Rutin promotes osteogenic differentiation of periodontal ligament stem cells through the GPR30-mediated PI3K/AKT/mTOR signaling pathway

Abstract

Rutin is one of the flavonoids found in fruits and vegetables. Recent reports have revealed that rutin is a major player in proliferation and bone development. However, data on how rutin regulates the proliferation of periodontal ligament stem cells (PDLSCs), as well as the differentiation of osteogenic cells are scanty. Here, our findings showed that rutin enhanced PDLSCs proliferation, increased ALP activity, and matrix mineralization. Moreover, rutin significantly promoted the expression of osteogenic genes and elevated phosphorylated AKT and mTOR. Treatment with LY294002 reversed these effects by inhibiting PI3K. We also found that the expression levels of GPR30 were increased by rutin. Interestingly, this upregulation was not altered after the addition of LY294002. In addition, G15, a selective antagonist of GPR30, could reduce the beneficial effects induced by rutin and interfere with the modulation of PI3K/AKT/mTOR signal transduction. Collectively, our findings revealed that rutin increased proliferation and osteogenic differentiation of PDLSCs through GPR30-mediated PI3K/AKT/mTOR signal transduction. Therefore, it could be deduced that rutin as a certain flavonoid possesses therapeutic value for periodontal bone regeneration and tissue engineering. Impact statement In our study, the effects and mechanisms of rutin on the osteogenic differentiation and proliferation of PDLSCs were investigated. Our findings might provide basic knowledge and guidance to understand and use rutin in the bioengineering of the periodontal tissues and regeneration of bones. The following is a short description of the main findings: rutin promotes the osteogenic differentiation and proliferation of PDLSCs; PI3K/AKT/mTOR signal pathway mediates the effects of rutin on PDLSCs; rutin activates PI3K/AKT/mTOR signal pathway via GPR30.

G Protein-Coupled Estrogen Receptor Mediates Cell Proliferation through the cAMP/PKA/CREB Pathway in Murine Bone Marrow Mesenchymal Stem Cells

“…In this study, we further showed it is also expressed in rat and mice osteogenic cells. GPER-1 has been suggested to play a role in bone development [7,12,27], and mediate the effect of chemicals, such as rutin and ligustilide, on osteogenic differentiation [28,29]. A study showed that GPER-1 activation promotes osteogenesis on the pre-osteoblast cells, MC3T3E1, through the AMPK/anti-acetyl-CoA carboxylase (ACC) pathway [30].…”

Phytochemicals in Chinese Chive (Allium tuberosum) Induce the Skeletal Muscle Cell Proliferation via PI3K/Akt/mTOR and Smad Pathways in C2C12 Cells

“…On the other hand, in cells treated with a high concentration of compound 7 , the expression level of MyoD was not different compared to that of the non-treated cells. Flavonoids and plant extracts containing flavonoid derivatives have been reported to activate osteogenic and myogenic differentiation as well as glucose resistance regulation via PI3K/Akt/mTOR pathways [ 25 , 26 , 27 , 28 ]. Meanwhile, amino acids are important regulators of the activation of mTOR complex 1, which regulates essential cellular processes such as growth, proliferation, and survival [ 29 ].…”

Biochanin A Regulates Key Steps of Inflammation Resolution in a Model of Antigen-Induced Arthritis via GPR30/PKA-Dependent Mechanism

“…GPR30 is a common target for isoflavones to promote a rapid cellular signaling (Khan et al, 2015;Liu et al, 2018), and it is expressed in the central nervous system, skin, adipose tissue, and skeletal muscle, as well as in monocytes, eosinophils, and neutrophils (Rettew et al, 2010;Notas et al, 2020). Furthermore, GPR30 expression was also observed in cartilage and bone during an inflammatory response (Kang et al, 2015;Ribeiro et al, 2020;Zhao et al, 2020). Activation of GPR30 results in increased intracellular levels of cyclic adenosine monophosphate (cAMP) and activates the PKA signaling pathway, the best known cAMP effector (Mizukami, 2010;Liu et al, 2018) and an essential pathway for a successful inflammation resolution (Lima et al, 2017;Tavares et al, 2020).…”