scholarly journals Inhibitory effect of chloroquine on bone resorption reveals the key role of lysosomes in osteoclast differentiation and function

2012 ◽  
Vol 32 (5) ◽  
pp. 222-231 ◽  
Author(s):  
Md. Abdul Alim Al-Bari ◽  
Masahiro Shinohara ◽  
Yusuke Nagai ◽  
Hiroshi Takayanagi
Keyword(s):  
Bone Resorption ◽  
Osteoclast Differentiation ◽  
Inhibitory Effect ◽  
And Function

scholarly journals Piceatannol attenuates RANKL-induced osteoclast differentiation and bone resorption by suppressing MAPK, NF-κB and AKT signalling pathways and promotes Caspase3-mediated apoptosis of mature osteoclasts

2019 ◽  
Vol 6 (6) ◽  
pp. 190360 ◽  
Author(s):  
Liuliu Yan ◽  
Lulu Lu ◽  
Fangbin Hu ◽  
Dattatrya Shetti ◽  
Kun Wei
Keyword(s):  
Bone Resorption ◽  
Osteoclast Differentiation ◽  
Giant Cells ◽  
Inhibitory Effect ◽  
Osteoclast Formation ◽  
Bone Diseases ◽  
Signalling Pathways ◽  
Dependent Manner ◽  
Underlying Mechanisms ◽  
And Function

Osteoclasts are multinuclear giant cells that have unique ability to degrade bone. The search for new medicines that modulate the formation and function of osteoclasts is a potential approach for treating osteoclast-related bone diseases. Piceatannol (PIC) is a natural organic polyphenolic stilbene compound found in diverse plants with a strong antioxidant and anti-inflammatory effect. However, the effect of PIC on bone health has not been scrutinized systematically. In this study, we used RAW264.7, an osteoclast lineage of cells of murine macrophages, to investigate the effects and the underlying mechanisms of PIC on osteoclasts. Here, we demonstrated that PIC treatment ranging from 0 to 40 µM strongly inhibited osteoclast formation and bone resorption in a dose-dependent manner. Furthermore, the inhibitory effect of PIC was accompanied by the decrease of osteoclast-specific genes. At the molecular level, PIC suppressed the phosphorylation of c-Jun N-terminal kinase (JNK), extracellular signal-regulated kinase (ERK1/2), NF-κB p65, IκBα and AKT. Besides, PIC promoted the apoptosis of mature osteoclasts by inducing caspase-3 expression. In conclusion, our results suggested that PIC inhibited RANKL-induced osteoclastogenesis and bone resorption by suppressing MAPK, NF-κB and AKT signalling pathways and promoted caspase3-mediated apoptosis of mature osteoclasts, which might contribute to the treatment of bone diseases characterized by excessive bone resorption.

scholarly journals Inorganic Pyrophosphate Promotes Osteoclastogenic Commitment and Survival of Bone Marrow Derived Monocytes mediated by Egr-1 up-regulation and MITF phosphorylation

2020 ◽  
Author(s):  
Samir M. Abdelmagid ◽  
Allison Zajac ◽  
Imad Salhab ◽  
Hyun-Duck Nah
Keyword(s):  
Bone Marrow ◽  
Bone Resorption ◽  
Osteoblast Differentiation ◽  
Ex Vivo ◽  
Osteoclast Differentiation ◽  
Mouse Bone Marrow ◽  
Matrix Mineralization ◽  
Inorganic Pyrophosphate ◽  
And Function

ABSTRACTSeveral reports emphasized the importance of inorganic pyrophosphate (PPi) in hindering osteoblast differentiation and bone matrix mineralization. Its ubiquitous presence is thought to prevent “soft” tissue calcification, whereas its degradation to Pi in bones and teeth by alkaline phosphatase (ALP) may facilitate crystal growth. While the inhibiting role of PPi on osteoblast differentiation and function is largely understood, less is known about its effects on osteoclast determination and activity. In this study, we investigated the role of PPi in bone resorption using calverial organ cultures ex vivo. We present an evidence that PPi stimulated calvarial bone resorption marked by calcium (Ca2+) release in the condition media (CM). We then examined PPi effects on osteoclast differentiation using mouse bone marrow-derived monocytes (BMMs). Our results revealed that PPi enhanced osteoclast differentiation ex vivo, marked by increased number and size of TRAP-stained mature osteoclasts. Moreover, PPi stimulated osteoclastogenesis in BMMs co-cultured with osteoblasts. These data supported the increased osteoclast activity in bone resorption using functional osteo-assays. The finding of PU.1-Egr-1 dependent up-regulation of c-FMS and RANK receptors in BMMs supported the enhanced pre-osteoclast commitment and differentiation. Moreover, osteoclast survival was enhanced by activation of MITF-BCL-2 pathway that was mediated by MAPK-ERK1/2 signaling. Last, our data showed that PPi up-regulated ANK; PPi transporter, during osteoclast differentiation through ERK1/2 phosphorylation whereas mutation of ANK inhibited osteoclastogenesis. Collectively, our data suggest that PPi promotes osteoclast differentiation, survival, and function through PU.1 up-regulation and MITF phosphorylation whereas ANK loss-of-function inhibited osteoclastogenesis.

scholarly journals Unexpected Role of Matrix Gla Protein in Osteoclasts: Inhibiting Osteoclast Differentiation and Bone Resorption

2019 ◽  
Vol 39 (12) ◽  
Author(s):  
Yan Zhang ◽  
Liting Zhao ◽  
Naining Wang ◽  
Jing Li ◽  
Fang He ◽  
...  
Keyword(s):  
Bone Resorption ◽  
Nuclear Translocation ◽  
Current Knowledge ◽  
Bone Matrix ◽  
Osteoclast Differentiation ◽  
Matrix Gla Protein ◽  
Activated T Cells ◽  
And Function

ABSTRACT Matrix Gla protein (MGP) is an extracellular protein responsible for inhibiting mineralization. MGP inhibits osteoblast mineralization and bone formation by regulating the deposition of bone matrix. However, Mgp–/– mice display an osteopenic phenotype. To explain this contradiction, we investigated the role of MGP in osteoclastogenesis, the other side of bone remodeling. We found that MGP expression is markedly increased by osteoclastic commitment. Osteoclast differentiation and bone resorption are accelerated by MGP depletion while suppressed by MGP overexpression. The in vivo results confirmed its inhibitory role in osteoclastogenesis by the administration of Cre-dependent FLEX-On recombinant MGP-AAV to LysM Cre mice. Furthermore, we found that the expression and nuclear translocation of nuclear factor of activated T cells, cytoplasmic 1 (NFATc1), are under the control of MGP. MGP loss results in elevation of intracellular Ca2+ flux. Vitronectin-induced activation of Src/Rac1 is magnified in the absence of MGP but reduced when MGP is overexpressed. Inhibition of Src activation or NFATc1 nuclear import rescues the increased osteoclastogenesis induced by MGP deficiency. These observations (i) establish, for the first time to our knowledge, that MGP plays an essential role in osteoclast differentiation and function, (ii) enrich the current knowledge of MGP function, and (iii) indicate the potential of MGP as a therapeutic target for low-bone-mass disorders.

scholarly journals Lumican Inhibits Osteoclastogenesis and Bone Resorption by Suppressing Akt Activity

2021 ◽  
Vol 22 (9) ◽  
pp. 4717
Author(s):  
Jin-Young Lee ◽  
Da-Ae Kim ◽  
Eun-Young Kim ◽  
Eun-Ju Chang ◽  
So-Jeong Park ◽  
...  
Keyword(s):  
Bone Resorption ◽  
Bone Formation ◽  
Map Kinases ◽  
Osteoclast Differentiation ◽  
Dependent Manner ◽  
Dual Action ◽  
Dose Dependent ◽  
Resorptive Activity

Lumican, a ubiquitously expressed small leucine-rich proteoglycan, has been utilized in diverse biological functions. Recent experiments demonstrated that lumican stimulates preosteoblast viability and differentiation, leading to bone formation. To further understand the role of lumican in bone metabolism, we investigated its effects on osteoclast biology. Lumican inhibited both osteoclast differentiation and in vitro bone resorption in a dose-dependent manner. Consistent with this, lumican markedly decreased the expression of osteoclastogenesis markers. Moreover, the migration and fusion of preosteoclasts and the resorptive activity per osteoclast were significantly reduced in the presence of lumican, indicating that this protein affects most stages of osteoclastogenesis. Among RANKL-dependent pathways, lumican inhibited Akt but not MAP kinases such as JNK, p38, and ERK. Importantly, co-treatment with an Akt activator almost completely reversed the effect of lumican on osteoclast differentiation. Taken together, our findings revealed that lumican inhibits osteoclastogenesis by suppressing Akt activity. Thus, lumican plays an osteoprotective role by simultaneously increasing bone formation and decreasing bone resorption, suggesting that it represents a dual-action therapeutic target for osteoporosis.

The inhibitory effect of vitamin K on RANKL-induced osteoclast differentiation and bone resorption

2015 ◽  
Vol 6 (10) ◽  
pp. 3351-3358 ◽  
Author(s):  
Wei-Jie Wu ◽  
Min Seuk Kim ◽  
Byung-Yong Ahn
Keyword(s):  
Bone Resorption ◽  
Vitamin K ◽  
Osteoclast Differentiation ◽  
Inhibitory Effect

Vitamins K1, MK-4 and MK-7 have anti-osteoporotic properties, while their regulation effects on osteoclastogenesis are somewhat different.

scholarly journals Hedgehog Inhibitors Suppress Osteoclastogenesis in In Vitro Cultures, and Deletion of Smo in Macrophage/Osteoclast Lineage Prevents Age-Related Bone Loss

2020 ◽  
Vol 21 (8) ◽  
pp. 2745
Author(s):  
Yukihiro Kohara ◽  
Ryuma Haraguchi ◽  
Riko Kitazawa ◽  
Yuuki Imai ◽  
Sohei Kitazawa
Keyword(s):  
Bone Resorption ◽  
Bone Loss ◽  
Signaling Pathway ◽  
Early Stage ◽  
Osteoclast Differentiation ◽  
Osteoclast Formation ◽  
Age Related ◽  
Hh Signaling

The functional role of the Hedgehog (Hh)-signaling pathway has been widely investigated in bone physiology/development. Previous studies have, however, focused primarily on Hh functions in bone formation, while its roles in bone resorption have not been fully elucidated. Here, we found that cyclopamine (smoothened (Smo) inhibitor), GANT-58 (GLI1 inhibitor), or GANT-61 (GLI1/2 inhibitor) significantly inhibited RANKL-induced osteoclast differentiation of bone marrow-derived macrophages. Although the inhibitory effects were exerted by cyclopamine or GANT-61 treatment during 0–48 h (early stage of osteoclast differentiation) or 48–96 h (late stage of osteoclast differentiation) after RANKL stimulation, GANT-58 suppressed osteoclast formation only during the early stage. These results suggest that the Smo-GLI1/2 axis mediates the whole process of osteoclastogenesis and that GLI1 activation is requisite only during early cellular events of osteoclastogenesis. Additionally, macrophage/osteoclast-specific deletion of Smo in mice was found to attenuate the aging phenotype characterized by trabecular low bone mass, suggesting that blockage of the Hh-signaling pathway in the osteoclast lineage plays a protective role against age-related bone loss. Our findings reveal a specific role of the Hh-signaling pathway in bone resorption and highlight that its inhibitors show potential as therapeutic agents that block osteoclast formation in the treatment of senile osteoporosis.

scholarly journals Inhibitory effect of omega-3 fatty acids on alveolar bone resorption and osteoclast differentiation

2020 ◽  
Vol 62 (3) ◽  
pp. 298-302 ◽  
Author(s):  
Yu Ozaki ◽  
Toshiya Morozumi ◽  
Kiyoko Watanabe ◽  
Toshizo Toyama ◽  
Haruka Sasaki ◽  
...  
Keyword(s):  
Fatty Acids ◽  
Bone Resorption ◽  
Alveolar Bone ◽  
Osteoclast Differentiation ◽  
Inhibitory Effect ◽  
Omega 3 Fatty Acids ◽  
Omega 3

scholarly journals Inhibition of osteoclast differentiation and bone resorption by polyunsaturated fatty acids in RAW 264.7 murine macrophages

2012 ◽  
Vol 31 (1) ◽  
Author(s):  
J. C. Boeyens ◽  
W-H. Chua ◽  
M.C. Kruger ◽  
A.M. Joubert ◽  
M. Coetzee
Keyword(s):  
Fatty Acids ◽  
Bone Resorption ◽  
Polyunsaturated Fatty Acids ◽  
Cell Line ◽  
Osteoclast Differentiation ◽  
Inhibitory Effect ◽  
Osteoclast Formation ◽  
Raw 264.7 ◽  
Murine Macrophages

This study investigated the effects of polyunsaturated fatty acids on osteoclast formation and bone resorption in RAW 264.7 murine pre-osteoclasts. Data obtained suggests an inhibitory effect of these compounds on osteoclastogenesis and bone resorption in the cell line tested.

scholarly journals The skeleton: a multi-functional complex organ. The role of key signalling pathways in osteoclast differentiation and in bone resorption

2011 ◽  
Vol 211 (2) ◽  
pp. 131-143 ◽  
Author(s):  
David J Mellis ◽  
Cecile Itzstein ◽  
Miep H Helfrich ◽  
Julie C Crockett
Keyword(s):  
Bone Matrix ◽  
Osteoclast Differentiation ◽  
Osteoclast Formation ◽  
Signalling Pathways ◽  
Monogenic Diseases ◽  
Formation Function ◽  
Functional Complex ◽  
And Function ◽  
Cytoskeletal Rearrangements

Osteoclasts are the specialised cells that resorb bone matrix and are important both for the growth and shaping of bones throughout development as well as during the process of bone remodelling that occurs throughout life to maintain a healthy skeleton. Osteoclast formation, function and survival are tightly regulated by a network of signalling pathways, many of which have been identified through the study of rare monogenic diseases, knockout mouse models and animal strains carrying naturally occurring mutations in key molecules. In this review, we describe the processes of osteoclast formation, activation and function and discuss the major transcription factors and signalling pathways (including those that control the cytoskeletal rearrangements) that are important at each stage.

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