Chlorogenic Acid Inhibits Osteoclast Differentiation and Bone Resorption by Down-Regulation of Receptor Activator of Nuclear Factor Kappa-B Ligand-Induced Nuclear Factor of Activated T Cells c1 Expression

Abstract

Excessive osteoclastic bone resorption plays a critical role in inflammation-induced bone loss such as rheumatoid arthritis and periodontal bone erosion. Therefore, identification of osteoclast targeted-agents may be a therapeutic approach to the treatment of pathological bone loss. In this study, we isolated chlorogenic acid (CGA) from fructus of Gardenia jasminoides to discover anti-bone resorptive agents. CGA is a polyphenol with anti-inflammatory and anti-oxidant activities, however, its effects on osteoclast differentiation is unknown. Thus, we investigated the effect of CGA in receptor activator of nuclear factor-kappa B (NF-κB) ligand (RANKL)-induced osteoclast differentiation and RANKL signaling. CGA dose-dependently inhibited RANKL-mediated osteoclast differentiation in bone marrow macrophages (BMMs) without any evidence of cytotoxicity. CGA inhibited the phosphorylation of p38, Akt, extracellular signal-regulated kinase (ERK), and inhibitor of nuclear factor-kappa B (IκB), and IκB degradation by RANKL treatment. CGA suppressed the mRNA expression of nuclear factor of activated T cells c1 (NFATc1), TRAP and OSCAR in RANKL-treated bone marrow macrophages (BMMs). Also, overexpression of NFATc1 in BMMs blocked the inhibitory effect of CGA on RANKL-mediated osteoclast differentiation. Furthermore, to evaluate the effects of CGA in vivo, lipopolysaccharide (LPS)-induced bone erosion study was carried out. CGA remarkably attenuated LPS-induced bone loss based on micro-computed tomography and histologic analysis of femurs. Taken together, our findings suggest that CGA may be a potential treatment option for osteoclast-related diseases with inflammatory bone destruction.

(−)-Epigallocatechin gallate but not chlorogenic acid upregulates osteoprotegerin synthesis through regulation of bone morphogenetic protein-4 in osteoblasts

“…However, the present study observed that EGCG had no significant effect on BMP-4-induced phosphorylation of Smad1 in osteoblast-like MC3T3-E1 cells, indicating that the stimulatory effect of EGCG on BMP-4-induced osteoprotegrin synthesis does not occur through upregulation of the Smad pathway. Recent studies have indicated that Smad-independent pathways, including the MAPK superfamily, may mediate the effects of BMPs in addition to Smad-dependent signaling (11,12). In previous studies by the present authors (24,26), it has been demonstrated that that BMP-4 promotes the activation of p38 MAPK in osteoblast-like MC3T3-E1 cells, resulting in enhanced synthesis of osteocalcin and VEGF.…”

“…CGA has been documented to increase mineralization in rat tibia and improve mechanical properties of the femoral diaphysis (11). In addition, CGA may suppress osteoclastic bone resorption by downregulating the effects of RANK ligand (12 osteoblastic bone formation (13,14), and green tea consumption may be associated with reduced age-related bone loss and fractures in the elderly (13). However, the underlying molecular mechanisms regarding the effects of CGA and EGCG on bone metabolism are currently unknown.…”

The Mechanism of the Osteoprotective Action of a Polyphenol-Rich Aronia melanocarpa Extract during Chronic Exposure to Cadmium is Mediated by the Oxidative Defense System

“…Moreover, other ingredients of A. melanocarpa berries, including vitamin C, vitamin E, β-carotene, and bioelements, which influence the activity of antioxidative enzymes such as manganese, zinc, copper, selenium, and iron [14], might also contribute to the favorable impact of AME. Owing to the relationship between the level of ROS and the rate of bone turnover [24][25][26][27], it should be taken into account that the direct beneficial impact of AME on the oxidative/antioxidative bone status under Cd exposure might also be related, at least partly, to the influence of some ingredients of the extract, including polyphenols and zinc, on the activity of osteoclasts and the process of bone formation [27,31,32]. Chlorogenic acid has also been reported to inhibit osteoclasts differentiation and bone resorption by the downregulation of RANKL [31], whereas quercetin and zinc have been noted to stimulate bone formation [27,[32][33][34].…”

“…Owing to the relationship between the level of ROS and the rate of bone turnover [24][25][26][27], it should be taken into account that the direct beneficial impact of AME on the oxidative/antioxidative bone status under Cd exposure might also be related, at least partly, to the influence of some ingredients of the extract, including polyphenols and zinc, on the activity of osteoclasts and the process of bone formation [27,31,32]. Chlorogenic acid has also been reported to inhibit osteoclasts differentiation and bone resorption by the downregulation of RANKL [31], whereas quercetin and zinc have been noted to stimulate bone formation [27,[32][33][34]. Zinc not only stimulates osteoblasts proliferation and differentiation, but it also suppresses osteoclasts differentiation by, among others, antagonizing NF-κB activation [27,33,34].…”

Amplification by (-)-epigallocatechin gallate and chlorogenic acid of TNF-α-stimulated interleukin-6 synthesis in osteoblasts

“…By contrast, it has been shown that CGA increases mineralization in the tibia, and improves mechanical properties of the femoral diaphysis in rat model (9). In addition, CGA reportedly inhibits osteoclast differentiation and bone resorption by downregulation of receptor activator of nuclear factor κB (RANK) ligand-induced nuclear factor of activated T cell c1 expression (10). However, the exact mechanisms underlying the effects of EGCG or CGA on bone metabolism remain to be elucidated.…”