Sirtuin 1 in osteoarthritis: Perspectives on regulating glucose metabolism.

Osteoarthritis (OA) is a degenerative disease characterised by articular cartilage destruction, and its complex aetiology contributes to suboptimal clinical treatment outcomes. A close association exists between glucose metabolism dysregulation and OA pathogenesis. Owing to the unique environment of low oxygen and glucose concentrations, chondrocytes rely heavily on their glycolytic capacity, exhibiting distinct spatiotemporal differences. However, under pathological stimulation, chondrocytes undergo excessive glycolytic activity while mitochondrial respiration and other branches of glucose metabolism are compromised. This metabolic change induces cartilage degeneration by reprogramming the inflammatory responses. Sirtuins, a highly conserved family of nicotinamide adenine dinucleotide (NAD+)-dependent deacetylases, regulate glucose metabolism in response to energy fluctuations in different cellular compartments，alleviating metabolic stress. SIRT1, the most extensively studied sirtuin, participates in maintaining glucose homeostasis in almost all key metabolic tissues. While actively contributing to the OA progression and displaying diverse biological effects in cartilage protection, SIRT1's role in regulating glucose metabolism in chondrocytes has not received sufficient attention. This review focuses on discussing the beneficial role of SIRT1 in OA progression from a metabolic regulation perspective based on elucidating the primary characteristics of chondrocyte glucose metabolism. We also summarise the potential mechanisms and therapeutic strategies targeting SIRT1 in chondrocytes to guide clinical practice and explore novel therapeutic directions.

Periodontal ligament cells under mechanical force regulate local immune homeostasis by modulating Th17/Treg cell differentiation.

OBJECTIVES: Improper orthodontic force often causes root resorption or destructive bone resorption. There is evidence that T helper 17 (Th17) cells and regulatory T (Treg) cells may be actively involved in bone remodeling during tooth movement. In a combination of in vitro and in vivo studies, we investigated the effect of human periodontal ligament cells (hPDLCs) on Th17/Treg cells under different orthodontic forces and corticotomy. MATERIAL AND METHODS: hPDLCs were cultured in vitro and subjected to different mechanical forces. The expression of interleukin (IL)-6 and transforming growth factor (TGF)-ß in the supernatant and the mRNA levels of hypoxia inducible factor (HIF)-1α, Notch1, and TGF-ß in hPDLCs were investigated. Supernatants were collected and co-cultured with activated CD4+T cells, and the differentiation of Th17/Treg cells was analyzed by flow cytometry. We also established an animal model of tooth movement with or without corticotomy. The tooth movement distance, alveolar bone height, and root resorption were analyzed using micro-computed tomography. Expression of interleukin (IL)-17A, forkhead Box P3 (Foxp3), and IL-6 were analyzed using immunohistochemistry, while osteoclasts were evaluated by tartrate-resistant acid phosphatase (TRAP) staining. The mRNA levels of IL-17A, IL-6, Foxp3, IL-10, HIF-1α, notch1, and C-X-C motif chemokine ligand 12 (CXCL12) in alveolar bone and gingiva were investigated. RESULTS: Heavy force repressed cell viability and increased the mortality rate of hPDLCs; it also improved the expression of IL-6, declined the expression of TGF-ß, and promoted the mRNA expression level of HIF-1α. The expression of TGF-ß and Notch1 mRNA decreased and then increased. The supernatant of hPDLCs under heavy force promotes the polarization of Th17 cells. The heavy force caused root resorption and decreased alveolar bone height and increased the positive area of IL-17A immunohistochemical staining and the expression of IL-17A, IL-6, HIF-1α, and Notch1 mRNA. Corticotomy accelerated tooth movement, increased the proportion of Foxp3-positive cells, and up-regulated the expression of Foxp3, IL-10, and CXCL12 mRNA. CONCLUSIONS: During orthodontic tooth movement, the heavy force causes root resorption and inflammatory bone destruction, which could be associated with increased expression of Th17 cells and IL-6. Corticotomy can accelerate tooth movement without causing root resorption and periodontal bone loss, which may be related to the increased expression of Treg cells. CLINICAL RELEVANCE: Altogether, this report provides a new perspective on the prevention of inflammatory injury via the regulation of Th17/Treg cells in orthodontics.

E. Coli LPS-induced calcium signaling regulates the expression of hypoxia-inducible factor 1α in periodontal ligament fibroblasts in a non-hypoxia-dependent manner.

Periodontitis, an inflammatory disease, can cause significant damage to the oral tissues which support the teeth. During the early development of periodontitis, periodontal ligament fibroblasts (PDLFs) undergo metabolic reprogramming regulated by hypoxia-inducible factor 1α (HIF-1α), which is strongly linked to the progression of inflammation. However, the precise mechanisms by which PDLFs regulate HIF-1α and its associated metabolic reprogramming during early inflammation remain unclear. This study illustrated that brief and low-dose exposure to Escherichia coli (E. coli) lipopolysaccharide (LPS) can serve as a non-hypoxic stimulus, effectively replicating early periodontal inflammatory reactions. This is evidenced by the upregulation of HIF-1α expression and the activation of HIF-1α-mediated crucial glycolytic enzymes, namely lactate dehydrogenase a, pyruvate kinase, and hexokinase 2, concomitant with an augmentation in the inflammatory response within PDLFs. We observed that the effects mentioned and their impact on macrophage polarization were notably attenuated when intracellular and extracellular stores of Ca2+ were depleted using BAPTA-AM and Ca2+-free medium, respectively. Mechanistically, our findings demonstrated that the transcriptional process of HIF-1α is regulated by Ca2+ during E. coli LPS stimulation, mediated through the signal transducer and activator of transcription 3 (STAT3) pathway. Additionally, we observed that the stabilization of intracellular HIF-1α proteins occurs via the endothelin (ET)-1-endothelin A receptor pathway, independent of hypoxia. Taken together, our research outcomes underscore the pivotal involvement of Ca2+ in the onset of early periodontitis by modulating HIF-1α and glycolysis, thereby presenting novel avenues for early therapeutic interventions.

IL-7-Treated Periodontal Ligament Cells Regulate Local Immune Homeostasis by Modulating Treg/Th17 Cell Polarization.

Both interleukin (IL)-7 and human periodontal ligament cells (hPDLCs) have immunomodulatory properties. However, their combined effect on CD4+T cells has never been studied. In this study, we aimed to investigate the effect of conditioned medium of hPDLCs treated with rhIL-7 on the differentiation of CD4+T cells into regulatory T cells/T helper 17 cells (Treg/Th17 cells) and observe the effect of IL-7 on the immunomodulatory properties of PDLCs. After hPDLCs were treated with different concentrations of rhIL-7 for 24 h, the collected supernatants were used to incubate CD4+T cells for 3 days. A gamma-secretase inhibitor (DAPT) was used to suppress the activation of the Notch1 signaling pathway. Cell proliferation, apoptosis, and necrosis were determined using the cell counting kit-8 (CCK-8) and flow cytometry (FCM). The expressions of forkhead box P3 (Foxp3) in CD4+T cells and transforming growth factor (TGF-ß) and IL-6 in the supernatants were determined by ELISA. Reverse transcription-quantitative PCR (RT-qPCR), and the Western blot (WB) determined the mRNA levels and protein expression of various target factors. FCM was used to detect the mean fluorescence intensity of PD-L1 in hPDLCs and to analyze the differentiation of Treg/Th17 cells. Our results showed that IL-7 promoted proliferation and inhibited apoptosis in hPDLCs, promoted the expression of TGF-ß, PD-L1, Notch1, Jagged1, and Hes1, and inhibited the levels of hypoxia-inducible factor (HIF)-1α and TCF7, whereas the addition of DAPT effectively reversed these effects. Importantly, we found that the conditioned medium of hPDLCs treated with rhIL-7 promoted the polarization of CD4+T cells into Treg cells but had no significant effect on the differentiation of Th17 cells. Our study indicated that treatment of PDLCs with IL-7 can promote the polarization of CD4+T cells into Treg cells by modulating the expression of inflammatory factors and signaling molecules through activating the Notch1 signaling pathway, thus participating in the regulation of immune homeostasis in the periodontal microenvironment.

mTOR participates in the formation, maintenance, and function of memory CD8+T cells regulated by glycometabolism.

Memory CD8+T cells participate in the fight against infection and tumorigenesis as well as in autoimmune disease progression because of their efficient and rapid immune response, long-term survival, and continuous differentiation. At each stage of their formation, maintenance, and function, the cell metabolism must be adjusted to match the functional requirements of the specific stage. Notably, enhanced glycolytic metabolism can generate sufficient levels of adenosine triphosphate (ATP) to form memory CD8+T cells, countering the view that glycolysis prevents the formation of memory CD8+T cells. This review focuses on how glycometabolism regulates memory CD8+T cells and highlights the key mechanisms through which the mammalian target of rapamycin (mTOR) signaling pathway affects memory CD8+T cell formation, maintenance, and function by regulating glycometabolism. In addition, different subpopulations of memory CD8+T cells exhibit different metabolic flexibility during their formation, survival, and functional stages, during which the energy metabolism may be critical. These findings which may explain why enhanced glycolytic metabolism can give rise to memory CD8+T cells. Modulating the metabolism of memory CD8+T cells to influence specific cell fates may be useful for disease treatment.