The Effect of Mangosteen Peel (Garcinia mangostana L) Extract on the Expression of BMP2, ALP, and FGF2 in the Periodontal Remodeling Process During Orthodontic Tooth Movement

Herniyati¹, Leliana Sandra Devi Ade Putri¹*, Noengki Prameswari²

¹Department of Orthodontics, Faculty of Dentistry, University of Jember, Jember, Indonesia.

²Department of Orthodontics, Faculty of Dentistry, University of Hang Tuah,

Surabaya, Indonesia.

*Corresponding Author E-mail: herny_is@unej.ac.id

ABSTRACT:

Background: Orthodontic treatment is relatively long and various efforts have been made to speed up orthodontic tooth movement. In orthodontic tooth movement, a periodontal tissue remodeling process occurs which involves osteoblastic and osteoclastic cells which are very sensitive to oxidative damage due to excessive ROS production. Natural antioxidants are a group of compounds that can neutralize or prevent free radicals. Mangosteen peel is a waste that contains nutritious chemical compounds such as flavonoids, tannins, xanthones, mangostin and garcinone. Flavonoids play an important role in eliminating oxidative stress by preventing ROS, protecting lipophilic antioxidants, and increasing enzymatic antioxidants. This research aimed to analyze the expression of BMP2, ALP, and FGF2, in the periodontal tissue remodeling process during orthodontic tooth movement after administration of mangosteen peel extract. Materials and Methods: This laboratory experimental study was conducted using 36 male Wistar rats. 36 wistar rats divided into 6 groups: control groups (C1, C2 and C3) : rats were given orthodontic mechanical force (OMF) for 1 weeks, 2 weeks and 3 weeks and treatment groups (T1, T2 and T3): rats were given OMF and mangosteen peel extract  for 1 week, 2 weeks and 3 weeks. OMF in rats was carried out by means of the right maxillary first molars and on both maxillary incisors were given ligature wires. Then a 10-gr/cm force was applied to the maxillary left first molar tooth of all the rats, using a nickel‒titanium closed-coil spring 6 mm long.ligated between the maxillary incisors and the left first molar tooth. Observations were made on the day 8, day 15 and day 22 with immunohistochemical examinations to count the expression of BMP2, ALP and FGF2. Results: The expression of BMP 2, ALP and FGF 2 on day 8, day 15 and day 22 in the treatment group was greater than the control group (˂ 0.05). The highest amount of BMP2, ALP and FGF2  expression was in the 15th day group, while the lowest was in the 8th day group. An increase the expression of BMP2, ALP, and FGF2 occurred on day 15 and a decrease on day 22 (˂ 0.05). Conclusion: Mangosteen peel extract was able to increase the expression of BMP2, ALP and FGF2 in osteoblasts, so it can be developed as an alternative material to accelerate the process of remodeling tooth periodontal tissue and speed up orthodontic treatment

KEYWORDS: BMP2, ALP, FGF2, OMF, Mangosteen peel.

INTRODUCTION: 

Malocclusion is any condition that deviates from normal occlusion.¹ The prevalence of malocclusion in Indonesia is still high, namely around 80% and is one of the biggest dental and oral health problems after dental caries and periodontal disease.²

In orthodontic treatment, tooth movement occurs due to mechanical stimulation followed by remodeling of the alveolar bone and periodontal ligament (PDL). Bone remodeling is a process that includes bone resorption in areas of pressure and bone formation in areas of tension. Bone resorption is carried out by osteoclasts and new bone formation by osteoblasts.

The application of orthodontic force during orthodontic treatment will initiate cellular and molecular signaling and regulation in periodontal. Fibroblasts, osteoblasts, osteoclasts and macrophages are cells that play arole in bone remodeling.³

Bhone Morphogenetic Proteins (BMPs) including BMP2 are growth factors that play a role in osteoblast differentiation which regulates the process of bone formation and mineralization. BMP2 stimulates the differentiation of mesenchymal cells into osteoblasts and chondrocytes.⁴

Alkaline phosphatase (ALP) is a glycoprotein involved in the formation of bone tissue minerals and cementum. Orthodontic tooth movement causes a biological response that involves changes in the architecture of the surrounding bone. Bone metabolism is related to alkaline phosphatase (ALP) by osteoblasts and acid phosphatase (ACP), by osteoclasts.⁵

Basic fibroblast growth factor (bFGF) or fibroblast growth factor-2 (FGF-2) is a cytokine involved in angiogenesis, tissue remodeling and stimulation of osteoblasts and osteoclasts. The role of this molecule is similar to that of VEGF and is involved in migration and proliferation of endothelial cells, angiogenesis and reconstruction of bone tissue in vivo.⁶

Mechanical pressure in orthodontic treatment induces a series of biological involvements of the local inflammatory response and the remodeling of the surrounding bone tissue. Initially, compression of the bone and periodontal cells causes the release of inflammatory mediators such as tumor necrosis factor-alpha (TNF-α) and interleukin-1 beta (IL-1β). These mediators can trigger a chain reaction leading to increased ROS production. ROS can overcome the capacity of cellular antioxidant defenses and cause damage to proteins, DNA, and lipids. Studies suggest that osteoblastic and osteoclastic cells involved in the bone remodeling process are particularly sensitive to oxidative damage. Excessive ROS production can inhibit osteoblast differentiation and increase osteoclast activity, thus compromising the balance between bone formation and resorption. This imbalance can lead to delays in tooth movement and post-treatment instability.⁷

The harmful effects of free radicals can be prevented by using substances called antioxidants. Antioxidants are a group of compounds that neutralize or prevent free radicals or reactive species and avoid cell or tissue damage caused by the oxidative potential of free radicals.⁸

The mechanism of action of antioxidants has two functions; The first function is to act as a donor of hydrogen atoms which is the main function. Antioxidants that have this main function are called primary antioxidants. The second function is a secondary function, namely as a preventive measure. These antioxidants reduce the rate of auto-oxidation by various mechanisms outside the auto-oxidation mechanism, namely chain breaking through the conversion of lipid radicals into a more stable form. ^{9 10}

Antioxidants can be endogenous or exogenous and function to deactivate free radicals.¹¹ Exogenous antioxidants are found in varying amounts in foods such as vegetables, fruits, and various other foods naturally.¹² The majority of the natural antioxidant content of the active substances are flavonoids, isoflavones, flavones, anthrocyanins, coumarins, lignans, catechins and isocatechins. ¹³

Mangosteen fruit (Garcinia mangostana L) has various potentials for healing health in the fruit and skin. Mangosteen peel is a waste that contains compounds such as flavonoids, tannins, xanthones, mangostin and garcinone. Flavonoids, including phenolic compounds, have antioxidant effects that play a role in eliminating oxidative stress.^{14 15 16 17} which can prevent ROS, protect lipophilic antioxidants, and increase enzymatic antioxidants. Oxidative stress can damage bone metabolism so that the bone remodeling process is disrupted.¹⁸

This research aimed to analyze the expression of BMP2, ALP, and FGF2, in the periodontal remodeling process during orthodontic tooth movement after administration of mangosteen peel extract.

MATERIALS AND METHODS:

Research Design:

This laboratory experimental research was carried out with a research design in the form of the post-test only control group design and has been approved by the Health Research Ethics Committee of the Faculty of Dentistry, Jember University with No.1796/UN25.8/KEPK/DL/2022.

Settings and Samples:

This research was carried out using 36 male Wistar rats of the Rattus norvegicus species with an age range of 3-4 months and a body weight of 250-300 grams. Rats were randomly divided into 6 groups: control group (C1, C2 and C3): rats were given orthodontic mechanical force (OMF) and 2ml of distilled water for an observation period of 1, 2 and 3 weeks and treatment group (T1, T2 and T3): given OMF and mangosteen peel extract at a dose of 20 mg/100 gr BW dissolved in 2 ml of distilled water. Mangosteen peel extract was given orally by gastric sondase every afternoon.

OMF on rats was carried out by anesthetizing the rats using ketamine xylazine.

Orthodontic appliances were designed and placed between the incisors and left molars to induce orthodontic movement of the left first molar. These consisted of 0.20 mm ligature wires (3M Unitek, Germany) attached to both ends of a NiTi closed-coil spring with an initial length of 6 mm. Distally, the ligatures passed through the contact area of the first and second molars and were secured at the cervical area of the first molar. Mesially, they were placed between the two incisors and situated in the previously prepared grooves, followed by etching with 37% phosphoric acid and application of 3M bonding agent and 3M Unitek TransbondTM XT light-cured adhesive paste. To provide better anchorage and maximum retention for the ligature wires, the labial, distal, and palatal surfaces of both incisors were covered with composite resin (Figure 1). After appliance fixation, the incisal edges of the lower incisors were reduced by 2 mm to avoid ligature wire damage and appliance displacement by the teeth. The spring force was adjusted to apply an initial force of 10-gr/cm using a Dentaurum stress and tension gauge while ligating the wire around the incisors. ¹⁹ (Fig. 1).

Figure 1. Installation of orthodontic appliances on rats.¹⁹

Data Collection Procedures:

Observations of expression of BMP2, ALP and FGF2 were made by sacrificing rats on day 8, 15 and 22, then taking the the left maxillary permanet first molar and second molar their periodontal. Immunihistochemical examinations were carried out to determine the expression of BMP2, ALP and FGF2

Observations were carried out using a binocular microscope (Olympus photo slide BX51 with Cam DP71 12 mpx) with a magnification of 400× to calculate the amount of expression in osteoblasts.

Statistical analysis:

Expression data of BMP2, ALP and FGF2 were analyzed using Shapiro Wilk test, Levene test , and continued with Kruskal-wallis and Mann-Whitney tests with with a confidence level of 95% (α = 0.05).

RESULTS:

The results of research on the effect of mangosteen peel extract on BMP2, ALP and FGF2 expression are shown in Figure 2, 4 and 6. Figures 2, 4 and 6 respectively showed that BMP2, ALP and FGF2 expression in all treatment groups was greater than in the control group. The highest average amount of BMP2, ALP and FGF2 expression was in the 15th day group, and there was a decrease on the 22nd day, while BMP2, ALP and FGF2 expression was the lowest in the 8th day group. The results of immunohistochemical examination of BMP2, ALP and FGF2 expression are shown in Figure 3,5, and 7

Figure 2 Histogram of the average amount of BMP2 expression in osteoblasts and its standard deviation in the tension area of the control and treatment groups

Figure 3. BMP2 expression in alveolar bone observed on day 8, day 15 and day 22, indicated by arrows: in the control group on day 8 (C1), 15 (C2), and 22 (C3), treatment group on day 8 (T1), 15 (T2), and 22 (T3) (Immunohistochemistry, 400x magnification).

Figure 4. Histogram of the average amount of ALP expression in osteoblasts and its standard deviation in the tension area of the control and treatment groups

Figure 5. ALP expression in alveolar bone observed on day 8, day 15 and day 22, indicated by arrows: in the control group on day 8 (C1), 15 (C2), and 22 (C3), treatment groupon day 8 (T1), 15 (T2), and 22 (T3) (Immunohistochemistry, 400x magnification).

Figure 6 Histogram of the average amount of FGF2 expression in osteoblasts and its standard deviation in the tension area of the control and treatment groups

Figure 7. FGF2 expression in alveolar bone observed on day 8, day 15 and day 22, indicated by arrows: in the control group on day 8 (C1), 15 (C2), and 22 (C3), treatment groupon day 8 (T1), 15 (T2), and 22 (T3) (Immunohistochemistry,400x magnification).

The research data obtained was then tested using SPSS version 26 software. Mann Whitney test results of BMP2, ALP and FGF2 expression are shown in tables 1, 2 and 3.

Table 1 shows that there was a significant increase in the amount of BMP2 expression in groups C1 to C2 and T1 to T2, while there was a significant decrease in the amount of BMP2 expression in groups C2 to C3 and T2 to T3. The amount of BMP2 expression of groups C3 and T3 was significantly higher than groups C1 and T1.

Table 2 shows that there was a significant increase in the amount of ALP expression in groups C1 to C2 and T1 to T2, while there was a significant decrease in the amount of ALP expression in groups C2 to

C3 and T2 to T3. The amount of ALP expression of groups C3 and T3 was significantly higher than groups C1 and T1.

Table 3 shows that there was a significant increase in the amount of FGF2 expression in groups C1 to C2 and T1 to T2, while there was a significant decrease in the amount of FGF2 expression in groups C2 to C3 and T2 to T3. The amount of FGF2 expression of groups C3 and T3 was significantly higher than groups C1 and T1.

Table 1. Results of the Mann-Whitney test for the amount of BMP2 expression in osteoblasts in research groups on day 8, 15 and 22

Research Group	Control Day 8 (C1)	Control Day 15 (C2)	Control Day 22 (C3)	Treatment Day 8 (T1)	Treatment Day 15 (T2)	Treatment Day 22 (T3)
Control Day 8(C1)	-	0,008*	0,053**	0,004*	0,004*	0,004*
Control Day 15(C2)	0,008*	-	0,015*	0,013*	0,004*	0,004*
Control Day 22(C3)	0.053**	0.015*	-	0,004*	0,004*	0,003*
Treatment Day 8(T1)	0,004*	0,013*	0,004*	-	0,004*	0,004*
Treatment Day 15(T2)	0,004*	0,004*	0,004*	0,004*	-	0,004*
Treatment Day 22(T3)	0,004*	0,004*	0,003*	0,004*	0,004*	-

* p < 0.05 = significant ** p > 0.05 = non significant

Table 2. Results of the Mann-Whitney test for the amount of ALP expression in osteoblasts in research groups on day 8, 15 and 22

Research Group	Control Day 8 (C1)	Control Day 15 (C2)	Control Day 22 (C3)	Treatment Day 8 (T1)	Treatment Day 15 (T2)	Treatment Day 22 (T3)
Control Day 8(C1)	-	0,004*	0,004*	0,004*	0,004*	0,004*
Control Day 15(C2)	0,004*	-	0,004*	0,024*	0,004*	0,004*
Control Day 22(C3)	0,004*	0,004*	-	0,004*	0,004*	0,004*
Treatment Day 8(T1)	0,004*	0,024*	0,004*	-	0,004*	0,004*
Treatment Day 15(T2)	0,004*	0,004*	0,004*	0,004*	-	0,004*
Treatment Day 22(T3)	0,004*	0,004*	0,004*	0,004*	0,004*	-

* p < 0.05 = significant

Table.3. Results of the Mann-Whitney test for the amount of FGF2 expression in osteoblasts in research groups on day 8, 15 and 22

Research Group	Control Day 8 (C1)	Control Day 15 (C2)	Control Day 22 (C3)	Treatment Day 8 (T1)	Treatment Day 15 (T2)	Treatment Day 22 (T3)
Control Day 8(C1)	-	0,004*	0,016*	0,004*	0,004*	0,004*
Control Day 15(C2)	0,004*	-	0,004*	0,004*	0,004*	0,004*
Control Day 22(C3)	0,016*	0,004*	-	0,004*	0,004*	0,004*
Treatment Day 8(T1)	0,004*	0,004*	0,004*	-	0,004*	0,010*
Treatment Day 15(T2)	0,004*	0,004*	0,004*	0,004*	-	0,004*
Treatment Day 22(T3)	0,004*	0,004*	0,004*	0,010*	0,004*	-

* p < 0.05 = significant

DISCUSSION:

The orthodontic force during orthodontic treatment will initiate cellular and molecular signaling and regulation in periodontal. Fibroblasts, osteoblasts, osteoclasts and macrophages are cells that play arole in bone remodeling. Orthodontic tooth movement relies on coordinated tissue resorption and formation in the surrounding bone and periodontal ligament. Tooth loading causes local hypoxia and fluid flow, initiating an aseptic inflammatory cascade culminating in osteoclast resorption in areas of compression and osteoblast deposition in areas of tension,³

The results showed that the amount of BMP2, ALP and FGF2 expression in the treatment group given mangosteen peel extract was greater than in the control group in the day 8, 15 and 22 study groups.

The increased expression of BMP2, ALP and FGF2 in osteoblasts when given mangosteen peel extract was caused by the flavonoid and xanthon content of mangosteen peel which have antioxidant properties.

Oxidative stress is triggered by free radicals, which seek stability through electron pairing with biological macromolecules such as proteins, lipids and DNA in cells and cause protein and DNA damage and lipid peroxidation.²⁰ The antioxidant content of mangosteen peel can inhibit oxidative stress so that osteoblast formation and the bone apposition process run well.²¹

Polyphenolic compounds such as flavonoids and gallate identified in the mangosteen peel are able to reduce oxidative stress by preventing the chain reaction of converting superoxide into hydrogen superoxide by donating hydrogen atoms from the aromatic hydroxyl (-OH) group of polyphenols to bind free radicals and remove them from the body through the excretory system. ^{22, 23}

Polyphenolic compounds are known to have antioxidant activity due to their redox properties which play an important role in absorbing and neutralizing free radicals, extinguishing singlet and triplet oxygen, or decomposing peroxides.²⁴

Flavonoids also act as chelating agents for metal ions that form Reactive Oxygen Species (ROS) such as Fe2+ and Cu+ ions. By binding metal ions by flavonoids, it can reduce the catalytic activity of Fe and Cu metals thereby reducing the formation of free radicals ²⁵

The xanthone compounds in mangosteen have been reported to have biological activities including antioxidative and anti-inflammatory effects. Tthe xanthones, alpha-mangostin (1,3,6-Trihydroxy-7- methoxy-2,8-bis(3-methyl-2-butenyl)-9H-xanthen9-one) has been identified as the most abundant xanthone in mangosteen. The xanthone compound in mangosteen which is the most important contributor to antioxidative activity is γ-mangostin. In several antioxidative xanthone mechanisms, the catechol moiety γ-mangostin has a more effective chelating effect than alfα-mangostin in scavenging radicals.^{26 27}

The effect of administering mangosteen peel extract can increase the activity of the body's endogenous enzymes, especially the SOD enzyme. This research proves that mangosteen peel extract can provide a protective effect by increasing the activity of antioxidant enzymes, thereby proving that α-mangosteen can reduce oxidative stress on free fatty acids ²⁸

The flavonoids in mangosteen peel are able to prevent the formation of free radicals in cells. Stable free radicals Stable free radicals in cells will be able to protect against oxidative damage and can accelerate macrophage stimulation. Furthermore, macrophages will secrete growth factors such as fibroblast growth factor (FGF)2. ²⁹

The effect of antioxidants on molecular oxidative stress is to inhibit the increase in the activity of acid phosphatase and bone protease which degrade bone matrix in osteoclasts and induces ALP and matrix protein synthesis in osteoblasts ²¹

Previous studies also showed that FGF-2 increased the expression of bone morphogenetic protein 2 (BMP-2) and markers of osteoblast differentiation, namely alkaline phosphatase (ALP), and osteocalcin. The mechanism of FGF-2 in periodontal regeneration in vivo is first, increasing the proliferation of fibroblasts originating from the bone marrow and PDL. Second, there is an increase in angiogenesis resulting in osteoblastic differentiation and bone formation, which is partly caused by increased production of BMP-2 as a result of being induced by FGF-2. Therefore, the multifaceted effects of FGF-2 promote the formation of new tissue in the early regeneration phase, leading to increased formation of new bone, cementum, and           PDL. ³⁰

The increase in BMP2, ALP and FGF2 expression in osteoblasts on days 8 and 15 is in accordance with research by Narmada et al (2019) which showed an increase in the number of osteoblasts and FGF2 expression on days 3 to 14.³¹ The significant decrease in the number of osteoblasts on day 22 is possibly due to the mechanical strength of orthodontics having decreased so that bone formation has also decreased, in accordance with the results of research by Widiastuti (2022), which shows that there was an increase in the number of osteoblasts on 7 days to 14 days. Furthermore, there was a decrease in the number of osteoblasts on 21 days.³²

CONCLUSION:

The conclusion of this study is that mangosteen peel extract is effective in increasing the expression of BMP2, ALP and FGF2 in osteoblasts. so it can be developed as an alternative material to accelerate the process of remodeling tooth periodontal tissue and speed up orthodontic treatment.

ACKNOWLEDGMENT:

Thank you to LP2M of University of Jember for funding this research.

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Received on 27.02.2024      Revised on 13.06.2024

Accepted on 24.09.2024 Published on 28.01.2025

Available online from February 27, 2025

Research J. Pharmacy and Technology. 2025;18(2):713-719.

DOI: 10.52711/0974-360X.2025.00105

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