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Asperpyrone A attenuates RANKL-induced osteoclast formation through inhibiting NFATc1, Ca²⁺ signalling and oxidative stress.

ABSTRACT: Imbalance of osteoblast and osteoclast in adult leads to a variety of bone-related diseases, including osteoporosis. Thus, suppressing the activity of osteoclastic bone resorption becomes the main therapeutic strategy for osteoporosis. Asperpyrone A is a natural compound isolated from Aspergillus niger with various biological activities of antitumour, antimicrobial and antioxidant. The present study was designed to investigate the effects of Asperpyrone A on osteoclastogenesis and to explore its underlining mechanism. We found that Asperpyrone A inhibited RANKL-induced osteoclastogenesis in a dose-dependent manner when the concentration reached 1 µm, and with no cytotoxicity until the concentration reached to 10 µm. In addition, Asperpyrone A down-regulated the mRNA and protein expression of NFATc1, c-fos and V-ATPase-d2, as well as the mRNA expression of TRAcP and Ctsk. Furthermore, Asperpyrone A strongly attenuated the RNAKL-induced intracellular Ca²⁺ oscillations and ROS (reactive oxygen species) production in the process of osteoclastogenesis and suppressed the activation of MAPK and NF-κB signalling pathways. Collectively, Asperpyrone A attenuates RANKL-induced osteoclast formation via suppressing NFATc1, Ca²⁺ signalling and oxidative stress, as well as MAPK and NF-κB signalling pathways, indicating that this compound may become a potential candidate drug for the prevention or treatment of osteoporosis.

SUBMITTER: Chen X

PROVIDER: S-EPMC6850946 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature

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Asperpyrone A attenuates RANKL-induced osteoclast formation through inhibiting NFATc1, Ca<sup>2+</sup> signalling and oxidative stress.

Chen Xi X Wang Chao C Qiu Heng H Yuan Yu Y Chen Kai K Cao Zhen Z Xiang Tan Ren R Tickner Jennifer J Xu Jiake J Zou Jun J

Journal of cellular and molecular medicine 20191015 12

Imbalance of osteoblast and osteoclast in adult leads to a variety of bone-related diseases, including osteoporosis. Thus, suppressing the activity of osteoclastic bone resorption becomes the main therapeutic strategy for osteoporosis. Asperpyrone A is a natural compound isolated from Aspergillus niger with various biological activities of antitumour, antimicrobial and antioxidant. The present study was designed to investigate the effects of Asperpyrone A on osteoclastogenesis and to explore its ...[more]

PMID: 31612613

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Project description:Excessive osteoclast-mediated bone resorption is a critical cause of osteoporosis affecting many aging people worldwide. 5'-Methylthioadenosine (MTA) is a natural sulfur-containing nucleoside normally produced in prokaryotes, plants, yeast, and higher eukaryotes via polyamine metabolism. MTA affects various physiological responses particularly the inflammatory pathway in both normal and cancerous cells and modulates the activation of nuclear factor-κB involved in the osteoclastogenesis signalling process. While several studies have reported that natural products possess anti-osteoclastogenesis phenolics and flavonoids, the effect of nucleoside derivatives on osteoclastogenesis remains limited. Therefore, this study aimed to explore the molecular mechanisms by which MTA affects pre-osteoclastic RAW 264.7 cells as a potential alleviation compound for inflammation-mediated bone loss. Osteoclasts were established by incubating RAW264.7 macrophage cells with receptor activator of nuclear factor kappa B ligand (RANKL) and macrophage colony-stimulating factor, the vital cytokines for activation of osteoclast differentiation. Cell viability was measured using MTT assays at 24, 48, and 72 h. The suppressive effect of MTA on RANKL-induced osteoclast differentiation and function was assessed using tartrate-resistant acid phosphatase (TRAP) analysis, qRT-PCR, and pit formation, Western blot, and immunofluorescence assays. MTA showed dose-dependent anti-osteoclastogenic activity by inhibiting TRAP-positive cell and pit formation and reducing essential digestive enzymes, including TRAP, cathepsin K, and matrix metallopeptidase 9. MTA was observed to suppress the osteoclast transduction pathway through (RANKL)-induced nuclear factor kappa-light-chain-enhancer of activated B cells (NFƘB); it attenuated NFƘB-P65 expression and down-regulated cFos proto-oncogene and nuclear factor of activated T cell c1 (NFATc1), the main regulators of osteoclasts. Moreover, the suppression of RANK (the initial receptor triggering several osteoclastogenic transduction pathways) was observed. Thus, this study highlights the potential of MTA as an effective therapeutic compound for restoring bone metabolic disease by inhibiting the RANK-NFATc1 signal pathway.

Project description:Osteoarthritis (OA) is the most common arthritis with a rapidly increasing prevalence. Disease progression is irreversible, and there is no curative therapy available. During OA onset, abnormal mechanical loading leads to excessive osteoclastogenesis and bone resorption in subchondral bone, causing a rapid subchondral bone turnover, cyst formation, sclerosis, and finally, articular cartilage degeneration. Moreover, osteoclast-mediated angiogenesis and sensory innervation in subchondral bone result in abnormal vascularization and OA pain. The traditional Chinese medicine Panax notoginseng (PN; Sanqi) has long been used in treatment of bone diseases including osteoporosis, bone fracture, and OA. In this study we established two-dimensional/bone marrow mononuclear cell/cell membrane chromatography/time of flight mass spectrometry (2D/BMMC/CMC/TOFMS) technique and discovered that diterbutyl phthalate (DP) was the active constituent in PN inhibiting osteoclastogenesis. Then we explored the therapeutic effect of DP in an OA mouse model with anterior cruciate ligament transaction (ACLT). After ACLT was conducted, the mice received DP (5 mg·kg-1·d-1, ip) for 8 weeks. Whole knee joint tissues of the right limb were harvested at weeks 2, 4, and 8 for analysis. We showed that DP administration impeded overactivated osteoclastogenesis in subchondral bone and ameliorated articular cartilage deterioration. DP administration blunted aberrant H-type vessel formation in subchondral bone marrow and alleviated OA pain assessed in Von Frey test and thermal plantar test. In RANKL-induced RAW264.7 cells in vitro, DP (20 μM) retarded osteoclastogenesis by suppressing osteoclast fusion through inhibition of the ERK/c-fos/NFATc1 pathway. DP treatment also downregulated the expression of dendritic cell-specific transmembrane protein (DC-STAMP) and d2 isoform of the vacuolar (H+) ATPase V0 domain (Atp6v0d2) in the cells. In conclusion, we demonstrate that DP prevents OA progression by inhibiting abnormal osteoclastogenesis and associated angiogenesis and neurogenesis in subchondral bone.

Dataset Information

Asperpyrone A attenuates RANKL-induced osteoclast formation through inhibiting NFATc1, Ca²⁺ signalling and oxidative stress.

Publications

Asperpyrone A attenuates RANKL-induced osteoclast formation through inhibiting NFATc1, Ca<sup>2+</sup> signalling and oxidative stress.

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Asperpyrone A attenuates RANKL-induced osteoclast formation through inhibiting NFATc1, Ca2+ signalling and oxidative stress.

Publications

Asperpyrone A attenuates RANKL-induced osteoclast formation through inhibiting NFATc1, Ca<sup>2+</sup> signalling and oxidative stress.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

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Asperpyrone A attenuates RANKL-induced osteoclast formation through inhibiting NFATc1, Ca²⁺ signalling and oxidative stress.