Abstract
Osteoporosis is a common disease characterized by a systemic impairment of bone mass and microarchitecture that results in fragility fractures. Severe bone loss due to osteoporosis triggers pathological fractures and consequently decreases the daily life activity and quality of life. Therefore, prevention of osteoporosis has become an important issue to be addressed. We have reported that the fungal secondary metabolite (+)-terrein (TER), a natural compound derived from Aspergillus terreus, has shown receptor activator of nuclear factor-κB ligand (RANKL)–induced osteoclast differentiation by suppressing nuclear factor of activated T-cell 1 (NFATc1) expression, a master regulator of osteoclastogenesis. TER has been shown to possess extensive biological and pharmacological benefits; however, its effects on bone metabolism remain unclear. In this study, we investigated the effects of TER on the femoral bone metabolism using a mouse-ovariectomized osteoporosis model (OVX mice) and then on RANKL signal transduction using mouse bone marrow macrophages (mBMMs). In vivo administration of TER significantly improved bone density, bone mass, and trabecular number in OVX mice (p < 0.01). In addition, TER suppressed TRAP and cathepsin-K expression in the tissue sections of OVX mice (p < 0.01). In an in vitro study, TER suppressed RANKL-induced phosphorylation of PKCα/βII, which is involved in the expression of NFATc1 (p < 0.05). The PKC inhibitor, GF109203X, also inhibited RANKL-induced osteoclastogenesis in mBMMs as well as TER. In addition, TER suppressed the expression of osteoclastogenesis-related genes, such as Ocstamp, Dcstamp, Calcr, Atp6v0d2, Oscar, and Itgb3 (p < 0.01). These results provide promising evidence for the potential therapeutic application of TER as a novel treatment compound against osteoporosis.
Highlights
At present, more than 15 million people have osteoporosis, which is a serious problem in Japan, where the population is extremely aged (Hagino et al, 2021)
We have reported that TER has an inhibitory effect on RANKL or tumor necrosis factor (TNF)-α–induced osteoclastogenesis by suppressing the expression of nuclear factor of activated T-cell c1 (NFATc1), a master regulator of osteoclast differentiation in mouse bone marrow macrophages (Nakagawa et al, 2020)
To elucidate the potential mechanism by which TER inhibits RANKL-induced osteoclastogenesis, we focused on the PKC signaling pathway, which is related to NFATc1 expression on RANK–RANKL signaling
Summary
More than 15 million people have osteoporosis, which is a serious problem in Japan, where the population is extremely aged (Hagino et al, 2021). In the United States, there were more than 2 million osteoporosis-related fractures in 2005, with associated costs of approximately $ 17 billion. By 2023, the annual number of fractures will exceed 3 million, and the U.S healthcare system is projected to cost $ 25 billion (Burge et al, 2007). Osteoporosis is caused by a deficiency of female hormone estrogen, which breaks bone homeostasis between osteoclasts and osteoblasts. Severe bone loss due to osteoporosis triggers pathological fractures and, decreases daily life activity and the quality of life. The prevention of osteoporosis is one of the most urgent issues in Japan (Tilman et al, 2011; Katrin, 2019)
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