Hinokitiol inhibits RANKL-induced osteoclastogenesis in vitro and prevents ovariectomy-induced bone loss in vivo

Yanben Wang; Qichang Yang; Ziyuan Fu; Peng Sun; Tan Zhang; Kelei Wang; Xinyu Li; Yu Qian

doi:10.1016/j.intimp.2021.107619

Hinokitiol inhibits RANKL-induced osteoclastogenesis in vitro and prevents ovariectomy-induced bone loss in vivo

Int Immunopharmacol. 2021 Jul:96:107619. doi: 10.1016/j.intimp.2021.107619. Epub 2021 Apr 5.

Authors

Yanben Wang¹, Qichang Yang², Ziyuan Fu¹, Peng Sun², Tan Zhang³, Kelei Wang¹, Xinyu Li¹, Yu Qian⁴

Affiliations

¹ Department of Orthopedics, Shaoxing Hospital, Zhejiang University School of Medicine, Shaoxing, Zhejiang 312000, China; Department of Orthopedics, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310000, China.
² Department of Orthopedics, Shaoxing Hospital, Zhejiang University School of Medicine, Shaoxing, Zhejiang 312000, China; The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, China.
³ Department of Orthopedics, Shaoxing Hospital, Zhejiang University School of Medicine, Shaoxing, Zhejiang 312000, China.
⁴ Department of Orthopedics, Shaoxing Hospital, Zhejiang University School of Medicine, Shaoxing, Zhejiang 312000, China. Electronic address: doctor120@hotmail.com.

PMID: 33831806
DOI: 10.1016/j.intimp.2021.107619

Abstract

Osteoporosis is a metabolic bone-loss disease characterized by abnormally excessive osteoclast formation and bone resorption. Identification of natural medicines that can inhibit osteoclastogenesis, bone resorption, and receptor activator of nuclear factor-κB ligand (RANKL)-induced signaling is necessary for improved treatment of osteoporosis. In this study, hinokitiol, a tropolone-related compound extracted from the heart wood of several cupressaceous plants, was found to inhibit RANKL-induced osteoclast formation and bone resorption in vitro. Hinokitiol inhibited early activation of the ERK, p38, and JNK-MAPK pathways, thereby suppressing the activity and expression of downstream factors (c-Jun, c-Fos, and NFATC1). Consistent with the above in vitro findings, hinokitiol treatment protected against ovariectomy-induced bone loss in vivo. Collectively, our results imply that hinokitiol can potentially serve as an effective agent for treating osteoclast-induced osteoporosis.

Keywords: Hinokitiol; MAPK; NFATc1; Osteoclast; RANKL.

MeSH terms

Actins / antagonists & inhibitors
Animals
Bone Density Conservation Agents / pharmacology*
Bone Density Conservation Agents / therapeutic use
Bone Resorption / diagnostic imaging
Bone Resorption / etiology
Bone Resorption / prevention & control*
Cell Line
Disease Models, Animal
Female
MAP Kinase Signaling System / drug effects
Macrophages / drug effects
Mice
Mice, Inbred C57BL
Monoterpenes / pharmacology*
Monoterpenes / therapeutic use
NFATC Transcription Factors / antagonists & inhibitors
Osteoclasts / drug effects
Osteogenesis / drug effects*
Osteogenesis / genetics
Osteoporosis / metabolism*
Osteoporosis / prevention & control*
Ovariectomy / adverse effects
Primary Cell Culture
Proto-Oncogene Proteins c-fos / antagonists & inhibitors
Proto-Oncogene Proteins c-jun / antagonists & inhibitors
RANK Ligand / toxicity
Transcription Factor AP-1 / antagonists & inhibitors
Tropolone / analogs & derivatives*
Tropolone / pharmacology
Tropolone / therapeutic use

Substances

Actins
Bone Density Conservation Agents
Monoterpenes
NFATC Transcription Factors
Nfatc1 protein, mouse
Proto-Oncogene Proteins c-fos
Proto-Oncogene Proteins c-jun
RANK Ligand
Transcription Factor AP-1
Tropolone
beta-thujaplicin