Cinchonine inhibits osteoclast differentiation by regulating TAK1 and AKT, and promotes osteogenesis

Jo, You-Jin; Lee, Hyein; Kim, Na-Rae; Hwang, Donghyun; Lee, Jiae; Lee, Gong-Rak; Hong, Seong-Eun; Lee, Hana; Kwon, Minjeong; Kim, Nam Young; Kim, Hyun Jin; Park, Jin Ha; Kang, Ye Hee; Kim, Han Sung; Lee, Soo Young; Jeong, Woojin

doi:10.1002/jcp.29968

Cited by 19 publications

(19 citation statements)

References 46 publications

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“…Key genes that govern OCs differential and function were behind the changes of these cell behaviors. We confirmed that D7 down-regulated the expression of essential genes and proteins for osteoclastogenesis and bone resorption, including Traf6, Nfatc1, and Ctsk [ 33 , 45 ]. ROS are critical intracellular signaling mediators that connect OC essential genes function, as well as the key regulator of cellular redox state that determines the post-translational modification of protein kinases and phosphatases in OC [ 46 , 47 ].…”

Section: Discussionsupporting

confidence: 60%

Network Pharmacology Deciphers the Action of Bioactive Polypeptide in Attenuating Inflammatory Osteolysis via the Suppression of Oxidative Stress and Restoration of Bone Remodeling Balance

Cui

Feng

Chen

et al. 2022

Oxidative Medicine and Cellular Longevity

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Oxidative stress involves enormously in the development of chronic inflammatory bone disease, wherein the overproduction of reactive oxygen species (ROS) negatively impacts the bone remodeling via promoting osteoclastogenesis and inhibiting osteogenesis. Lacking effective therapies highlights the importance of finding novel treatments. Our previous study screened a novel bioactive peptide D7 and demonstrated it could enhance the cell behaviors and protect bone marrow mesenchymal stem cells (BMSCs). Since BMSCs are progenitor cells of osteoblast (OB), we therefore ask whether D7 could also protect against the progress of inflammatory osteolysis. To validate our hypothesis and elucidate the underlying mechanisms, we first performed network pharmacology-based analysis according to the molecule structure of D7, and then followed by pharmacological evaluation on D7 by in vitro lipopolysaccharide(LPS)-induced models. The result from network pharmacology identified 20 candidate targets of D7 for inflammatory osteolysis intervention. The further analysis of Gene Ontology (GO)/KEGG pathway enrichment suggested the therapeutic effect of D7 may primarily affect osteoclast (OC) differentiation and function during the inflammatory osteolysis. Through validating the real effects of D7 on OC and OB as postulated, results demonstrated suppressive effects of D7 on LPS-stimulated OC differentiation and resorption, via the inhibition on OC marker genes. Contrarily, by improving the expression of OB marker genes, D7 displayed promotive effects on OB differentiation and alleviated LPS-induced osteogenic damage. Further mechanism study revealed that D7 could reduce LPS-induced ROS formation and strengthen antioxidants expressions in both OC and OB precursors, ameliorating LPS-triggered redox imbalance in bone remodeling. Taken together, our findings unveiled therapeutic effects of D7 against LPS-induced inflammatory osteolysis through the suppression of oxidative stress and the restoration of the bone remodeling process, providing a new therapeutic candidate for chronic inflammatory bone diseases.

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Section: Discussionsupporting

confidence: 60%

Network Pharmacology Deciphers the Action of Bioactive Polypeptide in Attenuating Inflammatory Osteolysis via the Suppression of Oxidative Stress and Restoration of Bone Remodeling Balance

Cui

Feng

Chen

et al. 2022

Oxidative Medicine and Cellular Longevity

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“…In addition, we con rmed that D7 reduces the expression of early osteoclast markers NFATc1 and TRAF6 at the gene and protein levels. NFATc1 is a key determinant of osteoclastogenesis [6]. CTSK, an essential enzyme released when osteoclasts undergo bone resorption [49] is regulated by NFATc1 [50], and the expression of CTSK was reduced by D7 compared with the control group.…”

Section: Discussionmentioning

confidence: 99%

“…The interaction between bone formation caused by osteoblasts and bone resorption caused by osteoclasts is tightly regulated during the bone remodeling process [6]. Osteogenic proteins are produced by osteoblasts, such as alkaline phosphatase (ALP) and type I collagen (COL1).…”

Section: Introductionmentioning

confidence: 99%

Cyclic Peptide D7 Promotes Osteogenesis and Inhibits Osteoclastogenesis by Regulating Redox Balance of Bone Remodeling

Cui

Feng

Chen

et al. 2021

Preprint

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BackgroundMilitary training usually causes excessive physical burden to the bones and joints of soldiers, which in turn disturbs the balance of bone homeostasis and eventually induces bone metabolic diseases. In our previous studies, a cyclic peptide D7 in was characterized through phage display technology from the peptide phage display library (Ph.D.‑C7C) and was proven to enhance the adhesion, expansion, and proliferation of bone marrow mesenchymal stem cells (BMSCs) on the biomaterial scaffold. However, we found that cyclic peptide D7 also has a certain affinity for mouse calvarial osteoblast precursor cells (OPCs) and bone marrow-derived monocytes/macrophages (BMMs). To investigate whether D7 can protect physiological bone remodeling and maintain bone homeostasis, we elucidated the mechanisms by which D7 promotes osteogenesis and inhibits osteoclastogenesis. MethodsThe affinity of D7 peptide towards calvarial OPCs and BMMs was investigated using fluorescence cytochemistry. The roles of D7 in osteogenesis and osteoclastogenesis by regulating redox balance was confirmed by cell counting kit-8, special stain assays (alkaline phosphatase stain, alizarin red stain and tartrate‐resistant alkaline phosphatase stain), fluorescence cytochemistry, western blotting, quantitative real-time polymerase chain reaction. ResultsThe results demonstrated that D7 promoted the osteogenesis of calvarial OPCs by upregulating the expression of osteogenic differentiation factors. In contrast, D7 inhibited osteoclast differentiation and resorption by downregulating the expression of osteoclast phenotype marker. We further identified that these phenomenons may be due to the suppressive effect of D7 on reactive oxygen species production and the enhancing effect on antioxidant expression in both OPCs and BMMs, thereby regulating the redox balance of bone remodeling.ConclusionsCyclic peptide D7 could maintain bone homeostasis by regulating redox balance and provide a potential approach to strengthen the skeletal fitness of soldiers and prevent the occurrence of bone metabolic diseases.

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“…Messenger RNA (mRNA) levels of each gene were normalized to actin mRNA level as an internal control gene. Most primers were previously described (Hong et al, 2017;Jo et al, 2020;J. Lee, Son, et al, 2019).…”

Section: Isolation Of Dna and Rna Reversetranscription And Real-time Polymerase Chain Reaction (Pcr) Analysismentioning

confidence: 99%

Flunarizine inhibits osteoclastogenesis by regulating calcium signaling and promotes osteogenesis

Kim

Lee

et al. 2021

Journal Cellular Physiology

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Many bone diseases such as osteoporosis and periodontitis are caused by hyperactivation of osteoclasts. Calcium (Ca 2+ ) signals are crucial for osteoclast differentiation and function. Thus, the blockade of Ca 2+ signaling may be a strategy for regulating osteoclast activity and has clinical implications. Flunarizine (FN) is a Ca 2+ channel antagonist that has been used for reducing migraines. However, the role of FN in osteoclast differentiation and function remains unknown. Here, we investigated whether FN regulates osteoclastogenesis and elucidated the molecular mechanism. FN inhibited osteoclast differentiation along with decreased expression of nuclear factor of activated T cells, cytoplasmic 1 (NFATc1), and attenuated osteoclast maturation and bone resorption. FN inhibition of osteoclast differentiation was restored by ectopic expression of constitutively active NFATc1. FN reduced calcium oscillations and its inhibition of osteoclast differentiation and resorption function was reversed by ionomycin, an ionophore that binds Ca 2+ . FN also inhibited Ca 2+ /calmodulin-dependent protein kinase IV (CaMKIV) and calcineurin leading to a decrease in the cAMP-responsive element-binding protein-dependent cFos and peroxisome proliferator-activated receptor-γ coactivator 1β expression, and NFATc1 nuclear translocation. These results indicate that FN inhibits osteoclastogenesis via regulating CaMKIV and calcineurin as a Ca 2+ channel blocker. In addition, FN-induced apoptosis in osteoclasts and promoted osteogenesis. Furthermore, FN protected lipopolysaccharide-and ovariectomy-induced bone destruction in mouse models, suggesting that it has therapeutic potential for treating inflammatory bone diseases and postmenopausal osteoporosis.

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Cinchonine inhibits osteoclast differentiation by regulating TAK1 and AKT, and promotes osteogenesis

Cited by 19 publications

References 46 publications

Network Pharmacology Deciphers the Action of Bioactive Polypeptide in Attenuating Inflammatory Osteolysis via the Suppression of Oxidative Stress and Restoration of Bone Remodeling Balance

Network Pharmacology Deciphers the Action of Bioactive Polypeptide in Attenuating Inflammatory Osteolysis via the Suppression of Oxidative Stress and Restoration of Bone Remodeling Balance

Cyclic Peptide D7 Promotes Osteogenesis and Inhibits Osteoclastogenesis by Regulating Redox Balance of Bone Remodeling

Flunarizine inhibits osteoclastogenesis by regulating calcium signaling and promotes osteogenesis

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