Dataset Information

Soluble RANKL Cleaved from Activated Lymphocytes by TNF-?-Converting Enzyme Contributes to Osteoclastogenesis in Periodontitis.

ABSTRACT: Host immune responses play a key role in promoting bone resorption in periodontitis via receptor activator of NF-?B 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-?-converting enzyme (TACE) is reported to cleave the following: 1) precursor TNF-? with release of mature, soluble TNF-? and 2) mRANKL with release of sRANKL. Both soluble TNF-? 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.

SUBMITTER: Kanzaki H

PROVIDER: S-EPMC5120874 | biostudies-literature | 2016 Nov

REPOSITORIES: biostudies-literature

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Soluble RANKL Cleaved from Activated Lymphocytes by TNF-α-Converting Enzyme Contributes to Osteoclastogenesis in Periodontitis.

Kanzaki Hiroyuki H Makihira Seicho S Suzuki Maiko M Ishii Takenobu T Movila Alexandru A Hirschfeld Josefine J Mawardi Hani H Lin Xiaoping X Han Xiaozhe X Taubman Martin A MA Kawai Toshihisa T

Journal of immunology (Baltimore, Md. : 1950) 20161007 10

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 ...[more]

PMID: 27815441

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Project description:Postmenopausal osteoporosis (PMO) has been recognized as an inflammatory condition. CD4+ T cells serve a key role in the interaction between bone metabolism and the immune system. Bu‑Shen‑Ning‑Xin decoction (BSNXD), a traditional Chinese medicine, has been ultilized as a remedy for PMO. In the present study, the aim was to investigate the immune modulatory effects of BSNXD on CD4+ T cells, receptor activation of nuclear factor κB ligand (RANKL)/osteoprotegerin (OPG) imbalance, skeletal parameters and osteoclastogenesis. Ovariectomized (OVX) mice were treated with a series of concentrations of BSNXD and then autopsied. The bone phenotype was analyzed by micro computed tomography. CD4+ T cells were isolated and their percentage was measured using flow cytometry (FCM). RANKL and OPG expression by the CD4+ T cells at the transcriptional and translational levels were quantified by reverse transcription-quantitative polymerase chain reaction, ELISA and FCM. CD4+ T cells were cultured with blood serum derived from BSNXD‑treated OVX mice (BSNXD‑derived serum) and the apoptosis rate was quantified by FCM. CD4+ T cells were co-cultured with bone marrow‑derived macrophages and exposed to BSNXD‑derived serum to whether CD4+ T cells are involved in BSNXD‑modulated osteoclastogenesis and the results were quantified via tartrate‑resistant acid phosphatase staining. The results revealed that BSNXD ameliorated OVX‑induced bone loss, prevented the expansion of CD4+ T cells and restored the RANKL/OPG imbalance in the CD4+ T cells of OVX mice. In vitro, BSNXD‑derived serum promoted the apoptosis of CD4+ T cells. The co‑culture system demonstrated that CD4+ T cells from OVX mice increase osteoclastogenesis, while this effect was suppressed by BSNXD administration. The findings of the study collectively suggest that BSNXD exerts an immunoprotective effect on the bone phenotype of OVX mice by ameliorating RANKL/OPG imbalance in CD4+ T cells and attenuating osteoclastogenesis.

Dataset Information

Soluble RANKL Cleaved from Activated Lymphocytes by TNF-?-Converting Enzyme Contributes to Osteoclastogenesis in Periodontitis.

Publications

Soluble RANKL Cleaved from Activated Lymphocytes by TNF-α-Converting Enzyme Contributes to Osteoclastogenesis in Periodontitis.

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