Abstract
Yukmijihwang-tang (YJ) has been used to treat diabetes mellitus, renal disorders, and cognitive impairment in traditional medicine. This study aimed to evaluate the anti-osteoporotic effect of YJ on ovariectomy (OVX)-induced bone loss in a rat and receptor activator of nuclear factor kappa-B ligand (RANKL)-mediated osteoclast differentiation in bone marrow macrophages (BMMs). YJ reduced the formation of tartrate-resistant acid phosphatase (TRAP)-positive multinucleated cells (MNCs) in an osteoclast/osteoblast co-culture system by regulating the ratio of RANKL/osteoprotegerin (OPG) by osteoblasts. Overall, YJ reduced TRAP-positive cell formation and TRAP activity and F-actin ring formation. Analysis of the underlying mechanisms indicated that YJ inhibited the activation of the nuclear factor of activated T cell cytoplasmic 1 (NFATc1) and c-Fos, resulting in the suppression of osteoclast differentiation-related genes such as TRAP, ATPase, H+ transporting, lysosomal 38 kDa, V0 subunit d2, osteoclast-associated receptor, osteoclast-stimulatory transmembrane protein, dendritic cell-specific transmembrane protein, matrix metalloproteinase-9, cathepsin K, and calcitonin receptor. YJ also inhibited the nuclear translocation of NFATc1. Additionally, YJ markedly inhibited RANKL-induced phosphorylation of signaling pathways activated in the early stages of osteoclast differentiation including the p38, JNK, ERK, and NF-κB. Consistent with these in vitro results, the YJ-administered group showed considerably attenuated bone loss in the OVX-mediated rat model. These results provide promising evidence for the potential novel therapeutic application of YJ for bone diseases such as osteoporosis.
Highlights
Osteoporosis is a common disorder of bone remodeling characterized by loss of bone mass and density, which results in an increased risk of fractures [1]
We examined the pharmacological effects of YJ on receptor activator of nuclear factor kappa-B ligand (RANKL)-mediated osteoclast differentiation in bone marrow macrophages (BMMs) and animal models of OVX-induced bone destruction
MAPKs, Akt, and signaling pathways, are differentiation, we examined the effects of YJ on RANKL-induced which early activation of fundamental for osteoclast differentiation and function
Summary
Osteoporosis is a common disorder of bone remodeling characterized by loss of bone mass and density, which results in an increased risk of fractures [1]. Osteoporosis is related to various factors, such as age, menopause, and chronic medical conditions, and is correlated with increased mortality in the elderly due to the fact of pathological fractures. It can be classified into two subtypes: type I and type II osteoporosis. Type I osteoporosis, known as postmenopausal osteoporosis, is caused by estrogen deficiency after menopause, and it mainly affects trabecular bone resorption. Type II osteoporosis is called senile osteoporosis and is characterized by age-related loss of cortical and trabecular bone in women and men [2,3,4]. Numerous therapeutic agents are being used to treat osteoporosis
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