Abstract
Postmenopausal osteoporosis (PMOP) is a metabolic bone disease characterized by decreased bone density and strength due to the imbalance between osteogenesis and osteoclastogenesis. Postmenopausal estrogen withdrawal increases proinflammatory cytokines and increases the serum level of Receptor activator of NF-kB ligand (RANKL)/Osteoprotegerin (OPG), which then leads to the overactivation of osteoclastogenesis. Tetrandrine, a bis-benzylisoquinoline alkaloid, has been widely used in the treatment of rheumatoid arthritis clinically in China. Here, we demonstrate that tetrandrine significantly prevented ovariectomy-induced bone loss and inhibited RANKL-induced osteoclastogenesis. In vivo, we found that intraperitoneal injection of tetrandrine (30 mg/kg) every other day markedly reduced bone loss in ovariectomized mice and the serum levels of TRAcp5b, TNF-a, IL-6, CTX-I, and RANKL/OPG were significantly decreased. In vitro, we found that tetrandrine significantly inhibited osteoclast differentiation in bone marrow monocytes (BMMs) and RAW264.7 cells according to the results of osteoclastogenesis‐related gene expression, tartrate-resistant acid phosphatase (TRAP) staining and actin-ring formation as well as bone resorption assay. Mechanistically, tetrandrine inhibited RANKL‐induced osteoclastogenesis by suppressing NF-kB, Ca2+, PI3K/AKT, and MAPKs signaling pathways. Taken together, our findings suggest that tetrandrine suppresses osteoclastogenesis through modulation of multiple pathways and has potential value as a therapeutic agent for PMOP, especially for those suffering from RA and PMOP at the same time.
Highlights
Postmenopausal osteoporosis is the most common type of primary osteoporosis, and, resulted from global aging, its incidence is increasing recently (Compston et al, 2019)
The results indicated that M-CSF (20 ng/ml) cannot induce RAW264.7 or BMMS to osteoclasts without RANKL
For RAW 264.7 cells treated with tetrandrine (0, 0.125, 0.25, 0.5, or 1 mM), M-CSF (20 ng/ml) and RANKL (50 ng/ml), the number of tartrate-resistant acid phosphatase (TRAP)-positive cells reduced in a dosedependent manner compared with the control groups
Summary
Postmenopausal osteoporosis is the most common type of primary osteoporosis, and, resulted from global aging, its incidence is increasing recently (Compston et al, 2019). The cytokine M‐CSF is a prerequisite for the induction of osteoclast It facilitated the proliferation and survival of osteoclast precursors and made it possible for RANKL to bind to RANK on the cell membrane. (Shinohara et al, 2008; Cao, 2018; Liu et al, 2018)The binding of RANKL to the RANK receptor activated multiple intracellular signal pathways, including NF-kB, MAPKs, Ca2+, and PI3K/AKT pathways, and thereby initiates osteoclast differentiation and bone resorption by inducing transcription and expression of osteoclast associated genes, such as tartrate-resistant acid phosphatase (TRAP), cathepsin K (CTSK), c-Fos, and NFATc1 (Nemeth et al, 2011; Sobacchi et al, 2013; Croft et al, 2017). PMOP has a strong correlation with rheumatoid arthritis considering inflammatory cytokines played key roles in both of them. We carried out this study to investigate the effects of tetrandrine on ovariectomy-induced bone loss and to explore the possible underlying molecular mechanisms
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
