin A
MA
Taubman
Department of Immunology and Infectious Diseases, Forsyth Institute, Cambridge, MA 02142; tkawai@forsyth.org.
Toshihisa
T
Kawai
D000072198:ADAM17 Protein / Q000235:genetics / Q000378:metabolism*; D001402:B-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D001862:Bone Resorption; D002478:Cells, Cultured; D005881:Gingiva / Q000166:cytology / Q000276:immunology; D006801:Humans; D008070:Lipopolysaccharides / Q000276:immunology; D008213:Lymphocyte Activation; D008297:Male; D009000:Monocytes / Q000276:immunology; D010010:Osteoclasts / Q000276:immunology; D010012:Osteogenesis; D010518:Periodontitis / Q000276:immunology* / Q000503:physiopathology; D053245:RANK Ligand / Q000235:genetics / Q000378:metabolism*; D012995:Solubility; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism
D008070:Lipopolysaccharides; D053245:RANK Ligand; C505688:TNFSF11 protein, human; D000072198:ADAM17 Protein