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Berberine's effect on periodontal tissue degradation by matrix metalloproteinases: an in vitro and in vivo experiment.





matrix metalloproteinase




Periodontal disease involves tissue destruction caused by interactions among bacterial antigens and inflammatory mediators including matrix metalloproteinases (MMPs). Berberine, an isoquinoline alkaloid isolated from medicinal herbs, can inhibit the degradative action of extracellular MMPs. The effect of berberine on the periodontal expression of MMPs was examined in vitro and in vivo. Gelatinolytic activity of pro-MMP-2. MMP-2, and MMP-9 in the human gingival fibroblast and/or U-937 was compared after treatment with Porphyromonas gingivalis lipopolysaccharide (P.g. LPS) in four medias containing 0, 1, 10 and 100 [micro]M of berberine each. Twelve animals were divided into three groups for the study: (A) non-ligation, (B) ligation, and (C) ligation-plus-berberine (75 mg/kg berberine by gastric lavage daily); and the effect of berberine on periodontal destruction was evaluated in the ligature-induced periodontitis in rats for 8 days by micro computerized tomography (micro-CT), histology and immunohistochemistry (IHC). An enhancing effect of P.g. LPS on MMP activities was identified, with a greater effect on fibroblasts/U937 co-culture than on either culture alone. When berberine was added to the LPS-treated cultures, the activities of MMPs were significantly reduced in dose-dependent manner. In the animals, the trends of the following parameters were compared. 1. Micro-CT distances between cemento-enamel junction (CEJ) and dental alveolar bone crest: B > C > A. 2. Histometrically measured crest bone levels: B> C> A. 3. Amount of collagen deposited in tissue areas: A> C> B. 4. Attachment loss: B> C[approximately equal to]A. 5. Connective tissue (CT) attachment: B> either A or C. 6. Expression of cells stained positive for MMP-2 and -9 by IHC: B > C> A. In conclusion, berberine demonstrated in vitro an inhibitory effect on P.g. LPS-enhanced MMP activities of HGF and U937 macrophages, reducing in vivo gingival tissue degradation in periodontitic rats. We thus propose that berberine may slow periodontal degradation through the regulation of MMPs in periodontitis induced by bacterial plaque.

[c] 2013 Elsevier GmbH. All rights reserved.


Periodontal disease is an inflammatory disorder in which inflammatory reaction may damage surrounding cells and tissue structures including the alveolar bone, causing tooth loss. In the inflamed periodontal tissues, dental plaque bacteria and their products induce polymorphonuclear leukocyte infiltration, edema and vascular dilatation (Page, 1991). Complex interactions among various inflammatory mediators and tissue degradation have been carefully examined in vitro and in vivo and suggested to be involved in the pathogenic mechanisms of periodontitis (Kuo et al., 2012; Sundararaj et al., 2009; Fiehn et al., 1992; Di Paola et al., 2004).

Berberine, an isoquinoline alkaloid, can be isolated from many medicinal herbs, such as Rhizoma coptidis (Huanglian), Hydrastis canadensis (goldenseal) and Cortex phellodendri (Huangbai) (lkram, 1975). Berberine-containing plants are used medicinally in many traditional medical systems, including Chinese herbal and Ayurvedic herbal medicine (lmanshahidi and Hosseinzadeh, 2008). Studies have indicated that berberine has multiple pharmacological activities including anti-inflammatory, anti-cyclooxygenase, and anti-inducible nitric oxide synthases effects (Jiang et al., 2011; Lee et al., 2007). Recently, the effect of berberine against the extracellular matrix degradation through the regulation of the matrix metalloproteinase (MMP) has been evaluated (Huang et al., 2011: Jeong et al., 2009). MMPs are a family of structurally related proteins that degrade most components of the extracellular matrix and basal membranes (Bode et al., 1993). They have been implicated in extracellular matrix remodeling in embryonic development, inflammation, tumor invasion, metastasis and fibrosis (Stamenkovic, 2003). The activation and over-expression of host MMPs caused by periodontal pathogens and by inflammatory cytokines have been reported (Chang et al., 2002). The increased activity/levels of proteinases during experimental gingivitis (Kowashi et al., 1979) and their decrease after periodontal therapy (Figueredo et al., 2004) further suggest the involvement of certain MMPs in periodontal tissue destruction and degradation.

Berberine can in vitro effectively suppress the induced MMP-9 expressions in the induced macrophages (Huang et al., 2011). In human keratinocytes, berberine prevents skin inflammation and degradation of extracellular matrix proteins, including collagen, by MMPs (Kim et al., 2008). In order to understand the effect of berberine on local degradation caused by periodontitis, the expression of MMP-2 and -9 in periodontium was in vitro and in vivo evaluated.

Materials and methods

The in vitro experiment

Human gingival fibroblasts (HGF) were obtained as described elsewhere (Chin et al., 2011). In brief, the gingival specimens were immersed in Leibovitz L-15 medium containing 2 mg/ml dispase II (Roche Diagnostics, Indianapolis, IN, USA) and 10% fetal bovine serum at 4[degrees]C for 2 d. After separation from the outer epithelial layer, the connective tissue was minced and digested in medium containing 10% FBS and 2 mg/ml collagenase for 24h. The tissue was then placed in flasks containing 10% FBS in DMEM/F-12 media to allow the cells to migrate from the explants. Confluent fibroblasts were starved in serum-free medium for 24 h before experiments. Various concentrations of P.g. LPS (InvivoGen, San Diego, CA, USA) between 0 and 100 ng/ml were adjusted for the individual cultures and co-cultures. The gelatinolytic activity of proMMP-2, MMP-2, and MMP-9, in supernatants of the cultures treated with LPS (100 ng/ml) or berberine, at the concentrations of 0, 1, 10, and 100 [micro]M, for 24 and/or 48 hours was investigated using zymography. Similar to our previous study (Kuo et al., 2012), the U-937 macrophages at concentration of 105 per ml were also selected and used. The serum free RPMI-1640 media (InvitroGen, Grand Island, NY, USA) was used for the U937 cells. In the co-cultures of the U937 and HGF, the same condition for the media was maintained for the fibroblast cultures throughout the experiment. In the in vitro experiments, all the HGFs or/and U937 cells were incubated in a humidified atmosphere of 5% [CO.sup.2] at 37[degrees]C, whereas the HGFs used were from the third to seventh passages.

Gelatin zymography

The release of MMPs (proMMP-2, MMP-2, and MMP-9) from cell cultures were evaluated using gelatin zymography. The proteins in the medium in which the cells were incubated were separated under nonreducing conditions using a 10% SDS-polyacrylamide gel containing 0.1% gelatin. Equal amounts of protein, measured using the BCATM protein assay (Pierce, Rockford, IL, USA), were loaded into each lane of the gel. After electrophoresis, the gel was shaken gently in renaturing buffer (2.5% Triton-X100) to remove SDS and then incubated in developing buffer for 16 h. The gel was stained with 2.5% Coomassie Brilliant Blue. The latent and active forms of MMP-2 were identified as the 72 kDa and 62 kDa bands, respectively, while MMP-9 was detected as the 92 kDa band. The gel images were scanned directly (Transilluminator/SPOT, Diagnostic Instruments, Sterling Heights, MI, USA).

In vivo experiment

The effect of berberine on the dental alveolar bony level of rats with the periodontis caused by ligation around molars was evaluated. After being approved by the Institutional Animal Care and Use Committee, National Defense Medical Center, Taipei, Taiwan (IACUC-12-147), twelve male Sprague Dawley (SD) rats, six-week-old and weighing 180-230g. were randomly divided into three groups (four rats per group). Rats in the ligation group had 3-0 silk (surgical silk sutures; UNIK, Taiwan) placed on the cervices of the second maxillary and first mandibular molars as that described in our previous study (Cheng et al., 2010). Rats in these two groups were fed daily with the solvent, the mixture of dimethyl sulfoxide (DMSO) (SIGMA-ALORICH, Inc., MO, USA) with normal saline (1/3 by volume). Rats in the ligation-plus-berberine group were given the same silk ligations as rats in the ligation group, with daily doses of berberine (75 mg/kg in the solvent of DMSO) from the day before the ligation by gastric lavage. All animals were caged in clear plastic cages and kept in an environmentally controlled room maintained at 23[degrees]C, relative humidity 55%, and a light-dark cycle of 12 hours/12 hours in the Animal Center of National Defense Medical Center, Taipei, Taiwan. On day 8 of experiment, all rats were sacrificed by carbon dioxide inhalation. The maxillary and mandibular specimens (including gingivae, teeth and bones) were taken and fixed in 4% paraformaldehyde and prepared for micro computerized tomography (micro-CT) and histological examination.

Micro computed tomography imaging

Twelve jaw biopsies, four from each group, were subjected to micro-CT imaging using a multimodality preclinical imaging system (FLEX Triumph; Gamma Medica-Ideas, Northridge, CA, US) equipped with an X-0 CT. The x-ray tube was operated at an accelerated potential of 75 kVp with a beam current of 120 [micro]A. The field-of-view for micro-CT was fixed at 61.44 mm leading to 2 x magnification of images. The micro-CT images were taken under fly mode with 1024 projections and one frame per projection to achieve a voxel size of 120x 120x 120 [micro][m.sup.3]. Micro-CT data were acquired and reconstructed using Triumph XO software (Gamma Medica-Ideas) and then visualized and analyzed using VIVID software (Gamma Medica-Ideas). This enabled us to observe the morphology around the tooth and dental alveolar bone in all dimensions, including the cemento-enamel junction (CEJ), root surface and dental alveolar crest, as well as the relationships between these areas, and assess the distance between the CEJ and the coronal level of the alveolar bone crests (the micro-CT bone levels) at 12 sites, including the mesio- and disto-buccal sites, the mesio- and disto-palatal sites of the right and left second maxillary molars, and the disto-buccal and disto-lingual sites of the right and left first mandibular molars on reconstructed three-dimensional micro-CT images.

Histology, histometry and immunohistochemistry

In this study, the maxillary specimens were prepared for histological examination in the same way as our previous study (Cheng et al., 2010). In brief, the palatal specimens were sectioned buccopalatally into 4-[micro]m-thick sections after EDTA decalcification, dehydration and paraffin embedding, and then prepared for hematoxylin and eosin (H&E) staining. On the mesial surfaces of the second molars in each rat, the following histometric measurements were performed: the distance of the CEJ to the coronal level of epithelial cells (JEc) (attachment loss); the distance of the CEJ to the alveolar bone crest (ABC) (the alveolar crest bone level); the distance of the apical level of epithelial cells (JEa) to the ABC (the CT attachment); and the region of collagen deposited connective tissue in a zone of 0.14 m[m.sup.2] of sub-epithelial gingiva on the mesial surface of the second maxillary molar in each rat as that in our previous study (Cheng et al., 2010). In this study, the protein expression of MMP-2 and MMP-9 in gingival tissue was further evaluated by IHC. After fixation in acetone, tissue sections were incubated in 0.1% hydrogen peroxide in distilled water to quench endogenous peroxidase activity. They were then incubated for 2 h with unconjugated primary polyclonal antibodies against MMP-2 and -9 (mouse IgG) (Chemicon International Inc., Temecula, CA, USA), followed by incubation with biotinylated secondary antibody, streptaviclin-conjugated horseradish peroxidase complexes and 3-amino-9-ethyl carbazole solution for 4 min, 20 min, and 20 min, respectively. The specimens were then washed with distilled water and counterstained with hematoxylin. The tissue sections were dehydrated and mounted for microscopic observation. Positively stained MMP-2 and -9 cells were detected using a microscope as our previous study described (Chiu et al., 2009).

Statistical Analysis

A one-way ANOVA and Duncan's test for post hoc analysis was used to evaluate the differences of the gelatinolytic activity of pro-MMP-2, MMP-2 and proMMP-9 among the independent cultures of U937 macrophages and human gingival fibroblasts, as well as their co-cultures. Regression analysis was used to determine the close effect of LPS or CsA on the MMP activities. Repeated-measures analysis of variance (ANOVA) was used to evaluate the influence of the inter-subject factor (berberine or ligation treatment), as well as the intra-subject factors (including the maxillary or mandibular jaw, the left or right side, the buccal or palatal/lingual site, and mesial or distal end) on the location of dental alveolar bone crest measured by micro-CT. One-way ANOVA, with Duncan's test for post hoc analysis, was used to determine the effect of berberine on the histometric measurements. P< 0.05 was considered significant.


P.g. LPS significantly increased the activities of MMPs in all independent cultures and co-culture of U937 and HGF (Fig. 1). In the co-cultures, the activities of MMPs were increased if compared with those in the independent cultures. The activity of pro-MMP-9 is mainly present in the independent cultures of U-937, while the activities of pro-MMP-2 and MMP-2 were mainly expressed in the independent culture of HGF.

The berberine treatments significantly decreased, in dose dependent manner, the activities of MMPs in the cultures treated with P. gingivalis LPS, regardless the type of culture (Fig. 2).

                 U937                     HGF               Co-cultures

              Pro-MMP-9     Pro-MP-2   Pro-MMP-2     MMP-2    Pro-MMP-9

Coefficient      -0.339       -0.123      -0.037    -0.195       -0.195

[R.sup.2]         0.687        0.870       0.570     0.620        0.725

Pvalue          -0.001 *   < 0.001 *     = 0.005   = 0.002      < 0.001
                                               *         *            *
               Pro-MMP-2       MMP-2

Coefficient       -0.049      -0.120

[R.sup.2]          0.719       0.816

Pvalue         < 0.001 *     < 0.001

* Fig. 2. Effect of berberine on the activities of MMP-9,
pro-MMP-2 and MMP-2 in independent cultures and the
co-cultures of HGFs and U937 macrophages received the
P.g LPS treatment. (A: the images of zymography, and
B: the dose effect of berberine on the MMP activities
in the cultures received LPS) (Data are expressed as
means and standard errors, significant difference at p <0.05).

In the animal study, the distance of CEJ to bone (the micro-CT bone levels) was significantly different among the experimental groups (Fig. 3A). The distance was shortest in the non-ligation group, longest in the ligation group, and intermediate in the ligation-plus-berberine group although it was influenced by other factors such as jaw location (maxillae or mandible), buccal or palatal/lingual surface, and mesial or distal site (Fig. 3B-C).

Periodontal destruction was further histologically evaluated (Fig. 4A). By histometry, the level of bone crestin the ligation-plus-berberine group was coronally positioned if compare with that in the ligation group, but it was apically positioned when compare to that in the non-ligation group (Fig. 4B). The collagen deposited connective tissue areas in the ligation-plus-berberine group significantly greater than that of the ligation group but lesser than that of the non-ligation group. The attachment loss (CEJ to JEc) in the ligation and the ligation-plus-berberine groups was significantly greater than that in the non-ligation group. The CT attachment in the ligation group was significantly greater than that in the non-ligation and the ligation-plus-berberine groups. By IHC, the gingiva from the ligation group contained greater number of cells stained positive for MMP-2 and MMP-9 than that from the non-ligation group; and that from the ligation-plus-berberine group showed an intermediate value (Fig. 5).


The effects of berberine on periodontal MMPs, including MMP-2 and MMP-9, expressions were examined in vitro and in vivo in the present study. In the in vivo model, periodontitis in rats was induced by ligature (Figs. 3 and 4), whereas in the in vitro model the co-culture of human gingival fibroblasts and U-937 human monocytes cell line was given Porphyromonas gingivalis (P. gingivalis) LPS treatment to simulate local inflammation in periodontium (Figs. 1 and 2).

In the present study, the inhibitory effect of berberine was first in vitro tested in the individual cultures or co-cultures of fibroblasts and macrophages as in our previous study. The P. gingivalis LPS treatment significantly increased the activities of MMPs in the independent cultures of HGF and U937 macrophages and those in the co-culture (Fig. 4) in this and our previous study (Kuo et al., 2012). In a study by Sundararaj and colleagues, the co-cultures of gingival fibroblasts and macrophages were tested for normal and high glucose conditions to investigate the hyperglycemic effect on MMP expression via intercellular communications (Sundararaj et al., 2009). In the result, the augmentation of MMP-1 expression was observed in the co-cultures of fibroblasts and HGF and this augmentation was further enhanced by high glucose concentration. Because interleukin-6 released by gingival fibroblasts was essential for the augmentation of MMP-1 expression by the macrophages, intercellular communication between the two cell types was implicated. In another co-culture study, interleukin-6 release increased 100-fold of that of independent cultures of macrophages (Lind et al., 1998). The exact mechanism of intercellular communication between fibroblasts and U937 remains obscure and further investigation is indicated.

In our study, the processes of periodontal destruction and osteoclastic bone resorption were induced in vivo by silk ligation around the molars of rats (Cai et al., 2008) in similar methods to our previous study. In the present study, the destruction of dental alveolar bone was evaluated by micro-CT and histologic parameters. In terms of micro-CT bone level (the distance from CEJ to bone crest), rats in the ligation group showed greater length than the non-ligation group while the ligation-plus-berberine group measures in between the two (Fig. 3). With this finding we formulated that dental alveolar bone level could be deduced from the micro-CT observations as well as histologic estimation, but this may not be the precise representation of the periodontal soft tissue loss. In this study, the attachment losses (CEJ to JEc) in the ligation and the ligation-plus-berberine groups were similar (both significantly greater than in the non-ligation group). In terms of the amount of collagen deposit, the ligation-plus-berberine group showed less increase than the ligation group and significantly greater increase than the non-ligation group. The observed finding reflected reduced inflammatory condition by berberine.

In addition, the development of periodontitis involves complex mechanisms associated with bacteria and immune modulations, thus our experimental periodontitis in rats still faces certain limitations (Graves et al., 2008). For the purpose of bacterial retention, the periodontitis in the experiment was induced by inserting the ligature around the tooth neck. This artificial plaque retention, however, inflicted an inevitable trauma to the local gingival tissue (Lohinai et al., 1998). Besides, the tissue observation was limited to a short period of 7 days. Longer observational period is implicated from the chronic patter of periodontal disease.

In the present study, our in vitro results showed that the berberine treatments significantly decreased, in dose dependent manner, the activities of pro-MMP-9, pro-MMP-2 or MMP-2 in the cultures of hGF, U937 and hGF/U937 cells received the P. gingivalis LPS treatment (Fig. 2). In the rats with experimental periodontitis, by ligature placement for 8 days, the berberine treatment not only attenuated the degradation process of periodontal tissue but also reduced the number of gingival cells stained positive for MMP-2 and MMP-9 (Figs. 4-5). The precise mechanism remains to be elucidated; however, berberine attenuated the degradation process of periodontal tissue through inhibition of matrix metalloproteinases was suggested. In recent researches, the extracellular matrix metalloproteinase inducer (EMMPRIN), a glycoprotein extensively glycosylated to the plasma membrane, was identified and its expression is considered to induce the fibroblasts to secrete MMPs (Foda et al., 2001). EMMPRIN (CD147) contains two immunoglobulin superfamily domains, a transmembrane domain, and a stoplasmic domain (Biswas et al., 1995) and was originally identified on the surfaces of tumor cells. Its expression on tumor cells may enhance tumor progression and invasion by triggering the production and release of MMPs by fibroblasts and endothelial cells (Zucker et al., 2001). The ability of EMMPRIN to stimulate MMP production implies that this molecule may be associated with several physiological and pathological tissue modulatory processes and tissue remodeling (Gabison et al., 2005). We examined the expression of EMMPRIN in gingiva with the ligature-induced experimental periodontitis by IHC and an increased expression was observed; however, the expression was attenuated by berberine administration (un-published data). Nevertheless, the role of EMMPRIN in the berberine-inhibited matrix metalloproteinases requires further investigation.

Berberine is commonly known as an important compound in traditional Chinese medicine (Imanshahidi and Hosseinzadeh, 2008). Berberine has been thought to be a candidate for preventing various diseases because of the discoveries of its therapeutic biological effects, including anti-inflammation and anti-matrix-degradation (Huang et al., 2011; Jeong et al., 2009; Jiang et al., 2011). In this study, we provided the in vitro and in vivo evidences showing that berberine might have a preventive potential in the periodontal tissue degradation during inflammation. Because the primary etiology of periodontitis is the microbial pathogens, the removal of pathogens, as well as the prevention of microbial recurrence, is the principal strategy of treatment. However, the chemotherapies and the host modulations are still be used as the adjunctive therapies due to the complex interactions among inflammatory mediators and tissue degradation are involved in the pathogenic mechanisms of periodontitis (Page, 1991).

In conclusion, this was the first study to in vitro and in vivo demonstrate that berberine could inhibit the P.g. LPS-enhanced MMP activities in the cultures of HGFs and U937 macrophages and attenuate the tissue matrix degradation in the experimental periodontitis of rats. We therefore suggest that berberine may attenuate the periodontal tissue degradation through the regulation of MMPs during the progression of periodontitis.


This study was partially supported by the research grants from the Department of National Defence (TSGH-C98-28) and the C.Y. Foundation for Advancement of Education, Sciences and Medicine.

Abbreviations: MMP, Matrix metalloproteinase; P.g., porphyromonas gingivalis: LPS, lipopolysaccharide; micro-CT, Micro Computed Tomography; CEJ, cementoenamel junction; IHC, immunohistochemistry; CT. connective tissue; HGF, human gingival fibroblasts.

* Corresponding author at: Department of Periodontology, School of Dentistry, National Defense Medical Center, PO Box 90048-507, Taipei, Taiwan, ROC. Tel.: +886 2 87927150; fax: +886287927145.

E-mail address: (E. Fu).

0944-7113/S--see front matter [c] 2013 Elsevier GmbH. All rights reserved.


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Hsiao-Pei Tu (a), (b), Martin M.J. Fu (c), Po-Jan Kuo (a), Yu-Tang Chin (a), Cheng-Yang Chiang (a), Cheng-Long Chung (a), Earl Fua (a) *

(a) Department of Periodontology, School of Dentistry. National Defense Medical Center and Tri-Service General Hospital, Taipei, Taiwan. ROC

(b) Department of Dental Hygiene, China Medical University, Taichung, Taiwan. ROC

(c) Resident, Division of Periodontology, Department of Oral Medicine, Infection and Immunity, Harvard School of Dental Medicine, Boston, MA, USA
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Author:Tu, Hsiao-Pei; Fu, Martin M.J.; Kuo, Po-Jan; China, Yu-Tang; Chiang, Cheng-Yang; Chung, Cheng-Long;
Publication:Phytomedicine: International Journal of Phytotherapy & Phytopharmacology
Article Type:Report
Geographic Code:9TAIW
Date:Oct 15, 2013
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