Skip to main content
NCBI home page
Wiley Open Access Collection logoLink to Wiley Open Access Collection
. 2025 May 15;52(8):1115–1124. doi: 10.1111/jcpe.14175

Increasing Serum Vitamin D Levels Reduces Gingival Crevicular Fluid Matrix Metalloproteinase‐9 Levels in Periodontal Health and Diseases

Vusal Gurbanov 1, Ayla Öztürk 1,2,✉, Fatma Doğruel 3, Hatice Saraçoğlu 4, Cevat Yazıcı 4
PMCID: PMC12259403  PMID: 40373828

ABSTRACT

Aims

To investigate whether restoring serum vitamin D levels in a population requiring supplementation affects matrix metalloproteinase‐9 (MMP‐9) levels in the gingival crevicular fluid (GCF) of individuals with periodontal health, gingivitis and periodontitis.

Materials and Methods

This prospective cohort study enrolled 101 participants with vitamin D deficiency, including those with periodontitis (34) and gingivitis (34) and healthy individuals (33). The periodontal status was evaluated using radiographic and clinical assessments of probing depth, clinical attachment loss, gingival index and plaque index. The analysis of MMP‐9 levels in the GCF collected from the same dental sites was performed at baseline and 1 month post supplementation.

Results

After 1 month of vitamin D supplementation, a significant decrease in GCF MMP‐9 levels was observed across all groups, with the most notable reduction observed in the periodontitis group. The healthy group exhibited the highest percentage reduction at 47%. Linear regression analysis confirmed that changes in vitamin D levels and pocket depth influenced MMP‐9 alterations in the GCF.

Conclusions

Restoration of vitamin D levels in vitamin D‐deficient patients to the recommended average level (30 ng/mL), according to established guidelines, led to decreased MMP‐9 levels in individuals with different periodontal statuses (healthy, gingivitis or periodontitis), potentially mitigating periodontal risks.

Keywords: cholecalciferol, collagenases, gelatinases, precision medicine, vitamin D deficiency

1. Introduction

Periodontitis is a chronic inflammatory disease that affects the supporting tissues of teeth; if left untreated, it can ultimately lead to tooth loss (Papapanou et al. 2018). Globally, approximately half of all adults aged over 30 years are affected by periodontitis, making it a prevalent disease (Eke et al. 2012; Nazir 2017). This disease is initiated by a microbial biofilm that colonises the subgingival area, causing an immune response that leads to periodontal tissue breakdown (Papapanou et al. 2018). One of the key enzymes involved in tissue breakdown is matrix metalloproteinase‐9 (MMP‐9) (Bostanci et al. 2018; Sapna et al. 2014).

MMP‐9 is a member of the MMP family of enzymes involved in extracellular matrix remodelling. MMP‐9 is produced by various cell types, including neutrophils, macrophages and fibroblasts (Sorsa et al. 2006). In periodontitis, MMP‐9 is up‐regulated and contributes to the breakdown of collagen and other extracellular matrix components in periodontal tissues (Sapna et al. 2014). Machine learning‐based modelling has identified MMP‐9 as a protein that effectively distinguishes disease states in periodontal diseases (Bostanci et al. 2018). Notably, studies have shown a correlation between periodontitis severity and MMP‐9 expression. MMP‐9 levels are found to be higher in patients with severe periodontitis than in those with mild disease (Maeso et al. 2007; Sorsa et al. 2006). These findings suggest that excessive MMP‐9 production plays a key role in the progression of periodontitis. Furthermore, conventional periodontal treatment reduces the concentrations of MMP‐9 in the gingival crevicular fluid (GCF) and serum (Gonçalves et al. 2013; Marcaccini et al. 2009, 2010), thus supporting its role in periodontal diseases.

One potential way to reduce MMP‐9 and its contribution to periodontal tissue destruction is the use of vitamin D (Sundar et al. 2011; Vo et al. 2023). Vitamin D has been shown to have a regulatory effect on MMP‐9 activity in mice by down‐regulating its expression (Sundar et al. 2011).

Vitamin D may be playing a role in the prevention and management of periodontitis (Machado et al. 2020; Lu 2023). Several studies have reported an association between low vitamin D levels and an increased risk of periodontitis (Machado et al. 2020; Asante et al. 2024). A study conducted by Dietrich et al. (2005) found that individuals with serum vitamin D levels below 20 ng/mL had a significantly higher risk of developing periodontitis than those with levels ≥ 30 ng/mL (Dietrich et al. 2004). Additional evidence supporting the involvement of vitamin D in periodontal diseases has been found in clinical trials, indicating that vitamin D supplementation can reduce tooth loss and the severity of periodontal disease or gum inflammation (Assaf and Aboelsaad 2019; Garcia et al. 2011; Perayil et al. 2015).

However, the mechanisms underlying the relationship between vitamin D levels and periodontitis are not fully understood. Vitamin D may regulate the expression of genes involved in immune response and inflammation (Chun et al. 2014). Vitamin D has been found to have a potential regulatory effect on both the activity and production of MMP‐9 (Bahar‐Shany et al. 2010; Kim et al. 2014; Sundar et al. 2011). Several studies have suggested that vitamin D may have an inhibitory effect on MMP‐9 expression and activity in various tissues and cell types, which could potentially reduce tissue damage associated with inflammatory diseases (Oh et al. 2019; Wang et al. 2015; Wasse et al. 2011).

In a previous cross‐sectional study (Yıldırım et al. 2024), we found that individuals with low serum vitamin D levels had elevated MMP‐9 levels in the GCF, particularly in those with gingivitis and periodontitis. These findings suggest a potential link between low vitamin D levels and increased MMP‐9 expression in patients with periodontal disease. To confirm this relationship, we conducted a prospective study to explore the impact of restoring serum vitamin D levels in periodontal tissues, specifically by assessing MMP‐9 levels in GCF. This study targeted a population requiring supplementation through medication, as this method provides an efficient and manageable approach for increasing vitamin D levels and investigating its role in periodontal health.

2. Materials and Methods

2.1. Study Participants

This interventional study, with a pre/post design, was approved by the Clinical Research Ethics Committee of Erciyes University on 9 February 2022 (ERU KAEK 2022/112) and conducted in accordance with the tenets of the Helsinki Declaration. Comprehensive information about the study objectives and content was provided to the enrolled participants, all of whom provided written informed consent.

The individuals in our study who were referred to the Periodontology Clinic from the Internal Medicine Clinic of Erciyes University between February and October 2022 were initially tested for vitamin D deficiency due to common non‐specific symptoms such as

  • fatigue, easy tiring,

  • bone and joint pain (especially in the back),

  • muscle weakness, aches or cramps and

  • mood changes, such as depression.

These symptoms are frequently associated with vitamin D deficiency (Bordelon et al. 2009). The patients diagnosed with vitamin D deficiency requiring medical supplementation were referred to our clinic.

The definition of vitamin D status was adopted according to the Institute of Medicine's (IOM) guidelines, whereby vitamin D insufficiency was listed at < 20 ng/mL (≤ 50 nmol/L) (Amrein et al. 2020). Clinical and radiological examinations of all the volunteers who fulfilled the following inclusion criteria were performed: older than 18 years, systemically healthy individuals, not taking any medication regularly (including antibiotics), no periodontal treatment in the previous 6 months, non‐smokers, non‐pregnant women and no orthodontic treatment.

2.2. Oral Examination

Clinical and radiological examinations were performed on all volunteers. Periodontal examinations included probing depth (PD), clinical attachment level (CAL), plaque index (PI), gingival index (GI) and bleeding on probing (BOP). All measurements were conducted by a periodontal resident (V.G.) at six sites on each tooth (except the third molars). The calibration was verified by an expert periodontist (A.Ö.) and was considered valid if 90% of the recordings could be reproduced within a difference of 1 mm. The participants were allocated to three groups based on their periodontal status: Group 1, periodontal health (33); Group 2, gingivitis (34); and Group 3, periodontitis (34).

The diagnosis and classification of periodontal diseases (periodontitis and periodontal health) were performed according to the current classification of periodontal diseases and conditions published by the World Consensus of the European Federation of Periodontology (Papapanou et al. 2018).

The participants were classified as having periodontitis if they satisfied the following criteria: radiographic evidence of alveolar bone loss, with periodontal pocket depth ≥ 4 mm and CAL > 3 mm in at least two interproximal sites (not on the same tooth).

The participants were classified as having gingivitis if they had no previous or existing evidence of periodontal disease, no evidence of radiographic or clinical attachment loss and BOP > 10%.

The participants were included in the periodontally healthy group if they had no previous or existing evidence of periodontal diseases, no evidence of radiographic or clinical attachment loss and BOP ≤ 10%.

Details of GCF collection, blood sample collection and vitamin D supplementation are given in Supporting Information.

2.3. Enzyme‐Linked Immunosorbent Assay Test

MMP‐9 levels were analysed using a commercial USCN human MMP‐9 enzyme‐linked immunosorbent assay (ELISA) kit (Cat No: SEA553Hu, CV < 10%) according to the manufacturer's instructions. Refer to Supporting Information for further details.

2.4. Statistical Analysis

The Wilcoxon test was used to compare the clinical parameters before and after treatment, whereas the Kruskal–Wallis H test was used to compare the parameters among groups, with Dunn–Bonferroni adjustments for multiple comparisons. Spearman's and partial correlation analyses were used to assess the relationship between the changes in vitamin D and MMP‐9 levels. Single and multiple linear regression analyses identified the risk factors for MMP‐9 changes, with the results presented as standardised regression coefficients and 95% confidence intervals (CIs). Data were analysed using TURCOSA software (Turcosa Analytics Ltd. Co, Turkey, www.turcosa.com.tr), with a significance level set at p < 0.05.

Power analysis was conducted as follows: The primary outcome of the study was the change in MMP‐9 level after vitamin D supplementation. Data from the study by Marcaccini et al. (2010) were used to calculate the sample size (Supporting Information). Power analysis was carried out using G Power statistical software. The analysis indicated that a total of 96 individuals were required (32 for each group) to achieve a minimum effect size of 0.262 f with 95% CI and 80% power.

3. Results

3.1. Demographic and Clinical Parameters

This study included 101 individuals of whom 33 were healthy, 34 had gingivitis and 34 had periodontitis based on clinical and radiographic data. Descriptive data on participant demographics and clinical variables are shown in Table 1.

TABLE 1.

Demographic characteristics of patients.

Cohort Total (n = 101) p
Healthy (n = 33) Periodontitis (n = 34) Gingivitis (n = 34)
Age 23.00 (22.00–24.00)a 38.00 (34.50–42.25)b 23.00 (23.00–25.25)a 25.00 (23.00–35.50) < 0.001
Sex (female n (%)) 22 (66.7) 25 (73.5) 21 (61.8) 68 (37.3) 0.583
Plaque index 0.41 (0.33–0.50)a 2.47 (1.86–2.57)b 1.36 (1.22–1.49)c 1.37 (0.50–1.88) < 0.001
Gingival index 0.40 (0.36–0.47)a 2.30 (1.51–2.32)b 1.39 (1.20–1.51)c 1.4 (0.47–1.59) < 0.001
Probing depth 1.91 (1.87–1.96)a 3.43 (2.96–3.73)b 1.91 (1.87–1.93)a 1.95 (1.88–3.03) < 0.001
sampled site Probing depth 2.33 (2.00–2.50)a 4.83 (4.33–5.16)b 2.33 (2.16–2.50)a 2.50 (2.16–4.33) < 0.001
Attachment loss 0 1.4 (0.92–2.85) 0 — < 0.001
Open in a new tab

Note: Values are expressed as median (25th–75th percentile) and n (%). p: comparison of differences between groups; different lowercase letters (a, b, c) in the same row indicate statistically significant differences among the groups. Significant p‐values are shown in bold.

All participants were non‐smokers. Most patients were females (67.3%). No significant difference was noted between the groups (p = 0.58). No significant differences were seen between the gingivitis group and the periodontally healthy control group. However, the periodontitis group had the highest age distribution, with a median value of 38.00 (p < 0.001).

Periodontal examination revealed that the participants were almost equally distributed between stage I (35.3%), stage II (32.4%) and stage III (29.4%) periodontitis. Only one participant had stage IV periodontitis (0.03%). According to the grading system, most patients had grade B periodontitis (64.7%), followed by grade C (29.4%). Only two cases of grade A periodontitis were recorded (0.06%).

As expected, the baseline median PI and GI scores were highest in the periodontitis group (2.47 and 243, respectively), followed by the gingivitis and healthy groups. Significant differences in PI and GI were observed between the groups (p < 0.001). Additionally, CAL, PD and sample tooth PD had the highest median values in the periodontitis group (p < 0.0001); no significant differences were observed in CAL and CD between the gingivitis and healthy groups (Table 1).

3.2. Serum Vitamin D Levels

At baseline, no significant difference was noted in the median serum vitamin D levels between the groups (p = 0.985, Table 2). Following vitamin D supplementation at 1 month, serum vitamin D levels increased in all groups and across the entire population, rising from a mean of 9.75 ng/mL (CI: 6.61–14.05; range: 3–19.8) to 28.60 ng/mL (CI: 23.5–33.15; range: 9.08–50.1). The mean vitamin D levels across the three groups showed similar increases (p > 0.05): the details are as follows: 28.50 ng/mL (CI: 23.35–33.95; range 18.5–41.3), 30.45 ng/mL (CI: 26.55–34.00; range 18.7–42.1) and 27.67 ng/mL (CI: 22.65–32.28; range 16.9–50.1). Despite similar mean increases, the data revealed variability in individual responses. A detailed examination of the entire group revealed three distinct categories of vitamin D levels post supplementation: > 30 ng/mL (44.5% of total population), between 20 and 30 ng/mL (46.5%) and < 20 ng/mL (6.9%). Additionally, one patient (9.08 ng/mL in the healthy group) did not show elevated serum vitamin D levels despite supplementation.

  • Effects of Vitamin D Supplementation on GCF Volume, GI and PI (Supporting Information).

  • Effects of Vitamin D Supplementation on MMP‐9 Levels

TABLE 2.

Comparison of MMP‐9, vitamin D and GCF levels between groups before and after supplementation.

Parameter Cohort Total (n = 101) p
Healthy (n = 33) Periodontitis (n = 34) Gingivitis (n = 34)
MMP‐9
Before 16.00 (9.22–19.03)a 62.97 (44.76–104.81)b 29.50 (24.10–35.37)c 29.95 (19.03–44.93) < 0.001
After 6.92 (4.54–8.82)a 47.47 (33.70–68.34)b 21.71 (15.42–27.30)c 21.56 (8.35–35.38) < 0.001

Change

(% change)

7.54 (2.90–10.48)a

(47%)

16.91 (8.05–32.22)b

(27%)

8.53 (3.11–14.16)a

(29%)

9.09 (4.23–15.79)

(30%)

 < 0.001
p ǂ < 0.001 < 0.001 < 0.001 < 0.001
Vitamin D
Before 11.70 (7.00–15.00) 7.96 (5.90–13.80) 9.11 (6.00–13.28) 9.75 (6.61–14.05) 0.210
After 28.50 (23.35–33.95) 30.45 (26.55–34.00) 27.67 (22.65–32.28) 28.80 (23.50–33.15) 0.231
Change 17.50 (22.50–2.28) 19.05 (25.59–16.10) 18.10 (23.15–14.03) 18.60 (23.25–14.20) 0.243
p ǂ < 0.001 < 0.001 < 0.001 < 0.001
GCF
Before 0.18 (0.17–0.19)a 0.53 (0.501–0.55)b 0.29 (0.274–0.304)c 0.33 (0.304–0.36) < 0.001
After 0.17 (0.160–0.18)a 0.52 (0.50–0.54)b 0.28 (0.264–0.30)c 0.32 (0.29–0.36) < 0.001
Change 0.03 (< 0.001–0.041)a 0.35 (0.29–0.41)b 0.11 (0.08–0.14)c 0.11 (0.05–0.29) < 0.001
p ǂ < 0.001 < 0.001 < 0.001 < 0.001
GI
Before 0.40 (0.36–0.47)a 2.30 (1.51–2.32)b 1.39 (1.20–1.51)c 1.4 (0.47–1.59) < 0.001
After 0.38 (0.35–0.46)a 2.23 (1.50–2.31)b 1.32 (1.16–1.44)c 1.34 (0.46–1.57) < 0.001

Change

(% change)

0.01 (0.01–0.02)a

(2.5%)

0.01 (0.01–0.02)a

(0.4%)

0.04 (0.03–0.06)b

(2.9%)

0.02 (0.01–0.04)

(1.4%)

 < 0.001
p ǂ < 0.001 < 0.001 < 0.001 < 0.001
PI
Before 0.41 (0.33–0.50)a 2.47 (1.86–2.57)b 1.36 (1.22–1.49)c 1.37 (0.50–1.88) < 0.001
After 0.37 (0.31–0.44)a 2.43 (1.85–2.51)b 1.29 (1.15–1.44)c 1.31 (0.44–1.85) < 0.001

Change

(% change)

0.01 (0.01–0.07)a

(2.4%)

0.02 (0.01–0.04)a

(0.08%)

0.07 (0.05–0.09)b

(5%)

0.04 (0.01–0.07)

(2.9%)

 < 0.001
p ǂ < 0.001 < 0.001 < 0.001 < 0.001
Open in a new tab

Note: Data are expressed as median (25th–75th percentile). p: comparison of differences between groups; p ǂ : comparison of differences before and after treatment; different lowercase letters (a, b, c) in the same row represent statistically significant differences among groups. Significance is denoted by bold p‐values. Change: measurement of the variable of interest (before).

Abbreviations: GCF, gingival crevicular fluid; GI, gingival index; n, number; PI, plaque index.

A significant reduction in GCF MMP‐9 levels following vitamin D supplementation was observed across all groups and the overall population (p < 0.001; Table 2). The periodontitis group exhibited the most substantial decline in MMP‐9 levels, from a median of 62.97 ng/30 s before supplementation to 47.47 ng/30 s after supplementation. This was followed by the gingivitis group (29.5 ng/30 s before and 21.75 ng/30 s after) and the healthy group (16.00 ng/30 s before and 6.92 ng/30 s after, Table 2).

Furthermore, univariate linear regression models revealed significant correlations between alterations in serum vitamin D levels and age (p = 0.046), pocket depth (p < 0.001) and changes in GCF MMP‐9 levels (p < 0.001). However, after adjustment in the linear regression model, the changes in serum vitamin D concentration were statistically significant only for alterations in MMP‐9 levels (p < 0.001) and pocket depth (p = 0.002). Controlling for age, sex, PI, GI and pocket depth effects showed that an elevation in serum vitamin D levels corresponded to a reduction in GCF MMP‐9 levels, whereas an increase in pocket depth was positively correlated with an increase in GCF MMP‐9 levels. Specifically, a 1‐unit increase in serum vitamin D levels decreased the GCF MMP‐9 level by a factor of 0.447. Of all the factors examined, alterations in serum vitamin D levels resulted in the most pronounced association with changes in MMP‐9 levels, as highlighted by its higher standardised β‐coefficient. This suggests that the alteration in vitamin D levels is the main contributor to the changes in MMP‐9 levels. Furthermore, the multiple linear regression model confirmed that the changes in both vitamin D levels and pocket depth were statistically significant factors affecting alterations in MMP‐9 levels in the GCF (Table 3).

TABLE 3.

Univariate and multiple linear regression analyses to identify risk factors for MMP‐9 changes in all groups.

Variable Univariate p Adjusted p Multivariate p
Beta %95 CI Beta %95 CI Beta %95 CI
Δ Vitamin D −0.525 −0.695; −0.355 < 0.001 −0.432 −0.606; −0.259 < 0.001 −0.447 −0.616; −0.277 < 0.001
Age 0.199 0.004; 0.394 0.046 −0.156 −0.406; 0.093 0.216 — — —
Sex −0.022 −0.221; 0.178 0.830 −0.102 −0.267; 0.064 0.226 — — —
Δ Plaque index −0.010 −0.210; 0.189 0.919 0.044 −0.122; 0.210 0.603 — — —
Δ Gingival index 0.064 −0.135; 0.263 0.523 0.106 −0.065; 0.278 0.218 — — —
Pocket depth 0.401 0.218; 0.583 < 0.001 0.422 0.160; 0.684 0.002 0.272 0.102; 0.442 0.002
Cohort 0.017 −0.182; 0.216 0.866 −0.011 −0.178; 0.157 0.898 — — —
Open in a new tab

Note: Bold values denote statistical significance at p < 0.05.

Abbreviations: Beta, standardised regression coefficient; CI, confidence interval; Δ, change in the variable of interest (before—after).

In the periodontitis group, univariate analysis showed that the changes in both vitamin D levels (p < 0.001) and probing depth (p = 0.02) were statistically significant factors affecting alterations in MMP‐9 levels in the GCF. Multivariate regression analysis also showed that vitamin D levels and probing depth were significant predictors of MMP‐9 levels in the GCF (Table 4).

TABLE 4.

Univariate and multiple linear regression analyses to identify risk factors for MMP‐9 changes in the periodontitis group.

Variable Univariate p Multivariate p
Beta %95 GA Beta %95 GA
Δ Vitamin D −0.766 −0.998; −0.535 < 0.001 −0.716 −0.960; −0.473 < 0.001
Pocket depth 0.388 0.056; 0.719 0.024 0.150 −0.093; 0.394 0.217
Attachment loss 0.29 0.035; 0.618 0.09 — — —
Open in a new tab

Note: Bold values denote statistical significance at p < 0.05.

Abbreviations: Beta, standardised regression coefficient; CI, confidence interval; Δ, change in the variable of interest (before—after).

4. Discussion

This study investigated the potential effects of serum 25‐hydroxyvitamin D [25(OH)D] levels on MMP‐9 production in individuals with periodontal health, gingivitis and periodontitis. Notably, a substantial decline in GCF MMP‐9 levels was noted across all groups after vitamin D supplementation, suggesting its potential to mitigate the deleterious effects associated with periodontal disease.

The multiple linear regression model highlighted the statistical significance of both serum vitamin D level variation and pocket depth in predicting MMP‐9 variation. Particularly, an increase in serum vitamin D levels corresponded to a decrease in GCF MMP‐9 levels, whereas an increase in pocket depth was positively correlated with an increase in GCF MMP‐9 levels.

GCF MMP‐9 levels were monitored at baseline and 1 month after vitamin D supplementation without any periodontal intervention. Following supplementation, the periodontitis group exhibited the greatest linear reduction in MMP‐9 levels (16.91 ng/30 s), followed by the gingivitis (8.53 ng/30 s) and healthy (7.54 ng/30 s) groups. However, the percentage of reduction compared to baseline GCF MMP‐9 levels was much larger in the healthy group (47%) than in the gingivitis (29%) and periodontitis (27%) groups.

The results of this study are consistent with those of our previous cross‐sectional study, where we found that GCF MMP‐9 levels were higher in vitamin D‐deficient patients with gingivitis and periodontitis than in those who were not deficient. Additionally, we observed an inverse association between 25(OH)D levels and MMP‐9 concentrations in the GCF, with lower vitamin D levels correlating with higher MMP‐9 levels (Yıldırım et al. 2024).

To the best of our knowledge, no study so far has investigated the effect of serum vitamin D supplementation on MMP‐9 levels in vivo in patients with periodontitis. Consequently, a direct comparison of our findings with those of previous studies was not feasible. Nevertheless, our findings are consistent with a previous study showing that vitamin D supplementation leads to a 68% reduction in serum MMP‐9 levels and a 23% reduction in C‐reactive protein (CRP) levels (Timms et al. 2002). Furthermore, prior studies have indicated that vitamin D inhibits MMP‐9 secretion in various inflammatory diseases (Anand and Selvaraj 2009; Komolmit et al. 2017; Vo et al. 2023; Wasse et al. 2011; Meghil and Cutler 2023).

Microbial dental plaque is the primary aetiological factor in periodontal disease. Although it is necessary to initiate the disease, not all individuals are equally susceptible to developing periodontal disease or experiencing its damaging effects. Identifying the factors that increase the susceptibility to the disease is important. Our results suggest that vitamin D deficiency increases the risk of periodontal disease or exacerbates damage by modulating MMP‐9 expression.

Our results also showed that restoration of serum vitamin D levels decreased MMP‐9 levels in both healthy individuals and those with periodontal disease. This suggests that increasing serum vitamin D levels may help control excessive MMP‐9 production in periodontal tissues, potentially reducing disease progression. The substantial reduction in MMP‐9 levels observed in the periodontitis group can be attributed to the exaggerated baseline inflammatory state due to vitamin D deficiency in these patients. Restoring vitamin D levels to recommended levels with supplementation results in a more pronounced anti‐inflammatory effect compared to less inflamed or healthy periodontal tissues, alleviating this response. Periodontal disease is an inflammatory condition initiated by plaque accumulation; without addressing this primary etiologic factor, treating the disease effectively is not possible. Despite the reduction in MMP‐9 levels, our results indicated that the periodontitis group still had the highest MMP‐9 levels, even after supplementation, compared to healthy individuals and patients with gingivitis.

Although vitamin D supplementation cannot replace conventional periodontal therapy, it may enhance outcomes in vitamin D‐deficient patients by reducing MMP‐9 expression, which helps prevent tissue breakdown and supports the prevention of periodontitis. In the context of precision medicine (Rakic et al. 2021), an approach that tailors treatment based on individual differences in genetics, environment and lifestyle, vitamin D plays a crucial role in tissue repair and immune function. Collagen deficiency disrupts collagen turnover and reduces antimicrobial peptide levels (Bayirli et al. 2020), thereby weakening the immune response to infection (Prietl et al. 2013).

Personalised vitamin D supplementation adjusted for an individual's deficiency can optimise treatment outcomes (Rakic et al. 2021). Future research should explore the combined effects of vitamin D supplementation and periodontal therapy to develop more precise and individualised treatment strategies, ultimately enhancing patient care for periodontal health.

The outcomes of an in vitro investigation by Oh et al. (2019) align with those of the present study, suggesting that vitamin D strengthens E‐cadherin junctions in junctional gingival keratinocytes by reducing MMP‐9 production, which was induced by TNF‐α. Hence, it could be hypothesised that vitamin D down‐regulation of MMP‐9 reinforces the epithelial barrier, potentially safeguarding periodontal tissues against bacterial invasion. Moreover, the significant impact of vitamin D on the production of antimicrobial peptides in gingival tissues and GCF (Bayirli et al. 2020) underscores its broad influence on oral health.

The secondary outcomes of our study revealed heightened MMP‐9 levels in periodontitis (62.97 ng/30 s) compared to gingivitis (29.5 ng/30 s) or oral health (16 ng/30 s), in agreement with similar observations reported in the literature (Sapna et al. 2014). MMP‐9′s heightened activity or function in periodontal disease indicates its involvement in the disease process characterised by the inflammatory destruction of the periodontal attachment apparatus (Mäkelä et al. 1994).

MMP‐9 levels were quantified based on the total protein collected during a 30‐s interval. This methodology was supported by Lamster et al. (1986), who found that measuring specific protein expression as absolute values in standardised fluid collection periods was a more sensitive and reliable technique for assessing changes in GCF composition. Their study also revealed a mismatch between clinical features and GCF content when the data were expressed as concentrations within a standardised GCF volume (Lamster et al. 1986).

Vitamin D levels are affected by various factors, including sun exposure, diet, age, skin pigmentation and overall health status (Holick 2011). To address the potential fluctuations in serum vitamin D levels after supplementation, such as those caused by malabsorption, seasonal variation, skin type or increased body fat, the blood samples were collected at baseline within 3 days of referral and again at the 1‐month mark on the same day as the GCF sample collection. This approach ensured that the changes in serum vitamin D levels accurately reflected the changes in MMP‐9 levels in the GCF.

Furthermore, the main goal of this study was not to examine the effects of vitamin D supplementation on periodontal disease. Instead, we aimed to determine whether restoring serum vitamin D levels through sunlight exposure, dietary supplements or medication had any impact on periodontal tissues. To achieve this, we focused on a population that required vitamin D supplementation through medication, as this method provides a quicker and more manageable way of increasing vitamin D levels.

The earliest changes in serum vitamin D levels after supplementation can appear within 3–4 days (Barker et al. 2013), with more significant increases typically observed after 2–3 weeks. Factors such as baseline deficiency, dosage and individual responses affect the magnitude of the increase. Supplementation for approximately 3 weeks can significantly increase serum 25(OH)D levels, particularly in patients with severe deficiency (Jetter et al. 2014; Tóth et al. 2017; Żebrowska et al. 2020; Zhang et al. 2024; Zwart et al. 2013).

The strength of this study lies in its prospective design, which allowed the establishment of a clear temporal relationship between serum vitamin D and MMP‐9 levels in both periodontal diseases and health. To our knowledge, this is the sole in vivo prospective study examining this aspect. Additionally, we excluded smokers (a major confounder of periodontal diseases) (Albandar 2002), vitamin D concentration (Yuan and Ni 2022) and MMP expression (Victor et al. 2014).

Although this study provides valuable insights, it is not without limitations. One limitation was the choice of antigenic MMP‐9 measurement, which—although preferred for its ease of application, compatibility with commonly used techniques and reduced sensitivity to pre‐analytical variables affecting enzyme activity during sample collection and processing—may not fully reflect the complexity of MMP‐9 activity in periodontal tissues. MMP‐9 is primarily secreted as an inactive pro‐enzyme (pro‐MMP‐9) that is activated by various proteinases and regulated by tissue inhibitors of metalloproteinases (TIMPs) (Sternlicht and Werb 2001).

Although antigenic measurements provide valuable information on MMP‐9 production and secretion, they capture both the active and inactive forms, including those inactivated by TIMPs. In contrast, measuring active MMP‐9, which is directly relevant to understanding disease pathogenesis, requires more complex techniques, such as zymography or activity‐based ELISA. However, these methods were not employed in this study because of practical constraints. Additionally, enzyme stability and activity are highly sensitive to sample collection and processing conditions (Panteghini and Infusina 2023).

Although distinguishing between MMP‐9 production and activity is crucial, antigenic and active MMP‐9 levels are generally correlated and increase together in inflammatory conditions such as periodontitis (Kim et al. 2013). Thus, our findings based on antigenic MMP‐9 provide valuable insights. Additionally, modest reductions in surrogate markers of periodontal inflammation, such as the GI and GCF volume, were observed across all groups following vitamin D supplementation, supporting the hypothesis that active MMP‐9 may also decrease with supplementation.

Despite these limitations, our findings are valuable for pioneering future studies to enhance our understanding of periodontal diseases and improve treatment strategies. Future studies should evaluate MMP‐9 activity in addition to protein levels.

Notably, a small but consistent decrease in the PI and GI scores was observed across all groups after supplementation. In the periodontitis group, the improvement in GI and PI scores was less than 1%, whereas in the other groups the changes ranged from 2% to 5%, with the most significant reduction observed in the gingivitis group.

As no periodontal treatment was provided, this reduction may have been due to the Hawthorne effect (McCarney et al. 2007), in which participants improved their oral hygiene because of their awareness of the study. Another possibility is that changes in the oral microbiota, influenced by vitamin D (Bellerba et al. 2021), led to reduced plaque formation and attenuated P. gingivalis virulence (De Filippis et al. 2017; Grenier et al. 2016). Increased post‐supplementation AMP levels may also contribute (Bayirli et al. 2020). Furthermore, while our study focused on the anti‐inflammatory properties of vitamin D via MMP‐9 modulation, it also has well‐documented antimicrobial effects (McMahon et al. 2011; Liu et al. 2006; Cafiero et al. 2022). Systemic supplementation could have influenced the subgingival plaque composition, potentially shifting it towards a less pathogenic and less proinflammatory biofilm. However, as we did not assess the changes in plaque microbiota, this remains speculative and should be interpreted with caution. Future studies incorporating longitudinal microbiome analyses and clinical trials assessing shifts in subgingival microbial communities in response to vitamin D supplementation would be necessary to clarify this potential mechanism.

The periodontitis group was somewhat older than the other groups, suggesting that age was a potential confounding factor. To address this, we adjusted the analysis for confounders including age and sex. However, none of the clinical parameters in the model fully explained the variability in the MMP‐9 levels.

Moreover, this study was limited by its focus on evaluating a single biomarker. Future studies investigating the complex biomarker network are warranted to understand comprehensively the multifaceted dynamics and interactions in this research field.

In summary, the evidence from this study suggests that vitamin D deficiency may increase the risk of periodontal disease by affecting MMP‐9 expression. Increased serum vitamin D levels lead to reduced MMP‐9 levels in healthy tissues, gingivitis and periodontitis. While our 1‐month follow‐up provides initial insights, we acknowledge that a longer follow‐up period and a more robust study design, including comparisons between patients with and without vitamin D supplementation, are necessary to draw definitive clinical conclusions. This study contributes to our understanding of the potential role of vitamin D in the pathogenesis of periodontitis and highlights the need for further research to develop new therapeutic approaches for the management of chronic inflammatory periodontal diseases.

Author Contributions

V.G. performed patient recruitment, dental examinations and sample collection; contributed to data collection; gathered participant data; and contributed to data analysis and interpretation. A.Ö. conceived and designed the study, coordinated and performed patient recruitment, contributed to the data analysis and interpretation and drafted and critically revised the manuscript. F.D. coordinated and performed patient recruitment and supplementation and critically revised the manuscript. H.S. and C.Y. performed the biochemical analyses, contributed to data analysis and interpretation and critically revised the manuscript. All authors approved the final version of the manuscript for publication.

Ethics Statement

This study was approved by the Clinical Research Ethics Committee of Erciyes University on 9 February 2022 (ERU KAEK 2022/112) and was conducted in accordance with the tenets of the Helsinki Declaration.

Conflicts of Interest

The authors declare no conflicts of interest.

Supporting information

Data S1.

JCPE-52-1115-s001.docx (29.6KB, docx)

Acknowledgements

The authors acknowledge that the Introduction section of this article was partially generated using ChatGPT (powered by OpenAI's language model, GPT‐3.5; http://openai.com). The authors edited the manuscript.

Gurbanov, V. , Öztürk A., Doğruel F., Saraçoğlu H., and Yazıcı C.. 2025. “Increasing Serum Vitamin D Levels Reduces Gingival Crevicular Fluid Matrix Metalloproteinase‐9 Levels in Periodontal Health and Diseases.” Journal of Clinical Periodontology 52, no. 8: 1115–1124. 10.1111/jcpe.14175.

Funding: This work was supported by Bilimsel Araştırma Projeleri, Erciyes Üniversitesi, TDH‐2022‐11928.

Data Availability Statement

The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.

References

  1. Albandar, J. M. 2002. “Global Risk Factors and Risk Indicators for Periodontal Diseases.” Periodontology 2000 29: 177–206. 10.1034/j.1600-0757.2002.290109.x. [DOI] [PubMed] [Google Scholar]
  2. Amrein, K. , Scherkl M., Hoffmann M., et al. 2020. “Vitamin D Deficiency 2.0: An Update on the Current Status Worldwide.” European Journal of Clinical Nutrition 74: 1498–1513. 10.1038/s41430-020-0558-y. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Anand, S. P. , and Selvaraj P.. 2009. “Effect of 1, 25 Dihydroxyvitamin D(3) on Matrix Metalloproteinases MMP‐7, MMP‐9 and the Inhibitor TIMP‐1 in Pulmonary Tuberculosis.” Clinical Immunology 133: 126–131. 10.1016/j.clim.2009.06.009. [DOI] [PubMed] [Google Scholar]
  4. Asante, E. O. , Chen Y., Eldholm R. S., et al. 2024. “Associations of Serum Vitamin D With Dental Caries and Periodontitis: The HUNT Study.” International Dental Journal 74: 500–509. 10.1016/j.identj.2024.03.005. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Assaf, M. , and Aboelsaad N.. 2019. “The Effectiveness of Vitamin D Supplementation in Chronic Periodontitis Patients: A Randomized Controlled Clinical Trial.” Egyptian Dental Journal 65, no. 2‐April (Oral Medicine, X‐Ray, Oral Biology & Oral Pathology): 1311–1321. 10.21608/edj.2019.72555. [DOI] [Google Scholar]
  6. Bahar‐Shany, K. , Ravid A., and Koren R.. 2010. “Upregulation of MMP‐9 Production by TNFα in Keratinocytes and Its Attenuation by Vitamin D.” Journal of Cellular Physiology 222: 729–737. 10.1002/jcp.22004. [DOI] [PubMed] [Google Scholar]
  7. Barker, T. , Schneider E. D., Dixon B. M., Henriksen V. T., and Weaver L. K.. 2013. “Supplemental Vitamin D Enhances the Recovery in Peak Isometric Force Shortly After Intense Exercise.” Nutrition and Metabolism 10: 69. 10.1186/1743-7075-10-69. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Bayirli, B. A. , Öztürk A., and Avci B.. 2020. “Serum Vitamin D Concentration Is Associated With Antimicrobial Peptide Level in Periodontal Diseases.” Archives of Oral Biology 117: 104827. 10.1016/j.archoralbio.2020.104827. [DOI] [PubMed] [Google Scholar]
  9. Bellerba, F. , Muzio V., Gnagnarella P., et al. 2021. “The Association Between Vitamin D and Gut Microbiota: A Systematic Review of Human Studies.” Nutrients 13: 3378. 10.3390/nu13103378. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Bordelon, P. , Ghetu M. V., and Langan R. C.. 2009. “Recognition and Management of Vitamin D Deficiency.” American Family Physician 80: 841–846. [PubMed] [Google Scholar]
  11. Bostanci, N. , Selevsek N., Wolski W., et al. 2018. “Targeted Proteomics Guided by Label‐Free Quantitative Proteome Analysis in Saliva Reveal Transition Signatures From Health to Periodontal Disease.” Molecular and Cellular Proteomics 17: 1392–1409. 10.1074/mcp.RA118.000718. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Cafiero, C. , Grippaudo C., Dell'Aquila M. E., et al. 2022. “Association Between Vitamin D Receptor Gene Polymorphisms and Periodontal Bacteria: A Clinical Pilot Study.” Biomolecules 12, no. 6: 833. 10.3390/biom12060833. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Chun, R. F. , Liu P. T., Modlin R. L., Adams J. S., and Hewison M.. 2014. “Impact of Vitamin D on Immune Function: Lessons Learned From Genome‐Wide Analysis.” Frontiers in Physiology 5: 151. 10.3389/fphys.2014.00151. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. De Filippis, A. , Fiorentino M., Guida L., Annunziata M., Nastri L., and Rizzo A.. 2017. “Vitamin D Reduces the Inflammatory Response by Porphyromonas gingivalis Infection by Modulating Human β‐Defensin‐3 in Human Gingival Epithelium and Periodontal Ligament Cells.” International Immunopharmacology 47: 106–117. 10.1016/j.intimp.2017.03.021. [DOI] [PubMed] [Google Scholar]
  15. Dietrich, T. , Joshipura K. J., Dawson‐Hughes B., and Bischoff‐Ferrari H. A.. 2004. “Association Between Serum Concentrations of 25‐Hydroxyvitamin D3 and Periodontal Disease in the US Population.” American Journal of Clinical Nutrition 80: 108–113. 10.1093/ajcn/80.1.108. [DOI] [PubMed] [Google Scholar]
  16. Dietrich, T. , Nunn M., Dawson‐Hughes B., and Bischoff‐Ferrari H. A.. 2005. “Association Between Serum Concentrations of 25‐Hydroxyvitamin D and Gingival Inflammation.” American Journal of Clinical Nutrition 82, no. 3: 575–580. 10.1093/ajcn.82.3.575. [DOI] [PubMed] [Google Scholar]
  17. Eke, P. I. , Dye B. A., Wei L., Thornton‐Evans G. O., Genco R. J., and CDC Periodontal Disease Surveillance Workgroup: James Beck (University of North Carolina, Chapel Hill, USA), Gordon Douglass (Past President, American Academy of Periodontology), Roy Page (University of Washin) . 2012. “Prevalence of Periodontitis in Adults in the United States: 2009 and 2010.” Journal of Dental Research 91: 914–920. 10.1177/0022034512457373. [DOI] [PubMed] [Google Scholar]
  18. Garcia, M. N. , Hildebolt C. F., Miley D. D., et al. 2011. “One‐Year Effects of Vitamin D and Calcium Supplementation on Chronic Periodontitis.” Journal of Periodontology 82: 25–32. 10.1902/jop.2010.100207. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Gonçalves, P. F. , Huang H., McAninley S., et al. 2013. “Periodontal Treatment Reduces Matrix Metalloproteinase Levels in Localized Aggressive Periodontitis.” Journal of Periodontology 84: 1801–1808. 10.1902/jop.2013.130002. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Grenier, D. , Morin M. P., Fournier‐Larente J., and Chen H.. 2016. “Vitamin D Inhibits the Growth of and Virulence Factor Gene Expression by Porphyromonas gingivalis and Blocks Activation of the Nuclear Factor Kappa B Transcription Factor in Monocytes.” Journal of Periodontal Research 51: 359–365. 10.1111/jre.12315. [DOI] [PubMed] [Google Scholar]
  21. Holick, M. F. 2011. “Vitamin D: Evolutionary, Physiological and Health Perspectives.” Current Drug Targets 12: 4–18. 10.2174/138945011793591635. [DOI] [PubMed] [Google Scholar]
  22. Jetter, A. , Egli A., Dawson‐Hughes B., et al. 2014. “Pharmacokinetics of Oral Vitamin D3 and Calcifediol.” Bone 59: 14–19. 10.1016/j.bone.2013.10.014. [DOI] [PubMed] [Google Scholar]
  23. Kim, K.‐A. , Chung S.‐B., Hawng E.‐Y., et al. 2013. “Correlation of Expression and Activity of Matrix Metalloproteinase‐9 and ‐2 in Human Gingival Cells of Periodontitis Patients.” Journal of Periodontal and Implant Science 43, no. 1: 24–29. 10.5051/jpis.2013.43.1.24. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Kim, S. H. , Baek M. S., Yoon D. S., et al. 2014. “Vitamin D Inhibits Expression and Activity of Matrix Metalloproteinase in Human Lung Fibroblasts (HFL‐1) Cells.” Tuberculosis Respiratory Disease 77: 73–80. 10.4046/trd.2014.77.2.73. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Komolmit, P. , Kimtrakool S., Suksawatamnuay S., et al. 2017. “Vitamin D Supplementation Improves Serum Markers Associated With Hepatic Fibrogenesis in Chronic Hepatitis C Patients: A Randomized, Double‐Blind, Placebo‐Controlled Study.” Scientific Reports 7: 8905. 10.1038/s41598-017-09512-7. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Lamster, I. B. , Oshrain R. L., and Gordon J. M.. 1986. “Enzyme Activity in Human Gingival Crevicular Fluid: Considerations in Data Reporting Based on Analysis of Individual Crevicular Sites.” Journal of Clinical Periodontology 13: 799–804. 10.1111/j.1600-051x.1986.tb00885.x. [DOI] [PubMed] [Google Scholar]
  27. Liu, P. T. , Stenger S., Li H., Wenzel L., Tan B. H., and Krutzik S. R.. 2006. “Toll‐Like Receptor Triggering of a Vitamin D‐Mediated Human Antimicrobial Response.” Science 311: 1770–1773. 10.1126/science.1123933. [DOI] [PubMed] [Google Scholar]
  28. Lu, E. M. C. 2023. “The Role of Vitamin D in Periodontal Health and Disease.” Journal of Periodontal Research 58: 213–224. 10.1111/jre.13083. [DOI] [PubMed] [Google Scholar]
  29. Machado, V. , Lobo S., Proença L., Mendes J. J., and Botelho J.. 2020. “Vitamin D and Periodontitis: A Systematic Review and Meta‐Analysis.” Nutrients 12: 2177. 10.3390/nu12082177. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Maeso, G. , Bravo M., and Bascones A.. 2007. “Levels of Metalloproteinase‐2 and‐g and Tissue Inhibitor of Matrix Metalloproteinase‐1 in Gingival Crevicular Fluid of Patients With Periodontitis, Gingivitis, and Healthy Gingiva.” Quintessence International 38: 247–252. [PubMed] [Google Scholar]
  31. Mäkelä, M. , Salo T., Uitto V. J., and Larjava H.. 1994. “Matrix Metalloproteinases (MMP‐2 and MMP‐9) of the Oral Cavity: Cellular Origin and Relationship to Periodontal Status.” Journal of Dental Research 73: 1397–1406. 10.1177/00220345940730080201. [DOI] [PubMed] [Google Scholar]
  32. Marcaccini, A. M. , Meschiari C. A., Zuardi L. R., et al. 2010. “Gingival Crevicular Fluid Levels of MMP‐8, MMP‐9, TIMP‐2, and MPO Decrease After Periodontal Therapy.” Journal of Clinical Periodontology 37: 180–190. 10.1111/j.1600-051X.2009.01512.x. [DOI] [PubMed] [Google Scholar]
  33. Marcaccini, A. M. , Novaes A. B. Jr., Meschiari C. A., et al. 2009. “Circulating Matrix Metalloproteinase‐8 (MMP‐8) and MMP‐9 Are Increased in Chronic Periodontal Disease and Decrease After Non‐Surgical Periodontal Therapy.” Clinica Chimica Acta; International Journal of Clinical Chemistry 409: 117–122. 10.1016/j.cca.2009.09.012. [DOI] [PubMed] [Google Scholar]
  34. McCarney, R. , Warner J., Iliffe S., van Haselen R., Griffin M., and Fisher P.. 2007. “The Hawthorne Effect: A Randomised, Controlled Trial.” BMC Medical Research Methodology 7: 30. 10.1186/1471-2288-7-30. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. McMahon, L. , Schwartz K., Yilmaz O., Brown E., Ryan L. K., and Diamond G.. 2011. “Vitamin D‐Mediated Induction of Innate Immunity in Gingival Epithelial Cells.” Infection and Immunity 79: 2250–2256. 10.1128/IAI.00099-11. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Meghil, M. M. , and Cutler C. W.. 2023. “Influence of Vitamin D on Periodontal Inflammation: A Review.” Pathogens 12: 1180. 10.3390/pathogens12091180. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Nazir, M. A. 2017. “Prevalence of Periodontal Disease, Its Association With Systemic Diseases and Prevention.” International Journal of Health Sciences (Qassim) 11: 72–80. [PMC free article] [PubMed] [Google Scholar]
  38. Oh, C. , Kim H. J., and Kim H.‐M.. 2019. “Vitamin D Maintains E‐Cadherin Intercellular Junctions by Downregulating MMP‐9 Production in Human Gingival Keratinocytes Treated by TNF‐α.” Journal of Periodontal and Implant Science 49: 270–286. 10.5051/jpis.2019.49.5.270. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Panteghini, M. , and Infusina I.. 2023. Enzyme and Rate Analysis, edited by Rifai N.. Elsevier Health Sciences. [Google Scholar]
  40. Papapanou, P. N. , Sanz M., Buduneli N., et al. 2018. “Periodontitis: Consensus Report of Workgroup 2 of the 2017 World Workshop on the Classification of Periodontal and Peri‐Implant Diseases and Conditions.” Journal of Periodontology 89: S173–S182. 10.1002/JPER.17-0721. [DOI] [PubMed] [Google Scholar]
  41. Perayil, J. , Menon K. S., Kurup S., et al. 2015. “Influence of Vitamin D & Calcium Supplementation in the Management of Periodontitis.” Journal of Clinical and Diagnostic Research 9: ZC35–ZC38. 10.7860/JCDR/2015/12292.6091. [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. Prietl, B. , Treiber G., Pieber T. R., and Amrein K.. 2013. “Vitamin D and Immune Function.” Nutrients 5, no. 7: 2502–2521. 10.3390/nu5072502. [DOI] [PMC free article] [PubMed] [Google Scholar]
  43. Rakic, M. , Pejcic N., Perunovic N., and Vojvodic D.. 2021. “A Roadmap Towards Precision Periodontics.” Medicina 57: 233. 10.3390/medicina57030233. [DOI] [PMC free article] [PubMed] [Google Scholar]
  44. Sapna, G. , Gokul S., and Bagri‐Manjrekar K.. 2014. “Matrix Metalloproteinases and Periodontal Diseases.” Oral Diseases 20: 538–550. 10.1111/odi.12159. [DOI] [PubMed] [Google Scholar]
  45. Sorsa, T. , Tjäderhane L., Konttinen Y. T., et al. 2006. “Matrix Metalloproteinases: Contribution to Pathogenesis, Diagnosis and Treatment of Periodontal Inflammation.” Annals of Medicine 38: 306–321. 10.1080/07853890600800103. [DOI] [PubMed] [Google Scholar]
  46. Sternlicht, M. D. , and Werb Z.. 2001. “How Matrix Metalloproteinases Regulate Cell Behavior.” Annual Review of Cell and Developmental Biology 17: 463–516. 10.1146/annurev.cellbio.17.1.463. [DOI] [PMC free article] [PubMed] [Google Scholar]
  47. Sundar, I. K. , Hwang J.‐W., Wu S., Sun J., and Rahman I.. 2011. “Deletion of Vitamin D Receptor Leads to Premature Emphysema/COPD by Increased Matrix Metalloproteinases and Lymphoid Aggregates Formation.” Biochemical and Biophysical Research Communications 406: 127–133. 10.1016/j.bbrc.2011.02.011. [DOI] [PMC free article] [PubMed] [Google Scholar]
  48. Timms, P. M. , Mannan N., Hitman G. A., et al. 2002. “Circulating MMP9, Vitamin D and Variation in the TIMP‐1 Response With VDR Genotype: Mechanisms for Inflammatory Damage in Chronic Disorders?” Quarterly Journal of Medicine 95, no. 12: 787–796. 10.1093/qjmed/95.12.787. [DOI] [PubMed] [Google Scholar]
  49. Tóth, B. , Takács I., Szekeres L., Szabó B., Bakos B., and Lakatos P. L.. 2017. “Safety and Efficacy of Weekly 30,000 IU Vitamin D Supplementation as a Slower Loading Dose Administration Compared to a Daily Maintenance Schedule in Deficient Patients: A Randomized, Controlled Clinical Trial.” Journal of Pharmacovigilance 5, no. 4. 10.4172/2329-6887.1000233. [DOI] [Google Scholar]
  50. Victor, D. J. , Subramanian S., Gnana P. P. S., and Kolagani S. P.. 2014. “Assessment of Matrix Metalloproteinases‐8 and −9 in Gingival Crevicular Fluid of Smokers and Non‐Smokers With Chronic Periodontitis Using ELISA.” Journal of International Oral Health 6: 67–71. [PMC free article] [PubMed] [Google Scholar]
  51. Vo, H. V. T. , Nguyen Y. T., Kim N., and Lee H. J.. 2023. “Vitamin A, D, E, and K as Matrix Metalloproteinase‐2/9 Regulators That Affect Expression and Enzymatic Activity.” International Journal of Molecular Sciences 24: 17038. 10.3390/ijms242317038. [DOI] [PMC free article] [PubMed] [Google Scholar]
  52. Wang, L.‐F. , Tai C.‐F., Chien C.‐Y., Chiang F.‐Y., and Chen J. Y.‐F.. 2015. “Vitamin D Decreases the Secretion of Matrix Metalloproteinase‐2 and Matrix Metalloproteinase‐9 in Fibroblasts Derived From Taiwanese Patients With Chronic Rhinosinusitis With Nasal Polyposis.” Kaohsiung Journal of Medical Sciences 31: 235–240. 10.1016/j.kjms.2015.02.001. [DOI] [PMC free article] [PubMed] [Google Scholar]
  53. Wasse, H. , Cardarelli F., De Staercke C., Hooper C., Veledar E., and Guessous I.. 2011. “25‐Hydroxyvitamin D Concentration Is Inversely Associated With Serum MMP‐9 in a Cross‐Sectional Study of African American ESRD Patients.” BMC Nephrology 12: 24. 10.1186/1471-2369-12-24. [DOI] [PMC free article] [PubMed] [Google Scholar]
  54. Yıldırım, Y. A. , Ozturk A., Doğruel F., Saraçoğlu H., and Yazıcı C.. 2024. “Serum Vitamin D Concentration Is Inversely Associated With Matrix Metalloproteinase‐9 Level in Periodontal Diseases.” Journal of Periodontology. 10.1002/JPER.24-0106. [DOI] [PMC free article] [PubMed] [Google Scholar]
  55. Yuan, L. , and Ni J.. 2022. “The Association Between Tobacco Smoke Exposure and Vitamin D Levels Among US General Population, 2001–2014: Temporal Variation and Inequalities in Population Susceptibility.” Environmental Science and Pollution Research International 29: 32773–32787. 10.1007/s11356-021-17905-5. [DOI] [PMC free article] [PubMed] [Google Scholar]
  56. Żebrowska, A. , Sadowska‐Krępa E., Stanula A., et al. 2020. “The Effect of Vitamin D Supplementation on Serum Total 25(OH) Levels and Biochemical Markers of Skeletal Muscles in Runners.” Journal of the International Society of Sports Nutrition 17: 18. 10.1186/s12970-020-00347-8. [DOI] [PMC free article] [PubMed] [Google Scholar]
  57. Zhang, X. , Wu J., Dong H., et al. 2024. “The Impact of Supplementing Vitamin D Through Different Methods on the Prognosis of COVID‐19 Patients: A Systematic Review and Meta‐Analysis.” Frontiers in Nutrition 11: 1441847. 10.3389/fnut.2024.1441847. [DOI] [PMC free article] [PubMed] [Google Scholar]
  58. Zwart, S. R. , Parsons H., Kimlin M., Innis S. M., Locke J. P., and Smith S. M.. 2013. “A 250 μg/Week Dose of Vitamin D Was as Effective as a 50 μg/d Dose in Healthy Adults, but a Regimen of Four Weekly Followed by Monthly Doses of 1250 μg Raised the Risk of Hypercalciuria.” British Journal of Nutrition 110: 1866–1872. 10.1017/S000711451300113. [DOI] [PubMed] [Google Scholar]

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

Data S1.

JCPE-52-1115-s001.docx (29.6KB, docx)

Data Availability Statement

The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.

Articles from Journal of Clinical Periodontology are provided here courtesy of Wiley

RESOURCES