The Natural Product 6-Gingerol Inhibits Inflammation-Associated Osteoclast Differentiation via Reduction of Prostaglandin E₂ Levels.

Youn-Hwan Hwang,Taesoo Kim,Hyunil Ha,Rajeong Kim

doi:10.3390/ijms19072068

Abstract

The natural product 6-gingerol, a major bioactive component of the rhizome of ginger (Zingiber officinale), is known to have several beneficial effects on health, including anti-inflammatory activity. The present study aimed to investigate the effects of 6-gingerol on osteoclast differentiation associated with inflammation. 6-Gingerol inhibited osteoclast differentiation in co-cultures of osteoblasts and osteoclast precursor cells in response to the pro-inflammatory cytokine, interleukin (IL)-1. However, it did not affect osteoclast precursor differentiation into osteoclasts induced by the receptor activator of nuclear factor-κB ligand (RANKL), a key cytokine causing osteoclast differentiation. 6-Gingerol inhibited IL-1-induced RANKL expression in osteoblasts, and the addition of RANKL to the co-cultures overcame 6-gingerol-mediated inhibition of osteoclast differentiation. It also suppressed IL-1-induced prostaglandin E2 (PGE2) production in osteoblasts, and the addition of exogenous PGE2 reversed 6-gingerol-mediated inhibition of IL-induced RANKL expression in osteoblasts and osteoclast differentiation in the co-cultures. We found that 6-gingerol reduced PGE2 levels by suppressing enzymatic activities of cyclooxygenase and PGE synthase, which cooperatively catalyze the conversion of arachidonic acid to PGE2. Our findings demonstrate that 6-gingerol inhibits IL-1-induced osteoclast differentiation via suppression of RANKL expression in osteoblasts though reduction of PGE2 levels, suggesting its potential use in treating inflammatory bone destruction associated with excessive PGE2 production.

Highlights

Osteoclasts, the sole bone-resorbing cells, are multinucleated giant cells derived from hematopoietic monocyte–macrophage linage cells, and have a pivotal role in the pathogenesis of inflammatory bone disorders, such as rheumatoid arthritis, periodontal diseases, and periprosthetic osteolysis [1,2]
We found that 6-gingerol reduced prostaglandin E2 (PGE2) levels by suppressing enzymatic activities of cyclooxygenase and PGE synthase, which cooperatively catalyze the conversion of arachidonic acid to PGE2
Our findings demonstrate that 6-gingerol inhibits IL-1-induced osteoclast differentiation via suppression of RANKL expression in osteoblasts though reduction of PGE2 levels, suggesting its potential use in treating inflammatory bone destruction associated with excessive PGE2 production

Summary

Introduction

Osteoclasts, the sole bone-resorbing cells, are multinucleated giant cells derived from hematopoietic monocyte–macrophage linage cells, and have a pivotal role in the pathogenesis of inflammatory bone disorders, such as rheumatoid arthritis, periodontal diseases, and periprosthetic osteolysis [1,2]. Down-regulation of RANKL availability via control of RANKL expression and that of its decoy receptor, osteoprotegerin (OPG), has been shown to reduce osteoclast differentiation and bone loss in inflammatory conditions [5,6,7,8]. In recent human and experimental animal studies, the rhizome of Z. officinale has been demonstrated to be effective against inflammatory bone disorders, such as rheumatoid arthritis and osteoarthritis [13,14,15]. 6-gingerol (C17H26O4; molecular weight, 294.39), a primary bioactive phenylpropanoid isolated from Z. officinale, has been shown to have anti-inflammatory, anti-oxidant, anti-tumoral, anti-diabetic, and anti-obesity activities in animal models [16]. We aimed to investigate the effects of 6-gingerol on osteoclast differentiation; the cellular and molecular mechanisms underlying the effects of 6-gingerol on inflammation-associated osteoclast differentiation were characterized

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