Quercetin inhibits macrophage polarization through the p‐38α/β signalling pathway and regulates OPG/RANKL balance in a mouse skull model

Abstract

Aseptic loosening caused by wear particles is a common complication after total hip arthroplasty. We investigated the effect of the quercetin on wear particle‐mediated macrophage polarization, inflammatory response and osteolysis. In vitro, we verified that Ti particles promoted the differentiation of RAW264.7 cells into M1 macrophages through p‐38α/β signalling pathway by using flow cytometry, immunofluorescence assay and small interfering p‐38α/β RNA. We used enzyme‐linked immunosorbent assays to confirm that the protein expression of M1 macrophages increased in the presence of Ti particles and that these pro‐inflammatory factors further regulated the imbalance of OPG/RANKL and promoted the differentiation of osteoclasts. However, this could be suppressed, and the protein expression of M2 macrophages was increased by the presence of the quercetin. In vivo, we revealed similar results in the mouse skull by μ‐CT, H&E staining, immunohistochemistry and immunofluorescence assay. We obtained samples from patients with osteolytic tissue. Immunofluorescence analysis indicated that most of the macrophages surrounding the wear particles were M1 macrophages and that pro‐inflammatory factors were released. Titanium particle‐mediated M1 macrophage polarization, which caused the release of pro‐inflammatory factors through the p‐38α/β signalling pathway, regulated OPG/RANKL balance. Macrophage polarization is expected to become a new clinical drug therapeutic target.

Quercetin as an Agent for Protecting the Bone: A Review of the Current Evidence

“…Quercetin at 50 or 100 mg/kg per day inhibited titanium-particle-induced osteolysis by increasing bone area and decreasing osteoclast formation in vivo [ 45 ]. In another study, female C57BL/6 mice with titanium-particle-induced osteolysis and treated with quercetin (2 or 5 mg/kg/day) for 14 days had higher BV/TV but lower total porosity, erosion area and osteoclast number [ 46 ].…”

“…Numerous studies have found that quercetin inhibits the formation of osteoclast-like cells (evidenced by TRAP-positive multinucleated cells), bone resorption pit and F-actin ring formation in RAW264.7 cells, human peripheral-blood mononuclear cells (PBMCs) or bone-marrow macrophages treated with macrophage colony-stimulating factor (M-CSF) and/or RANKL [ 31 , 32 , 45 , 46 , 68 , 74 , 94 , 95 , 96 ]. In another study using highly purified rabbit osteoclasts, treatment with 50 μM quercetin caused a reduction in the total area of resorption pit [ 97 ].…”

“…[ 85 ]. In RAW264.7 cells or bone-marrow macrophages treated with M-CSF and RANKL to generate osteoclast-like cells, it was found that expression of osteoclast markers (RANK, c-Fos, NFATc1, TRAP, CTSK, CalcR, alpha v integrin, MMP-9, H + ATPase and Dc-Stamp) was inhibited by quercetin [ 31 , 32 , 45 , 46 , 94 , 95 , 96 ], quercetin-6- C -β- d -glucopyranoside [ 32 ], quercetin-loaded hydroxyapatite [ 68 ], quercitrin [ 83 ] and quercitrin-nanocoated implant surfaces [ 51 ]. Likewise, treatment with quercetin yielded downregulation of TRAP, MMP-9, CTSK, RANK and TRAF6 expression in RAW264.7 cells stimulated by LPS.…”

“…Later on, Tang et al (2019) indicated that both quercetin and quercitrin reduced the LPS-stimulated elevation in NO• and ROS production in RAW264.7 [ 99 ]. In the following year, quercetin was shown to inhibit the expression of inducible nitric oxide synthase (iNOS) in RAW264.7 cells treated with M-CSF and RANKL [ 46 ].…”

Quercetin-Based Nanocomposites as a Tool to Improve Dental Disease Management

“…On the one hand, the increase in bacterial number is related to a reduction of innate and adaptative immunity; on the other hand, the growth of drug-resistant bacterial strains makes the treatment of these diseases a challenge. In light In recent years, the focus on this compound has increased due to its several therapeutic properties, such as anti-inflammatory [13][14][15], antioxidant [16], anti-tumoral [17], anti-ulcer [18], anti-allergy [19], anti-diabetic [20], antihypertensive [21], immunomodulatory [22], and gastroprotective [23] activities. Moreover, the proven antiviral [24] activity has suggested its administration in the prevention and treatment of SARS-CoV-2-related disease [25].…”