Osteogenic differentiation and inflammatory response of recombinant human bone morphogenetic protein-2 in human maxillary sinus membrane-derived cells

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Abstract

The aim of the present study was to investigate the osteogenic potential of human maxillary sinus membrane (hMSM)-derived cells, and the role of recombinant human bone morphogenetic protein-2 (rhBMP-2) in the inflammatory response of hMSM-derived cells and gingival fibroblasts following sinus floor elevation procedure (SFE). hMSM-derived cells from the samples were isolated, subcultured, and analyzed using immunohistochemical staining and flow cytometry. The hMSM-derived cells obtained from passage 6 were used for Alizarin Red staining and quantitative reverse transcription-quantitative PCR to observe its osteogenic activity and inflammatory reaction upon supplementation with rhBMP-2. The hMSM-derived cells were shown to be heterogeneous, as indicated by their positive expression of human mesenchymal stem cell markers (STRO-1, high mobility group AT-hook 2, CD44, CD105 and OCT-3/4), fibroblast cell marker (fibroblast-specific protein 1) and epithelial cell marker (epithelial cell adhesion molecule). Calcium nodules were found to be more notably evident in the rhBMP-2 group, following osteogenic differentiation. The gene expression of osteogenic markers was significantly upregulated in the cells supplemented with rhBMP-2. Supplementation with rhBMP-2 also enhanced the expression of inflammatory markers in hMSM-derived cells and gingival fibroblasts; however, NF-κB and TNF-α expression was not significantly increased compared with the control in the hMSM-derived cells. hMSM contains mesenchymal stem cells (MSCs) capable of differentiating into osteogenic cells. The supplementation of rhBMP-2 enhanced osteogenic differentiation and induced an inflammatory response which was greater in gingival fibroblasts compared with hMSM-derived cells. In summary, the hMSM is a potential contributor to the osteogenic process following SFE, and the use of rhBMP-2 may increase the inflammatory response accordingly. The gingival tissue may be responsible for the increased inflammatory response by rhBMP-2 and postoperative complications.

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Identification and characterization of a fibroblast marker: FSP1

F Strutz, CW Lo, T Danoff … (1995)

We performed subtractive and differential hybridization for transcript comparison between murine fibroblasts and isogenic epithelium, and observed only a few novel intracellular genes which were relatively specific for fibroblasts. One such gene encodes a filament-associated, calcium-binding protein, fibroblast-specific protein 1 (FSP1). The promoter/enhancer region driving this gene is active in fibroblasts but not in epithelium, mesangial cells or embryonic endoderm. During development, FSP1 is first detected by in situ hybridization after day 8.5 as a postgastrulation event, and is associated with cells of mesenchymal origin or of fibroblastic phenotype. Polyclonal antiserum raised to recombinant FSP1 protein stained the cytoplasm of fibroblasts, but not epithelium. Only occasional cells stain with specific anti-FSP1 antibodies in normal parenchymal tissue. However, in kidneys fibrosing from persistent inflammation, many fibroblasts could be identified in interstitial sites of collagen deposition and also in tubular epithelium adjacent to the inflammatory process. This pattern of anti-FSP1 staining during tissue fibrosis suggests, as a hypothesis, that fibroblasts in some cases arise, as needed, from the local conversion of epithelium. Consistent with this notion that FSP1 may be involved in the transition from epithelium to fibroblasts are experiments in which the in vitro overexpression of FSP1 cDNA in tubular epithelium is accompanied by conversion to a mesenchymal phenotype, as characterized by a more stellate and elongated fibroblast- like appearance, a reduction in cytokeratin, and new expression of vimentin. Similarly, tubular epithelium submerged in type I collagen gels exhibited the conversion to a fibroblast phenotype which includes de novo expression of FSP1 and vimentin. Use of the FSP1 marker, therefore, should further facilitate both the in vivo studies of fibrogenesis and the mapping of cell fate among fibroblasts.

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High doses of bone morphogenetic protein 2 induce structurally abnormal bone and inflammation in vivo.

Janette N. Zara, Ronald Siu, Xinli Zhang … (2011)

The major Food and Drug Association-approved osteoinductive factors in wide clinical use are bone morphogenetic proteins (BMPs). Although BMPs can promote robust bone formation, they also induce adverse clinical effects, including cyst-like bone formation and significant soft tissue swelling. In this study, we evaluated multiple BMP2 doses in a rat femoral segmental defect model and in a minimally traumatic rat femoral onlay model to determine its dose-dependent effects. Results of our femoral segmental defect model established a low BMP2 concentration range (5 and 10 μg/mL, total dose 0.375 and 0.75 μg in 75 μg total volume) unable to induce defect fusion, a mid-range BMP2 concentration range able to fuse the defect without adverse effects (30 μg/mL, total dose 2.25 μg in 75 μg total volume), and a high BMP2 concentration range (150, 300, and 600 μg/mL, total dose 11.25, 22.5, and 45 μg in 75 μg total volume) able to fuse the defect, but with formation of cyst-like bony shells filled with histologically confirmed adipose tissue. In addition, compared to control, 4 mg/mL BMP2 also induced significant tissue inflammatory infiltrates and exudates in the femoral onlay model that was accompanied by increased numbers of osteoclast-like cells at 3, 7, and 14 days. Overall, we consistently reproduced BMP2 side effects of cyst-like bone and soft tissue swelling using high BMP2 concentration approaching the typical human 1500 μg/mL.

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Human adipose-derived mesenchymal stem cells reduce inflammatory and T cell responses and induce regulatory T cells in vitro in rheumatoid arthritis.

E. Gonzalez-Rey, M. A. Gonzalez, N Varela … (2010)

Adult mesenchymal stem cells were recently found to suppress effector T cell and inflammatory responses and have emerged as attractive therapeutic candidates for immune disorders. In rheumatoid arthritis (RA), a loss in the immunological self-tolerance causes the activation of autoreactive T cells against joint components and subsequent chronic inflammation. The aim of this study is to characterise the immunosuppressive activity of human adipose-derived mesenchymal stem cells (hASCs) on collagen-reactive T cells from patients with RA. The effects of hASCs on collagen-reactive RA human T cell proliferation and cytokine production were investigated, as well as effects on the production of inflammatory mediators by monocytes and fibroblast-like synoviocytes from patients with RA. hASCs suppressed the antigen-specific response of T cells from patients with RA. hASCs inhibited the proliferative response and the production of inflammatory cytokines by collagen-activated CD4 and CD8 T cells. In contrast, the numbers of IL10-producing T cells and monocytes were significantly augmented upon hASC treatment. The suppressive activity of hASCs was cell-to-cell contact dependent and independent. hASCs also stimulated the generation of FoxP3 protein-expressing CD4(+)CD25(+) regulatory T cells, with the capacity to suppress collagen-specific T cell responses. Finally, hASCs downregulated the inflammatory response and the production of matrix-degrading enzymes by synovial cells isolated from patients with RA. The present work identifies hASCs as key regulators of immune tolerance, with the capacity to suppress T cell and inflammatory responses and to induce the generation/activation of antigen-specific regulatory T cells.

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Author and article information

Journal

Journal ID (nlm-ta): Exp Ther Med

Journal ID (iso-abbrev): Exp Ther Med

Journal ID (publisher-id): ETM

Title: Experimental and Therapeutic Medicine

Publisher: D.A. Spandidos

ISSN (Print): 1792-0981

ISSN (Electronic): 1792-1015

Publication date (Print): November 2020

Publication date (Electronic): 11 September 2020

Publication date PMC-release: 11 September 2020

Volume: 20

Issue: 5

Electronic Location Identifier: 81

Affiliations

[1 ]Department of Dentistry, Graduate School, Kyung Hee University, Seoul 02447, Republic of Korea

[2 ]Department of Oral and Maxillofacial Surgery, School of Dentistry, Kyung Hee University, Seoul 02447, Republic of Korea

[3 ]Department of Maxillofacial Regenerative Medicine, School of Dentistry, Kyung Hee University, Seoul 02447, Republic of Korea

[4 ]Department of Dental Hygiene, College of Medical Science, Konyang University, Daejeon 35365, Republic of Korea

Author notes

Correspondence to: Professor Yong-Dae Kwon, Department of Oral and Maxillofacial Surgery, School of Dentistry, Kyung Hee University, 26 Kyungheedae-ro, Dongdaemun-gu, Seoul 02447, Republic of Korea kwony@ 123456khu.ac.kr

^*Contributed equally

Article

Publisher ID: ETM-0-0-09208

DOI: 10.3892/etm.2020.9208

PMC ID: 7500044

PubMed ID: 32968438

SO-VID: b63347cd-ba0f-482e-96b0-1df5c0d8759a

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This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

Osteogenic differentiation and inflammatory response of recombinant human bone morphogenetic protein-2 in human maxillary sinus membrane-derived cells

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Most cited references 47

Identification and characterization of a fibroblast marker: FSP1

High doses of bone morphogenetic protein 2 induce structurally abnormal bone and inflammation in vivo.

Human adipose-derived mesenchymal stem cells reduce inflammatory and T cell responses and induce regulatory T cells in vitro in rheumatoid arthritis.

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