TY - JOUR
T1 - The Fungal Metabolite (+)-Terrein Abrogates Ovariectomy-Induced Bone Loss and Receptor Activator of Nuclear Factor-κB Ligand–Induced Osteoclastogenesis by Suppressing Protein Kinase-C α/βII Phosphorylation
AU - Sakaida, Kyosuke
AU - Omori, Kazuhiro
AU - Nakayama, Masaaki
AU - Mandai, Hiroki
AU - Nakagawa, Saki
AU - Sako, Hidefumi
AU - Kamei, Chiaki
AU - Yamamoto, Satoshi
AU - Kobayashi, Hiroya
AU - Ishii, Satoki
AU - Ono, Mitsuaki
AU - Ibaragi, Soichiro
AU - Yamashiro, Keisuke
AU - Yamamoto, Tadashi
AU - Suga, Seiji
AU - Takashiba, Shogo
N1 - Funding Information:
The authors would like to thank Atsushi Ikeda, Kimito Hirai, and Hidetaka Ideguchi (Department of Pathophysiology-Periodontal Science, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences) for their advice regarding the technical experimental procedures. The authors would like to thank Editage (www.editage.com) for English language editing.
Funding Information:
This study was supported by a Grant-in-Aid for Scientific Research (C) (no. 19K10108, to KO) and Young Investigator (B) (no. 20K18509, to SN) from the Japan Society for the Promotion of Science, Ryobi Memorial Foundation, and Wesco Scientific Promotion Foundation (to KO and HM).
Publisher Copyright:
© Copyright © 2021 Sakaida, Omori, Nakayama, Mandai, Nakagawa, Sako, Kamei, Yamamoto, Kobayashi, Ishii, Ono, Ibaragi, Yamashiro, Yamamoto, Suga and Takashiba.
PY - 2021/6/8
Y1 - 2021/6/8
N2 - 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.
AB - 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.
KW - (+)-terrein
KW - PKC
KW - RANKL
KW - osteoporosis
KW - ovariectomy
UR - http://www.scopus.com/inward/record.url?scp=85108609245&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85108609245&partnerID=8YFLogxK
U2 - 10.3389/fphar.2021.674366
DO - 10.3389/fphar.2021.674366
M3 - Article
AN - SCOPUS:85108609245
VL - 12
JO - Frontiers in Pharmacology
JF - Frontiers in Pharmacology
SN - 1663-9812
M1 - 674366
ER -