Naringenin inhibits osteoclastogenesis through modulation of helper T cells‐secreted IL‐4

Abstract

Naringenin (NAR) is a natural predominant flavanone and has a wide range of pharmacological activities. The aim of this study was to investigate the protective mechanisms of NAR on RANKL-induced osteoclastogenesis and osteoclast bone resorption. T cells were divided into four groups under different concentrations of NAR (0, 25, 50, 100 µM). CD4 T cell subsets in different groups were evaluated by flow cytometry. TRAP staining, pit formation assays and F-actin ring immunofluorescent staining were performed. In addition, gene expression of osteoclast-specific markers was analyzed by qPCR and Western blot. Our results showed that compared with the control group, there were relatively fewer Th1 and Th17 cells and more Th2 cells and Treg cells in the NAR groups. Besides, the number of TRAP-positive multinucleated osteoclasts, the areas of bone resorption pits and the size and number of F-actin rings were notably decreased in the bone marrow macrophages (BMMs) treated with T-cell supernatant containing NAR. Moreover, NAR treatment dramatically reduced the expressions of cathepsin K, c-Fos, DC-STAMP, NFATc1, TRAP, and V-ATPase d2 at mRNA and protein levels. However, these effects were abolished by adding a neutralizing antibody against IL-4. In conclusion, NAR suppressed RANKL-induced osteoclastogenesis and osteoclast bone resorption by promoting the release of IL-4 from T cells.

Naringenin is a Potential Anabolic Treatment for Bone Loss by Modulating Osteogenesis, Osteoclastogenesis, and Macrophage Polarization

“…In addition, naringenin improves osteogenic differentiation of rat BMSCs and hPDLSCs through SDF-1/CXCR4 signaling pathway ( Zhang L. et al, 2021 ; Wang et al, 2021 ). Wang et al reported that naringenin impedes osteoclast differentiation by the inhibition of p38 signaling and enhancing helper T cells-secreted IL-4 ( Wang et al, 2014 ; Wang et al, 2018 ). In this study, we confirmed naringenin treatment promoted osteoblastic differentiation of mice BMSCs in vitro and the best concentration was around 10–15 μM.…”

“…In addition, some pioneer studies illustrated the beneficial effects of naringenin on bone diseases such as chronic arthritis and osteoporosis ( Kaczmarczyk-Sedlak et al, 2016 ; Manchope et al, 2018 ). Naringenin could promote osteogenic differentiation of human periodontal ligament stem cells (hPDLSCs) and suppress osteoclastogenesis through enhancement of helper T-cell-secreted IL-4 ( Wang et al, 2018 ; Zhang L. et al, 2021 ; Wang et al, 2021 ). However, most of these studies do not supply high-quality data of naringenin’s effects in vivo .…”

The Natural Flavonoid Naringenin Elicits Analgesia through Inhibition of NaV1.8 Voltage-Gated Sodium Channels

“…Primary cultures of DRG neurons from adult female SD rats (pathogen-free; 140–160 g; Envigo) were made. ,,,,,,− Naringenin treatment was applied overnight at 100 μM using 0.1% DMSO as a vehicle control. While relatively high, a concentration of 100 μM naringenin has been previously reported to be needed to detect biological effects including neuroprotection against LPS-induced dopamine neurotoxicity, inhibition of osteoclast formation, induction of anion transport across the rat colonic mucosa, caspase-3 activity in neutrophils, or suppression of prostate tumor cell proliferation . The next day, cultures were analyzed by whole cell patch clamp to measure Ca 2+ and Na + currents exactly as before. , Recordings were all obtained from small-diameter DRG neurons (size of ∼20 μm ± 2).…”

Naringenin promotes SDF-1/CXCR4 signaling pathway in BMSCs osteogenic differentiation

“…In addition, it was found that naringenin exerted its protective effects by inhibiting osteoclastogenesis and osteoclast bone resorption [19,20]. Therefore, naringenin might have therapeutic potentials for a range of bone diseases such as osteoporosis, repairing of bone defects, alveolar bone resorption and other.…”

“…1), widely present in fruits such as orange, pomelo, and drynaria, is a dihydro-flavonoid compound that shows chemotactic activity [11] and other biological effects such as anti-inflammatory, antioxidative, anticancer and antiadipogenic activities [12][13][14][15], and was also shown to have anti-osteoporotic and anti-osteolytic effects [16]. Several experiments have shown that naringenin could reduce the osteolytic activities of osteoclasts, and improve the osteogenic differentiation and mineralization effects of the osteoblasts in osteolysis-related diseases [16][17][18][19][20]. The aim of the study was to investigate the effect of naringenin on the osteogenic differentiation of BMSCs and its role in the SDF-1/CXCR4 signaling pathway.…”