Action Mechanism of Fibroblast Growth Factor-2 (FGF-2) in the Promotion of Periodontal Regeneration in Beagle Dogs

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Abstract

Fibroblast growth factor-2 (FGF-2) enhances the formation of new alveolar bone, cementum, and periodontal ligament (PDL) in periodontal defect models. However, the mechanism through which FGF-2 acts in periodontal regeneration in vivo has not been fully clarified yet. To reveal the action mechanism, the formation of regenerated tissue and gene expression at the early phase were analyzed in a beagle dog 3-wall periodontal defect model. FGF-2 (0.3%) or the vehicle (hydroxypropyl cellulose) only were topically applied to the defect in FGF-2 and control groups, respectively. Then, the amount of regenerated tissues and the number of proliferating cells at 3, 7, 14, and 28 days and the number of blood vessels at 7 days were quantitated histologically. Additionally, the expression of osteogenic genes in the regenerated tissue was evaluated by real-time PCR at 7 and 14 days. Compared with the control, cell proliferation around the existing bone and PDL, connective tissue formation on the root surface, and new bone formation in the defect at 7 days were significantly promoted by FGF-2. Additionally, the number of blood vessels at 7 days was increased by FGF-2 treatment. At 28 days, new cementum and PDL were extended by FGF-2. Moreover, FGF-2 increased the expression of bone morphogenetic protein 2 (BMP-2) and osteoblast differentiation markers (osterix, alkaline phosphatase, and osteocalcin) in the regenerated tissue. We revealed the facilitatory mechanisms of FGF-2 in periodontal regeneration in vivo. First, the proliferation of fibroblastic cells derived from bone marrow and PDL was accelerated and enhanced by FGF-2. Second, angiogenesis was enhanced by FGF-2 treatment. Finally, osteoblastic differentiation and bone formation, at least in part due to BMP-2 production, were rapidly induced by FGF-2. Therefore, these multifaceted effects of FGF-2 promote new tissue formation at the early regeneration phase, leading to enhanced formation of new bone, cementum, and PDL.

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Most cited references 38

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New attachment following surgical treatment of human periodontal disease.

Jeffry S. Nyman, H Grady Rylander Iii, T Karring … (1982)

The present experiment was undertaken to test the hypothesis that new connective tissue attachment may form on a previously periodontitis involved root surface provided cells originating from the periodontal ligament are enabled to repopulate the root surface during healing. A mandibular incisor with advanced periodontal disease of long standing (the distance between the cemento-enamel junction and the alveolar bone crest was 9 mm) was subjected to periodontal surgery using a technique which during healing prevented the dentogingival epithelium and the gingival connective tissue from reaching contact with the curetted root surface. Preference was hereby given to the periodontal ligament cells to repopulate the previously diseased root surface. After 3 months of healing a block biopsy containing the incisor and surrounding tissue was sampled. The histological analysis revealed that new cementum with inserting principal fibers had formed on the previously diseased root surface. This new attachment extended in coronal direction to a level 5 mm coronal to the alveolar bone crest. This finding suggests that new attachment can be achieved by cells originating from the periodontal ligament and demonstrates that the concept that the periodontitis affected root surface is a major preventive factor for new attachment is invalid.

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Platelet-derived growth factor stimulates bone fill and rate of attachment level gain: results of a large multicenter randomized controlled trial.

B McAllister, James E. Hinrichs, S Nevins … (2005)

Growth factors are generally accepted to be essential mediators of tissue repair via well-established mechanisms of action that include stimulatory effects on angiogenesis and cellular proliferation, ingrowth, differentiation, and matrix biosynthesis. The aim of this study was to evaluate in a large-scale, prospective, blinded, and randomized controlled clinical trial the safety and effectiveness of purified recombinant human platelet-derived growth factor (rhPDGF-BB) mixed with a synthetic beta-tricalcium phosphate (beta-TCP) matrix for the treatment of advanced periodontal osseous defects at 6 months of healing. Eleven clinical centers enrolled 180 subjects, each requiring surgical treatment of a 4 mm or greater intrabony periodontal defect and meeting all inclusion and exclusion criteria. Subjects were randomized into one of three treatment groups: 1) beta-TCP + 0.3 mg/ml rhPDGF-BB in buffer; 2) beta-TCP + 1.0 mg/ml rhPDGF-BB in buffer; and 3) beta-TCP + buffer (active control). Safety data were assessed by the frequency and severity of adverse events. Effectiveness measurements included clinical attachment levels (CAL) and gingival recession (GR) measured clinically and linear bone growth (LBG) and percent bone fill (% BF) as assessed radiographically by an independent centralized radiology review center. The area under the curve (AUC), an assessment of the rate of healing, was also calculated for CAL measurements. The surgeons, clinical and radiographic evaluators, patients, and study sponsor were all masked with respect to treatment groups. CAL gain was significantly greater at 3 months for group 1 (rhPDGF 0.3 mg/ml) compared to group 3 (beta-TCP + buffer) (3.8 versus 3.3 mm; P = 0.032), although by 6 months, this finding was not statistically significant (P = 0.11). This early acceleration of CAL gain led to group 1 exhibiting a significantly greater rate of CAL gain between baseline and 6 months than group 3 as assessed by the AUC (68.4- versus 60.1-mm weeks; P = 0.033). rhPDGF (0.3 mg/ml)-treated sites also had significantly greater linear bone gain (2.6 versus 0.9 mm, respectively; P < 0.001) and percent defect fill (57% versus 18%, respectively; P < 0.001) than the sites receiving the bone substitute with buffer at 6 months. There was less GR at 3 months in group 1 compared to group 3 (P = 0.04); at 6 months, GR for group 1 remained unchanged, whereas there was a slight gain in gingival height for group 3 resulting in comparable GR. There were no serious adverse events attributable to any of the treatments. To our knowledge, this study is the largest prospective, randomized, triple-blinded, and controlled pivotal clinical trial reported to date assessing a putative periodontal regenerative and wound healing therapy. The study demonstrated that the use of rhPDGF-BB was safe and effective in the treatment of periodontal osseous defects. Treatment with rhPDGF-BB stimulated a significant increase in the rate of CAL gain, reduced gingival recession at 3 months post-surgery, and improved bone fill as compared to a beta-TCP bone substitute at 6 months.

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Differentiation of human bone marrow osteogenic stromal cells in vitro: induction of the osteoblast phenotype by dexamethasone.

L V Avioli, Alfred S. L. Cheng, Thomas Yang … (1993)

Human bone marrow stromal cells were examined for their osteogenic potential in an in vitro cell culture system. Dexamethasone (Dex) treatment induced morphological transformation of these cells from an elongated to a more cuboidal shape, increased their alkaline phosphatase activity and cAMP responses to PTH and prostaglandin E2, and was essential for mineralization of the extracellular matrix. Dex-induced differentiation of human bone marrow stromal cells was apparent after 2-3 days of treatment and reached a maximum at 7-14 days, as judged by alkaline phosphatase activity, although induction of osteocalcin by 1,25-dihydroxyvitamin D3 was attenuated by Dex. Withdrawal of Dex resulted in an enhancement of the 1,25-dihydroxyvitamin D3-induced secretion of osteocalcin, whereas alkaline phosphatase activity and the cAMP response to PTH remained at prewithdrawal levels. The steady state mRNA level of osteonectin was not affected by Dex. Our results, which demonstrate that Dex conditions the differentiation of human bone marrow osteogenic stromal cells into osteoblast-like cells, support the hypothesis of a permissive effect of glucocorticoids in ensuring an adequate supply of mature osteoblast populations. Furthermore, the established human bone marrow stromal cell culture provides a good model of an in vitro system to study the regulation of differentiation of human bone osteoprogenitor cells.

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Author and article information

Contributors

Takuya Matsumoto: Role: Editor

Journal

Journal ID (nlm-ta): PLoS One

Journal ID (iso-abbrev): PLoS ONE

Journal ID (publisher-id): plos

Journal ID (pmc): plosone

Title: PLoS ONE

Publisher: Public Library of Science (San Francisco, CA USA )

ISSN (Electronic): 1932-6203

Publication date (Electronic): 29 June 2015

Publication date Collection: 2015

Volume: 10

Issue: 6

Electronic Location Identifier: e0131870

Affiliations

[1 ]Pharmacology Department, Drug Research Center, Kaken Pharmaceutical Co., LTD., Kyoto, Kyoto, Japan

[2 ]Department of Periodontology, Osaka University Graduate School of Dentistry, Suita, Osaka, Japan

Department of Biomaterials, JAPAN

Author notes

Competing Interests: SM received research grants from Kaken Pharmaceutical Co., Ltd and accepted a position as a medical advisor. TNT, JA, ST, NS, AT, and TA are employees of Kaken Pharmaceutical Co., Ltd. TNT, JA, and TA are stockholders of Kaken Pharmaceutical Co., Ltd. AT and TA are listed on the patent ‘periodontal disease remedy’ (WO/1995/005840). This does not alter the authors' adherence to PLOS ONE policies on sharing data and materials.

Conceived and designed the experiments: TNT JA TA SM. Performed the experiments: TNT JA ST NS AT. Analyzed the data: TN MK. Wrote the paper: TNT JA TA SM.

[¤a]

Current Address: 14, Shinomiya, Minamigawara-cho, Yamashina-ku, Kyoto 607–8042, Japan

[¤b]

Current Address: 1-8 Yamadaoka, Suita, Osaka 565–0871, Japan

* E-mail: ipshinya@ 123456dent.osaka-u.ac.jp

Article

Publisher ID: PONE-D-14-48373

DOI: 10.1371/journal.pone.0131870

PMC ID: 4488280

PubMed ID: 26120833

SO-VID: be9c1411-0ce7-4761-9f90-d64d7220223e

License:

This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited

History

Date received : 12 November 2014

Date accepted : 1 June 2015

Page count

Figures: 7, Tables: 0, Pages: 19

Funding

This study was supported by Kaken Pharmaceutical Co., Ltd. and Osaka University Graduate School of Dentistry, which proposed study protocol and was responsible for data collection and prespecified statistical analysis.

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Data Availability All relevant data are within the paper and its Supporting Information files.

Action Mechanism of Fibroblast Growth Factor-2 (FGF-2) in the Promotion of Periodontal Regeneration in Beagle Dogs

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Most cited references 38

New attachment following surgical treatment of human periodontal disease.

Platelet-derived growth factor stimulates bone fill and rate of attachment level gain: results of a large multicenter randomized controlled trial.

Differentiation of human bone marrow osteogenic stromal cells in vitro: induction of the osteoblast phenotype by dexamethasone.

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