A relation between osteoclastogenesis inhibition and membrane-type estrogen receptor GPR30

Abstract

Disruption of the cooperative balance between osteoblasts and osteoclasts causes various bone disorders, some of which are because of abnormal osteoclast recruitment. Osteoporosis, one of the bone disorders, is not effectively treated by currently available medicines. In addition to the development of novel drugs for palliative treatment, the exploitation of novel compounds for preventive treatment is important in an aging society. Quercetin, a major flavonoid found in many fruits and vegetables, has been expected to inhibit cancer and prevent several diseases because of its anti-inflammatory and estrogenic functions. It has been reported that quercetin has the potential to reduce bone resorption, but the mechanism by which this compound affects the differentiation of osteoclasts remains unknown. Here, using a bone marrow cell-based in vitro osteoclast differentiation system from bone marrow cells, we found that the ability of quercetin to inhibit osteoclastogenesis was related to its estrogenic activity. The inhibition was partially blocked by a specific antagonist for the nuclear receptor estrogen receptor α, but a specific antagonist of the membrane-type receptor GPR30 completely ablated this inhibition. Furthermore, quercetin suppressed the transient increase of Akt phosphorylation induced by the stimulation of macrophage colony-stimulating factor and receptor activator of NF-κB ligand with no effect on MAPK phosphorylation, suggesting exquisite crosstalk between cytokine receptor and G-protein coupled receptor signaling. These results indicate the important role of GPR30 in osteoclast differentiation and provide new insights to the development of new treatments for osteoporosis.

The role of GPCRs in bone diseases and dysfunctions

“…3). Recent advances have shed light on the mechanisms of osteoclast 9,76,86,87 and chondrocyte 88–92 differentiation and function; however, how GPCR signaling regulates osteoclasts and chondrocytes remains largely unknown. The expression of multiple GPCRs by different bone cells and the activation of multiple signaling pathways by a single GPCR, together with the wide variety of GPCRs and the signaling redundancy often seen downstream of GPCR activation, pose significant challenges to clarifying a given GPCR’s function in bone development and disease.…”

Exploring the potential therapeutic effect of Eucommia ulmoides–Dipsaci Radix herbal pair on osteoporosis based on network pharmacology and molecular docking technology

“…36,37 Several studies illustrated that quercetin suppressed the phosphorylation of Akt and affected nuclear factor kappa B (NF-kB), AP-1 and NFATc1 to inhibit osteoclast differentiation. 38,39 Activation of NF-kB signaling pathway by RANKL, TNF-a or IL-1 can induce osteoclast differentiation to extend osteoclast survival and increase bone resorption. 40 Genistein directly suppressed osteoclastic differentiation induced by TNF-a and suppressed the expression of two transcription factors c-Fos and NFATc1 caused by NF-kB up regulation to inhibit bone resorption.…”

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

“…53 Similarly, our results confirmed that GPR30 could be activated by rutin. Although the G15 used in this experiment is a highly specific antagonist with no affinity for other receptors of estrogen, 54 the specific binding mode of rutin to GPR30 needs further study in the future. Besides, to further develop the understanding of the underlying mechanisms, more researches are also necessary.…”