Abstract
Dihydromyricetin (DMY), the main flavonoid component of Ampelopsis grossedentata, possesses pharmacological activities useful for treatment of diseases associated with inflammation and oxidative damage. Because osteoclasts are often involved in chronic low-grade systemic inflammation and oxidative damage, we hypothesized that DMY may be an effective treatment for osteoclast-related diseases. The effects of DMY on osteoclast formation and activity were examined in vitro. Female C57BL/6 mice were ovariectomized to mimic menopause-induced bone loss and treated with DMY, and femur samples were subjected to bone structure and histological analysis, serum biochemical indicators were also measured. DMY suppressed the activation of nuclear factor-κB, c-Fos and mitogen-activated protein kinase, and prevented production of reactive oxygen species. DMY decreased expression of osteoclast-specific genes, including Trap, Mmp-9, Cathepsin K, C-Fos, Nfatc1, and Rank. In addition, DMY prevented bone loss and decreased serum levels of tumor necrosis factor-α, interleukin-1β, and interleukin-6, and with a decrease in the ratio between receptor activator of nuclear factor-κB (RANK) ligand (RANKL) and osteoprotegerin (OPG) in vivo. These findings demonstrate that DMY attenuates bone loss and inhibits osteoclast formation and activity through modulation of multiple pathways both upstream and downstream of RANKL signaling. DMY may thus be a useful option for treatment of osteoclast-related diseases such as rheumatoid arthritis and osteoporosis.
Highlights
Osteoporosis is a systemic skeletal disorder characterized by low bone mass and structural deterioration of bone tissue resulting in fragility and susceptibility to fractures, it has become a major public health problem
Since nuclear factor-κB (NF-κB) pathways are essential for osteoclastogenesis (Boyle et al, 2003), we propose that there is an impact of DMY in osteoclastogenesis
RAW264.7 and Bone marrow mononuclear cells (BMMCs) were treated with RANKL (50 ng/ml, R&D Systems China) and various concentrations of DMY (12.5, 25, 50, or 75 μM) to induce osteoclast formation, and the culture medium was replaced every day
Summary
Osteoporosis is a systemic skeletal disorder characterized by low bone mass and structural deterioration of bone tissue resulting in fragility and susceptibility to fractures, it has become a major public health problem. Pro-inflammatory cytokines such as tumor necrosis factor-α (TNF-α), interleukin (IL-6), and interleukin-1β (IL-1β) stimulate osteoclast differentiation and activity by increasing production of RANKL (Zupan et al, 2012; Boyce et al, 2015). RANKL binds to RANK on osteoclast precursor-like cell line and mature osteoclasts, through TNF receptor-associated factor 6 (TRAF6), leading to the activation of several signaling cascades. The activated signaling pathways include nuclear factor-κB (NF-κB), ERK, c-Jun, N-terminal kinase (JNK), and p38 mitogen-activated protein kinase (MAPK) (Asagiri and Takayanagi, 2007). These pathways play essential roles in osteoclastogenesis, such that influence on any one of them may have profound effects on osteoclast differentiation and bone resorption (Teitelbaum and Ross, 2003). The present study aimed to investigate the activity of DMY on osteoclast formation and function using both in vivo and in vitro models
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