Hesperetin Alleviates the Inhibitory Effects of High Glucose on the Osteoblastic Differentiation of Periodontal Ligament Stem Cells

Abstract

Hesperetin (3′,5,7-trihydroxy-4-methoxyflavanone) is a metabolite of hesperidin (hesperetin-7-O-rutinoside), which belongs to the flavanone subgroup and is found mainly in citrus fruits. Hesperetin has been reported to be an effective osteoinductive compound in various in vivo and in vitro models. However, how hesperetin effects osteogenic differentiation is not fully understood. In this study, we investigated the capacity of hesperetin to stimulate the osteogenic differentiation of periodontal ligament stem cells (PDLSCs) and to relieve the anti-osteogenic effect of high glucose. Osteogenesis of PDLSCs was assessed by measurement of alkaline phosphatase (ALP) activity, and evaluation of the mRNA expression of ALP, runt-related gene 2 (Runx2), osterix (OSX), and FRA1 as osteogenic transcription factors, as well as assessment of protein expression of osteopontin (OPN) and collagen type IA (COLIA). When PDLSCs were exposed to a high concentration (30 mM) of glucose, osteogenic activity decreased compared to control cells. Hesperetin significantly increased ALP activity at doses of 1, 10, and 100 µM. Pretreatment of cells with hesperetin alleviated the high-glucose-induced suppression of the osteogenic activity of PDLSCs. Hesperetin scavenged intracellular reactive oxygen species (ROS) produced under high glucose condition. Furthermore, hesperetin increased the activity of the PI3K/Akt and β-catenin pathways. Consistent with this, blockage of Akt or β-catenin diminished the protective effect of hesperetin against high glucose-inhibited osteogenic differentiation. Collectively, our results suggest that hesperetin alleviates the high glucose-mediated suppression of osteogenic differentiation in PDLSCs by regulating ROS levels and the PI3K/Akt and β-catenin signaling pathways.

Osteogenic Effect of Inducible Nitric Oxide Synthase (iNOS)-Loaded Mineralized Nanoparticles on Embryonic Stem Cells

“…NO is known to induce osteogenesis of ESCs through activation of canonical Wnt signaling [21]. More recently, our group has reported that Wnt signaling is associated with the osteogenic differentiation of stem cells under various experimental conditions [41][42][43]. Based on previous studies and our present data, we suggest that NO can activate wide spectrum of signaling pathways involved in the osteogenic differentiation of stem cells.…”

Effects of Plants on Osteogenic Differentiation and Mineralization of Periodontal Ligament Cells: A Systematic Review

“…Two studies (Jittapiromsak et al ., ; Kim et al ., ) did not provide any information about the cell proliferation assay, and six studies analysed cell proliferation (Gao et al ., ; Nowwarote et al ., ; Pei et al ., ; Boonanantanasarn et al ., ; Chantarawaratit et al ., ; Kim et al ., ). Furthermore, six studies used the MTT assay to evaluate cell proliferation.…”

High glucose microenvironments inhibit the proliferation and migration of bone mesenchymal stem cells by activating GSK3β

“…The physiological functions of stems cells are altered by different microenvironments, such as high glucose, inflammation, and hypoxia [9][10][11]. We found that high glucose microenvironments at 16.5 mM affect proliferation, differentiation, and mineralization of rat mandibular osteoblasts compared with physiological concentration of glucose (5.5 mM) [12], although the process of stem cell-mediated bone regeneration requires the simultaneous interplay of a variety of factors.…”