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High glucose induces senescence in synovial mesenchymal stem cells through mitochondrial dysfunction

BMC Oral Health volume 25, Article number: 569 (2025) Cite this article

Abstract

Purpose

To investigate the impact of high glucose on the senescence of synovial mesenchymal stem cells (SMSCs) and to elucidate the role of mitochondrial dysfunction in this process.

Methods

‌SMSCs were treated with medium containing high glucose (25 mmol/L) or low glucose (5.5 mmol/L) concentrations. The effects of high glucose concentrations on the proliferation, senescence, mitochondrial reactive oxygen species (ROS) levels, mitochondrial fission, and mitophagy of SMSCs were investigated. First, the impact of 24-hour high glucose treatment on SMSCs was investigated‌. After this initial 24-hour exposure, the medium was subsequently changed to low glucose, and the cells were cultivated for an additional 24 h; this was then compared with the effects of continuous 48-hour high-glucose exposure and continuous 48-hour low-glucose exposure.

Results

High glucose concentrations did not promote the proliferation of SMSCs but rather accelerated their senescence by ‌upregulating‌ the mRNA expression of senescence-associated secretory phenotype (SASP) genes and increasing the number of senescence-associated β-galactosidase (SA-β-gal)-positive cells. Additionally, high glucose ‌concentrations elevated‌ ROS levels in mitochondria and ‌facilitated‌ mitochondrial fission; they also ‌inhibited‌ the mitophagy of SMSCs by suppressing the expression of mitophagy-related proteins (PINK1, PARKIN, and LC3B). High glucose-induced suppression of mRNA (Il-6, Cxcl1, Dnm1, Pink1, Prkn, Lc3b) and protein (P21) expression, along with increased SA-β-gal-positive cell numbers and elevated MitoSOX intensity, can be reversed by terminating the high glucose treatment.

Conclusion

High glucose concentrations induce senescence in SMSCs via mitochondrial dysfunction, manifested as ROS accumulation, excessive fission, and mitophagy suppression. Glucose normalization reversed senescence phenotypes, accompanied by restored mitophagy and reduced oxidative stress. Mitochondrial dysfunction may be one of the key mechanisms underlying high glucose-induced senescence in SMSCs.

Peer Review reports

Introduction

Osteoarthritis (OA) is a leading cause of disability and a source of societal cost in older adults [1]. It is a chronic disease that affects the joints and their constituent tissues, leading primarily to progressive degeneration of the articular cartilage, followed by damage to the subchondral bone and adjacent synovial structures [2]. Notably, OA is a prevalent complication among individuals with diabetes, with an incidence rate as high as 32.65% [3]. Research has demonstrated that the inflammatory response and hyperglycaemia associated with diabetes accelerate the destruction of articular cartilage [4]. However, the underlying pathogenesis remains incompletely understood. Further research is needed to clarify whether diabetes control and prevention can modulate OA occurrence and progression [5].

As a regenerative therapy for OA, mesenchymal stem cell (MSC) therapy represents an effective strategy due to its potential for self-renewal, chondrogenic differentiation, and immune regulation [6]. MSCs can be sourced from various tissues, including bone marrow, adipose tissue, amniotic fluid, placenta, umbilical cord, dental pulp, and synovium [7]. Notably, synovial mesenchymal stem cells (SMSCs), derived from synovial tissue, exhibit superior chondrogenicity compared with MSCs from other sources [8]. Robert and Matheus et al. suggested that stem cell-based therapies may be promising approaches for the treatment of temporomandibular joint osteoarthritis and for the regeneration of full-thickness cartilage and osteochondral defects in the temporomandibular joint [9, 10].

High glucose may impair the functional capabilities of MSCs. Specifically, high glucose levels hinder the osteogenic differentiation of MSCs [11] and inhibit the proliferation and migration of bone mesenchymal stem cells [12]. The depletion or dysfunction of MSCs is associated with several systemic diseases, including diabetes, but the precise underlying mechanism remains unclear [13]. Diabetes-induced inhibition of stem cell differentiation may occur through disrupted mitochondrial function [14]. Mitochondrial dysfunction is closely related to cell senescence [15]. We therefore propose that elevated glucose levels induce SMSC senescence through mitophagy dysregulation; this would establish impaired mitochondrial clearance as a putative mechanistic link in this pathological process.

To validate this hypothesis, SMSCs were cultured in high-glucose medium. First, high glucose-induced senescence in SMSCs was assessed by quantifying the senescence-associated secretory phenotype (SASP) and performing senescence-associated β-galactosidase (SA-β-gal) staining. We subsequently discovered that high glucose levels impair mitophagy, thereby promoting senescence in SMSCs. Finally, we discovered that the inhibition of mitophagy and senescence in SMSCs resulting from short-term high-glucose treatment can be reversed.

Materials and methods

Cell culture and treatment

Primary SMSCs derived from rats (Procell, China) were cultured in flasks containing Dulbecco’s modified Eagle’s medium (DMEM, Gibco) supplemented with 10% foetal bovine serum (FBS, Gibco). The cultures were maintained at 37 °C in a humidified incubator with 5% CO2, and the medium was replaced every two days. Once the cells reached 80-90% confluence, they were passaged at a split ratio of 1:2.

Effects of high glucose concentrations on the senescence of SMSCs

First, we investigated the impact of high glucose levels on the proliferation of SMSCs. Rat SMSCs at passage 4 (P4) were inoculated into 96-well plates at a density of 5,000 cells per well, with four replicate wells for each group. Once the cells were fully attached to the substrate, the high-glucose (HG) group was supplemented with complete medium containing 25 mmol/L glucose for media replacement, whereas the control group (LG) received complete medium containing 5.5 mmol/L glucose. After 24 h, 48 h, and 72 h of incubation, 10 µL of CCK solution was added to each well, and the plates were then placed in an incubator for an additional 2 h. The absorbance at 450 nm was subsequently determined, and the OD values for each group were obtained using an enzyme-labelled instrument.

We then detected the mRNA expression levels of SASP-related cytokines, including Il-6, Tnf-α, Mmp13, Cxcl1, and Ifn-β, via qRT‒PCR after the cells were treated with high glucose for 24 h. Total RNA was extracted from both the low-glucose group (LG24H: cultured in complete medium containing 5.5 mmol/L glucose) and the high-glucose group (HG24H: cultured in complete medium containing 25 mmol/L glucose) via the TRIzol method. The concentration and purity of the RNA were then assessed using an ultramicro ultraviolet‒visible spectrophotometer (Miulab, China). Then, a reverse transcription kit (Vazyme, China) was used to convert the extracted RNA into cDNA‌. Subsequently, real-time PCR amplification‌ was performed. A StarLighter HP SYBR qPCR Mix Kit (Foreverstar, China) was used to set up the PCR reaction mixture, with the purified cDNA used as the template, specific primers (Table 1), and PCR reagents‌. A Roche 480 fluorescence quantitative PCR system was used to amplify the cDNA, and the fluorescence signal generated during each PCR cycle was measured to quantify the amount of amplified product.

Ultimately, SA-β-gal activity was detected following 24 h of high-glucose treatment. The cell culture medium was removed, and the cells were washed once with PBS. Subsequently, 1 mL of fixing solution specific for β-galactosidase staining was added to the cells, which were subsequently incubated at room temperature for 15 min. After the fixation period, the fixative solution was thoroughly removed, and the cells were washed with PBS three times for 3 min each. The PBS was aspirated, and 1 mL of staining solution containing the SA-β-gal substrate was added to each well. The plate was then incubated at 37 °C overnight, and the cells were observed under an optical microscope and photographed.

Table 1 The primer sequences
Full size table

Detection of the effects of high glucose concentrations on ROS levels in mitochondria and mitochondrial fission

Following 24 h of treatment with high glucose, the level of mitochondrial reactive oxygen species (ROS) in the SMSCs was assessed via MitoSOX staining. The cells were initially rinsed with DMEM and then incubated with the MitoSOX Red probe (Affinity, China) at a final concentration of 2 µM in DMEM under dark conditions at room temperature for 20–30 min. After incubation, the cells were washed thoroughly with PBS twice, each time for 5 min. Following the washing steps, the cells were mounted onto microscope slides with mounting medium containing DAPI (Beyotime, China). The mounted cells were then visualized using a laser scanning confocal microscope (Leica, Germany) to detect the red fluorescence of MitoSOX and the blue fluorescence of DAPI.

The protein expression of mitochondrial fission (DRP1) was detected via Western blotting after treatment with high glucose for 24 h. The cells were washed three times with ice-cold PBS, lysed with lysis buffer (Beyotime, China), and then centrifuged at 14,000 rpm at 4 °C for 20 min. The protein concentration was then determined using a BCA protein assay kit (Solarbio, China) to ensure accurate loading. Following quantification, equal amounts of protein from each sample were mixed with loading buffer and denatured by heating to 99 °C for 5 min. The denatured protein samples were loaded onto a sodium dodecyl sulfate‒polyacrylamide gel for electrophoresis (SDS‒PAGE). An electric current was applied, initially at 80 V for compression, and subsequently increased to 130 V for separation. After electrophoresis, the separated proteins were transferred from the gel to a polyvinylidene fluoride (PVDF) membrane. The membrane was then incubated with blocking buffer and subsequently with primary antibodies (Abcam, United Kingdom) and secondary antibodies (Proteintech, China). The membrane was then photographed using an imaging device, specifically the TANON-5200 (China), which captured the signal and generated an image of the protein bands. The resulting image was analysed using ImageJ software to measure the grayscale values, allowing for quantification of the protein expression levels.

The mRNA expression of the mitochondrial fission gene Drp1 was detected via qRT‒PCR after treatment with high glucose for 24 h. The protocol for qRT‒PCR was as described above.

Detection of the effect of high glucose concentrations on the mitophagy of SMSCs

After the SMSCs were treated with high glucose for 24 h, total cell protein was extracted and detected via Western blotting. The protocol for Western blotting was as described above. The protein expression levels of mitophagy-related markers, including PINK1, PARKIN, and LC3B, were assessed.

Detection of whether SMSC senescence caused by high glucose levels can be reversed

To verify whether the senescence of SMSCs caused by high glucose levels can be ‌reversed‌ and to analyse the possible mechanisms, we divided the cells into three groups. For the first group, low-glucose medium (5.5 mmol/L) was used for continuous culture for 48 h (LG48H group). For the second group, high-glucose medium (25 mmol/L) was used for continuous culture for 48 h (HG48H group). For the third group, SMSCs were cultured in complete medium containing 25 mmol/L glucose for 24 h, which was then replaced with complete medium containing 5.5 mmol/L glucose ‌and cultured for an additional 24 h (HG24H + LG24H group). After the above treatments, the degree of senescence in SMSCs was analysed by detecting the mRNA expression of Il-6 and Cxcl1, the protein expression of P21, and SA-β-gal staining.

To assess any changes in mitophagy function in SMSCs, the mRNA expression of mitochondrial fission (Dnm1) and mitophagy markers (Pink1, Prkn, Lc3b) was subsequently detected, and the SMSCs were stained with the MitoSOX fluorochrome and observed via laser scanning confocal microscopy.

Statistical analysis

The experimental data are presented as the means ± standard deviations (SDs). The differences among groups were analysed using GraphPad Prism 9 software. For pairwise comparisons, an independent-samples t test was employed. All the data were collected from at least three independent experiments, each with independently generated samples (n ≥ 3). A P value < 0.05 was considered statistically significant.

Results

The impact of high glucose concentrations on the proliferation and senescence of SMSCs

The CCK-8 results revealed no significant difference in the proliferative activity of SMSCs between the LG and HG groups at 24 h, 48 h, or 72 h. This finding implies that the exposure of SMSCs to high glucose (25 mmol/L) for these durations did not alter their proliferative activity (Fig. 1A).

After the SMSCs were treated with high glucose (25 mmol/L) for 24 h, SA-β-gal staining revealed a significant increase in the number of senescent cells compared with that at baseline (Fig. 1B). The results of qRT‒PCR demonstrated that the mRNA expression levels of SASP components, including Il-6, Tnf-α, Mmp13, Cxcl1 and Ifn-β, were elevated in the high glucose group relative to the low glucose group, indicating that high glucose concentrations induced senescence in SMSCs (Fig. 1C).

Fig. 1
figure 1

Senescence of SMSCs. (A) Cell proliferative activity. (LG: low glucose [5.5 mmol/L], HG: high glucose [25 mmol/L]). (B) SA-β-gal staining. (C) The relative mRNA expression levels of Il-6, Tnf-α, Mmp13, Cxcl1 and Ifn-β. ns: no significant difference, *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001

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High glucose concentrations elevate ROS levels in mitochondria and promote mitochondrial fission

After the SMSCs were treated with high glucose (25 mmol/L) for 24 h, the cells were stained with the MitoSOX fluorochrome and subsequently observed via a laser scanning confocal microscope. As shown in Fig. 2A, the mitochondrial ROS levels in the high-glucose group were markedly elevated compared with those in the low-glucose group, as evidenced by the brighter red fluorescence. Semiquantitative analysis further confirmed that this difference was statistically significant (Fig. 2B). Additionally, both the relative mRNA and protein expression levels of mitochondrial dynamin-1 were upregulated following 24 h of high glucose treatment (Fig. 2C, D).

Fig. 2
figure 2

Effects of high glucose treatment on ROS levels in mitochondria and mitochondrial fission in SMSCs after 24 h. (A) ROS levels in mitochondria determined via MitoSOX staining. (B) Semiquantitative analysis of MitoSOX intensity in mitochondria. (C) The relative mRNA expression levels of Dnm1. (D) Protein expression levels of DRP1. *P < 0.05, ***P < 0.001

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High glucose concentrations inhibit the mitophagy of SMSCs

After the SMSCs were treated with high glucose (25 mmol/L) for 24 h, total protein was extracted from the cells, and the target protein was detected via Western blotting. Compared with that in the low glucose group, the expression of mitophagy-related proteins in the high glucose group was inhibited. Semiquantitative analysis revealed that the difference was statistically significant (Fig. 3).

Fig. 3
figure 3

The protein expression of PINK1, PARKIN, and LC3B. (A) Western blot bands of the PINK1 protein and semiquantitative analysis. (B) Western blot bands of the PARKIN protein and semiquantitative analysis. (C) Western blot bands of the LC3B protein and semiquantitative analysis. *P < 0.05

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SMSC senescence caused by high glucose concentrations can be reversed by removing high glucose treatment

The results of qRT‒PCR revealed that the mRNA expression of Il-6 and Cxcl1 decreased when the culture medium was replaced with low-glucose medium for another 24 h after treatment with high-glucose culture medium for 24 h (Fig. 4A). The WB results indicated that the protein expression of P21 decreased when the culture medium was replaced with low-glucose medium following 24 h of treatment with high-glucose culture medium (Fig. 4B). SA-β-gal staining revealed that the HG48H group contained the greatest number of positive cells. In the HG24H + LG24H group, the number of positive cells was close to that in the LG48H group. These findings suggest that senescence induced by high glucose levels can be reversed by ceasing high glucose treatment (Fig. 4C).

Fig. 4
figure 4

Reversal of SMSC senescence in the LG48H, HG48H, and HG24H + LG24H groups. (A) mRNA expression of Il-6 and Cxcl1. (B) Protein expression of P21. (C) SA-β-gal staining. ns: no significant difference, *P < 0.05, **P < 0.01, ***P < 0.001

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Changes in the mitophagy function of SMSCs were subsequently assessed. The MitoSOX staining indicated that the HG48H group exhibited significantly higher mitochondrial ROS levels, as evidenced by brighter red fluorescence, than the LG48H and HG24H + LG24H groups. The qRT‒PCR results demonstrated that the inhibition of Dnm1, Pink1, Prkn, and Lc3b mRNA expression caused by high-glucose treatment could be reversed by replacing the high-glucose medium with low-glucose medium (Fig. 5).

Fig. 5
figure 5

ROS levels, mitochondrial fission and mitophagy of SMSCs in the LG48H, HG48H, and HG24H + LG24H groups. (A) ROS levels in mitochondria determined via MitoSOX staining. (B) Semiquantitative analysis of MitoSOX intensity in mitochondria. (C) The relative mRNA expression of Dnm1. (D) The relative mRNA expression of Pink1, Prkn and Lc3b. ns: no significant difference, *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001

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Discussion

Research has revealed that high glucose concentrations can augment the expression of SASP factors and increase the number of SA-β-gal-positive SMSCs. These findings indicate that elevated glucose levels induce senescence in rat SMSCs. Subsequently, it was confirmed that this occurs by mitochondrial dysfunction, manifested as ROS accumulation, excessive fission, and mitophagy suppression. Notably, glucose normalization reversed senescence phenotypes, accompanied by restored mitophagy and reduced oxidative stress.

Under high-glucose conditions, the proliferation of SMSCs is impaired. Research indicates that high glucose promotes the proliferation of various types of cells, such as endothelial cells [16], keratinocytes [17], and HeLa and H9C2 cells [18]. However, this phenomenon may not be applicable to stem cells. ‌Persistent, uncontrolled hyperglycaemia induces alterations within the bone marrow microenvironment, ultimately resulting in impaired stem cell mobilization [19]. Nguyen et al. [20] reported a decreased proliferation rate of mesenchymal stem cells in patients with T2DM. In this study, the results obtained from the CCK-8 assay revealed that the anticipated enhanced proliferation of SMSCs in high-glucose medium did not occur, indicating that high glucose impairs the proliferation capability of SMSCs.

Further experiments revealed that high glucose also led to the senescence of SMSCs. SA-β-gal staining serves as the gold standard for detecting cellular senescence [21]. In the high-glucose group, the number of SA-β-gal-positive cells exceeded that in the control group, suggesting an increase in or accumulation of senescent SMSCs under high-glucose conditions. Furthermore, in addition to SA-β-gal, the SASP, which encompasses the relative mRNA expression of Il-6, Tnf-α, Mmp13, Cxcl1 and Ifn-β, was also examined in this study. The increase in β-galactosidase-positive cells and elevated SASP expression induced by high glucose are consistent with the trends observed in our previous findings. The SASP is a crucial indicator of stem cell senescence and encompasses a spectrum of cytokines, chemokines, extracellular matrix proteins, and growth factors [22]. IL-6 plays a crucial role in inflammation linked to OA, as its increased expression in the synovial fluid of OA patients is positively associated with MMPs [23]. Interferons regulate the homeostasis of the bone matrix and are associated with the expression of matrix metalloproteinases. The upregulation of Mmp13 in osteoarthritis leads to the cleavage of type II collagen, a key structural protein of cartilage, and destruction of the matrix [24]. Silencing Mmp13 reduces posttraumatic osteoarthritis articular cartilage degeneration/fibrillation, meniscus deterioration, synovial hyperplasia, osteophytes, and proinflammatory gene expression in a mouse model [25]. Consequently, increased SASP impacts the biological functions of SMSCs, such as by inhibiting cartilage regeneration, exacerbating inflammation, and degrading the cartilage matrix, thereby playing a significant role in the onset and progression of diabetic OA.

To further investigate the mechanisms underlying SMSC senescence induced by high glucose, this study examined the impact of high glucose levels on mitochondria. The results revealed that high glucose levels inhibit mitophagy, enhance mitochondrial fission and result in the accumulation of ROS within mitochondria. Mitochondria are involved in the maintenance of stem cell properties and differentiation [26, 27]. Dysregulation of mitochondrial dynamics, which encompass processes of fusion and fission, triggers the senescence of stem cells, thereby impacting their functionality [28]. When damaged or unfolded proteins accumulate in mitochondria, mitochondrial fission increases to dilute or separate damaged proteins for further degradation. Mitophagy facilitates the disposal of damaged proteins and mitigates the accumulation of ROS within mitochondria [26, 27]. Through mitophagy, impaired mitochondria are selectively eliminated, minimizing ROS production and inflammation and increasing cell survival [29,30,31,32]. However, our study revealed increases in both the gene and protein expression of DRP1, accompanied by increased mitochondrial fission and dysfunctional mitophagy, which significantly promote cell senescence [33]. We observed that high glucose levels lead to mitochondrial dysfunction, manifested as ROS accumulation, excessive fission, and mitophagy suppression.

When investigating whether the senescence of SMSCs induced by high glucose levels can be reversed, we observed a decrease in SA-β-gal-positive cells and the protein expression level of P21 subsequent to the replacement of the high glucose medium with low glucose medium. Moreover, the mRNA expression of the Il-6 and Cxcl1 genes was downregulated, as measured by qRT‒PCR. These results revealed that the senescence of SMSCs was reversed. To further explore the role of mitochondrial function in this process, the mRNA expression of mitochondrial fission and mitophagy markers was further detected, and the SMSCs were stained with the MitoSOX fluorochrome. These results suggest that mitochondrial dysfunction may be one of the mechanisms underlying high glucose-induced SMSCs senescence.

Conclusion

This study demonstrated that high glucose concentrations induce senescence in SMSCs through mitochondrial dysfunction, characterized by elevated mitochondrial ROS, excessive fission, and impaired mitophagy. Although proliferation remained unaffected, the levels of senescence-associated markers were significantly elevated under high-glucose conditions. Critically, this senescence phenotype was reversible upon glucose normalization, which coincided with restored mitophagy activity and reduced oxidative stress. Based on these findings, we propose that mitochondrial dysfunction may be one of the key mechanisms underlying high glucose-induced senescence in SMSCs.

Limitations: While this study provides evidence linking mitochondrial dysfunction to SMSC senescence under high-glucose conditions, two aspects should be acknowledged. First, the experimental scope has focused solely on mitochondrial pathways, potentially overlooking other mechanisms (e.g., epigenetic changes and telomere attrition). Second, in vitro models lack the physiological complexity of in vivo systems; the absence of animal data limits translational relevance. Future work should integrate multiomics analyses and genetic manipulation to validate these mechanisms in a holistic context.

Data availability

The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.

Abbreviations

BCA:

Bicinchoninic Acid Assay

CCK-8:

Cell Counting Kit-8

Cxcl1:

Chemokine Ligand 1 (Gene, Rat)

DAPI:

4’,6-diamidino-2-phenylindole

DMEM:

Dulbecco’s Modified Eagle’s Medium

Dnm1 :

Dynamin 1(Gene, Rat)

DRP1:

Dynamin-Related Protein 1(Protein, Rat), encoded by Dnm1

FBS:

Fetal Bovine Serum

Ifn-β :

Interferon Beta (Gene, Rat)

Il-6 :

Interleukin-6 (Gene, Rat)

IL-6 :

Interleukin-6 (Gene, Human)

Lc3b :

Microtubule-Associated Protein 1 Light Chain 3B (Gene, Rat)

LC3B:

Microtubule-Associated Protein 1 Light Chain 3B (Protein, Rat)

MitoSOX:

Mitochondrial Superoxide

Mmp13 :

Matrix Metalloproteinase 13 (Gene, Rat)

MMP :

Matrix Metalloproteinase (Gene, Human)

mRNA:

Messenger Ribonucleic Acid

MSCs:

Mesenchymal Stem Cells

OA:

Osteoarthritis

PBS:

Phosphate-Buffered Saline

Pink1 :

PTEN induced putative kinase 1 (Gene, Rat)

PINK1:

PTEN induced putative kinase 1 (Protein, Rat)

PARKIN:

Parkin RBR E3 Ubiquitin Protein Ligase (Protein, Rat)

Prkn :

Parkin RBR E3 Ubiquitin Protein Ligase (Gene, Rat)

PVDF:

Polyvinylidene Fluoride

qRT-PCR:

Quantitative Real-Time Polymerase Chain Reaction

ROS:

Reactive Oxygen Species

SASP:

Senescence-Associated Secretory Phenotype

SA-β-gal:

Senescence-Associated Beta-Galactosidase

SDS-PAGE:

Sodium Dodecyl Sulfate Polyacrylamide Gel Electrophoresis

SMSCs:

Synovial Mesenchymal Stem Cells

T2DM:

Type 2 Diabetes Mellitus

TMJ:

Temporomandibular Joint

TMJ-OA:

Temporomandibular Joint Osteoarthritis

Tnf-α :

Tumor Necrosis Factor Alpha (Gene, Rat)

References

  1. Hunter DJ, Bierma-Zeinstra S. Osteoarthritis. Lancet 2019, 393(10182):1745–1759.

  2. Giorgino R, Albano D, Fusco S, Peretti GM, Mangiavini L, Messina C. Knee osteoarthritis: epidemiology, pathogenesis, and mesenchymal stem cells: what else is new? An update. Int J Mol Sci. 2023;24(7).

  3. Wu JH, Chen HB, Wu YQ, Wu Y, Wang ZJ, Wu T, Wang MY, Wang SY, Wang XW, Wang JT, et al. [Prevalence and risk factors of osteoarthritis in patients with type 2 diabetes in Beijing, China from 2015 to 2017]. Beijing Da Xue Xue Bao Yi Xue Ban. 2021;53(3):518–22.

    PubMed  CAS  Google Scholar 

  4. Rios-Arce ND, Hum NR, Loots GG. Interactions between diabetes mellitus and osteoarthritis: from animal studies to clinical data. JBMR Plus. 2022;6(5):e10626.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Veronese N, Cooper C, Reginster JY, Hochberg M, Branco J, Bruyère O, Chapurlat R, Al-Daghri N, Dennison E, Herrero-Beaumont G, et al. Type 2 diabetes mellitus and osteoarthritis. Semin Arthritis Rheum. 2019;49(1):9–19.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  6. Zhu C, Wu W, Qu X. Mesenchymal stem cells in osteoarthritis therapy: a review. Am J Transl Res. 2021;13(2):448–61.

    PubMed  PubMed Central  CAS  Google Scholar 

  7. Ullah I, Subbarao RB, Rho GJ. Human mesenchymal stem cells - current trends and future prospective. Biosci Rep 2015, 35(2).

  8. Jeyaraman M, Muthu S, Jeyaraman N, Ranjan R, Jha SK, Mishra P. Synovium derived mesenchymal stromal cells (Sy-MSCs): A promising therapeutic paradigm in the management of knee osteoarthritis. Indian J Orthop. 2022;56(1):1–15.

    Article  PubMed  Google Scholar 

  9. Köhnke R, Ahlers MO, Birkelbach MA, Ewald F, Krueger M, Fiedler I, Busse B, Heiland M, Vollkommer T, Gosau M et al. Temporomandibular joint osteoarthritis: regenerative treatment by a stem cell containing advanced therapy medicinal product (ATMP)-An in vivo animal trial. Int J Mol Sci. 2021;22(1).

  10. Matheus HR, Özdemir ŞD, Guastaldi FPS. Stem cell-based therapies for temporomandibular joint osteoarthritis and regeneration of cartilage/osteochondral defects: a systematic review of preclinical experiments. Osteoarthritis Cartilage. 2022;30(9):1174–85.

    Article  PubMed  CAS  Google Scholar 

  11. Cao B, Liu N, Wang W. High glucose prevents osteogenic differentiation of mesenchymal stem cells via LncRNA AK028326/CXCL13 pathway. Biomed Pharmacother. 2016;84:544–51.

    Article  PubMed  CAS  Google Scholar 

  12. Zhang B, Liu N, Shi H, Wu H, Gao Y, He H, Gu B, Liu H. High glucose microenvironments inhibit the proliferation and migration of bone mesenchymal stem cells by activating GSK3β. J Bone Min Metab. 2016;34(2):140–50.

    Article  CAS  Google Scholar 

  13. Vizoso FJ, Eiro N, Costa L, Esparza P, Landin M, Diaz-Rodriguez P, Schneider J, Perez-Fernandez R. Mesenchymal stem cells in homeostasis and systemic diseases: hypothesis, evidences, and therapeutic opportunities. Int J Mol Sci. 2019;20(15).

  14. Fujimaki S, Kuwabara T. Diabetes-Induced dysfunction of mitochondria and stem cells in skeletal muscle and the nervous system. Int J Mol Sci. 2017;18(10).

  15. López-Otín C, Blasco MA, Partridge L, Serrano M, Kroemer G. Hallmarks of aging: an expanding universe. Cell. 2023;186(2):243–78.

    Article  PubMed  Google Scholar 

  16. Li XX, Liu YM, Li YJ, Xie N, Yan YF, Chi YL, Zhou L, Xie SY, Wang PY. High glucose concentration induces endothelial cell proliferation by regulating cyclin-D2-related miR-98. J Cell Mol Med. 2016;20(6):1159–69.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  17. Zhou P, Feng H, Qin W, Li Q. KRT17 from skin cells with high glucose stimulation promotes keratinocytes proliferation and migration. Front Endocrinol (Lausanne). 2023;14:1237048.

    Article  PubMed  Google Scholar 

  18. Li YG, Han BB, Li F, Yu JW, Dong ZF, Niu GM, Qing YW, Li JB, Wei M, Zhu W. High glucose induces Down-Regulated GRIM-19 expression to activate STAT3 signaling and promote cell proliferation in cell culture. PLoS ONE. 2016;11(4):e0153659.

    Article  PubMed  PubMed Central  Google Scholar 

  19. Fadini GP, Ferraro F, Quaini F, Asahara T, Madeddu P. Concise review: diabetes, the bone marrow niche, and impaired vascular regeneration. Stem Cells Transl Med. 2014;3(8):949–57.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  20. Nguyen LT, Hoang DM, Nguyen KT, Bui DM, Nguyen HT, Le HTA, Hoang VT, Bui HTH, Dam PTM, Hoang XTA, et al. Type 2 diabetes mellitus duration and obesity alter the efficacy of autologously transplanted bone marrow-derived mesenchymal stem/stromal cells. Stem Cells Transl Med. 2021;10(9):1266–78.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  21. Curnock R, Yalci K, Palmfeldt J, Jäättelä M, Liu B, Carroll B. TFEB-dependent lysosome biogenesis is required for senescence. Embo J. 2023;42(9):e111241.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  22. Wang C, Qu L. The anti-fibrotic agent nintedanib protects chondrocytes against tumor necrosis factor-ɑ (TNF-ɑ)-induced extracellular matrix degradation. Bioengineered. 2022;13(3):5318–29.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  23. Laavola M, Leppänen T, Hämäläinen M, Vuolteenaho K, Moilanen T, Nieminen R, Moilanen E. IL-6 in osteoarthritis: effects of pine stilbenoids. Molecules. 2018;24(1).

  24. Hu Q, Ecker M. Overview of MMP-13 as a promising target for the treatment of osteoarthritis. Int J Mol Sci. 2021;22(4).

  25. Bedingfield SK, Colazo JM, Di Francesco M, Yu F, Liu DD, Di Francesco V, Himmel LE, Gupta MK, Cho H, Hasty KA, et al. Top-Down fabricated microplates for prolonged, Intra-articular matrix metalloproteinase 13 SiRNA nanocarrier delivery to reduce Post-traumatic osteoarthritis. ACS Nano. 2021;15(9):14475–91.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  26. Li Q, Gao Z, Chen Y, Guan MX. The role of mitochondria in osteogenic, adipogenic and chondrogenic differentiation of mesenchymal stem cells. Protein Cell. 2017;8(6):439–45.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  27. Ren L, Chen X, Chen X, Li J, Cheng B, Xia J. Mitochondrial dynamics: fission and fusion in fate determination of mesenchymal stem cells. Front Cell Dev Biol. 2020;8:580070.

    Article  PubMed  PubMed Central  Google Scholar 

  28. Spurlock B, Tullet J, Hartman JLt, Mitra K. Interplay of mitochondrial fission-fusion with cell cycle regulation: possible impacts on stem cell and organismal aging. Exp Gerontol. 2020;135:110919.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  29. Piao S, Nagar H, Kim S, Lee I, Choi SJ, Kim T, Jeon BH, Kim CS. CRIF1 deficiency induced mitophagy via p66shc-regulated ROS in endothelial cells. Biochem Biophys Res Commun. 2020;522(4):869–75.

    Article  PubMed  CAS  Google Scholar 

  30. Tian Z, Chen Y, Yao N, Hu C, Wu Y, Guo D, Liu J, Yang Y, Chen T, Zhao Y, et al. Role of mitophagy regulation by ROS in hepatic stellate cells during acute liver failure. Am J Physiol Gastrointest Liver Physiol. 2018;315(3):G374–84.

    Article  PubMed  CAS  Google Scholar 

  31. Pickles S, Vigié P, Youle RJ. Mitophagy and quality control mechanisms in mitochondrial maintenance. Curr Biol. 2018;28(4):R170–85.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  32. Basit F, van Oppen LM, Schöckel L, Bossenbroek HM, van Emst-de Vries SE, Hermeling JC, Grefte S, Kopitz C, Heroult M, Hgm Willems P, et al. Mitochondrial complex I Inhibition triggers a mitophagy-dependent ROS increase leading to necroptosis and ferroptosis in melanoma cells. Cell Death Dis. 2017;8(3):e2716.

    Article  PubMed  PubMed Central  Google Scholar 

  33. Guo Y, Guan T, Shafiq K, Yu Q, Jiao X, Na D, Li M, Zhang G, Kong J. Mitochondrial dysfunction in aging. Ageing Res Rev. 2023;88:101955.

    Article  PubMed  CAS  Google Scholar 

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Acknowledgements

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Funding

This work was supported by the Scientific Research Talent Cultivation Program of Stomatology Hospital of Southern Medical University (No. RC202309).

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Authors and Affiliations

  1. Stomatological Hospital, School of Stomatology, Southern Medical University, Guangzhou, 510280, China

    Shuyi Tan, Wangxi Wu, Yifan Chen & Hai Gao

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  1. Shuyi Tan
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  2. Wangxi Wu
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  3. Yifan Chen
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Contributions

Shuyi Tan: Methodology, Formal analysis, Writing-original draft preparation, Writing-review & editing, Funding acquisition. Wangxi Wu: Formal analysis, technical supports, Software. Yifan Chen: Conceptualization, Technical supports. Gao Hai: Writing-review & editing, Supervision, Project administration.

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Correspondence to Hai Gao.

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Tan, S., Wu, W., Chen, Y. et al. High glucose induces senescence in synovial mesenchymal stem cells through mitochondrial dysfunction. BMC Oral Health 25, 569 (2025). https://doiorg.publicaciones.saludcastillayleon.es/10.1186/s12903-025-05938-y

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  • DOI: https://doiorg.publicaciones.saludcastillayleon.es/10.1186/s12903-025-05938-y

Keywords

BMC Oral Health

ISSN: 1472-6831

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