Pisidium coreanum Inhibits Multinucleated Osteoclast Formation and Prevents Estrogen-Deficient Osteoporosis

Mollusks have served as important sources of human food and medicine for a long time. Raw Pisidium coreanum, a freshwater bivalve of the phylum Mollusca, is used in traditional therapies in parts of Asia. However, the therapeutic effects of Pisidium coreanum on bone diseases are not known. We investigated the functional roles of Pisidium coreanum in osteoporotic bone diseases. Pisidium coreanum inhibited the differentiation of bone marrow-derived monocytic cells into mature osteoclasts in vitro. The ovariectomized mice that received oral administration of Pisidium coreanum showed improvements in both trabecular and cortical bones. This preventive activity of Pisidium coreanum against bone loss was due to limited osteoclast maturation with reduced osteoclast surface extent in trabecular bone tissue. The formation of large multinucleated osteoclasts in vitro was significantly decreased in response to Pisidium coreanum, consistent with the reduced expression levels of osteoclast markers and fusion-related genes, such as NFATc1, p65, integrin αvβ3, DC-STAMP, OC-STAMP, Atp6v0d2, FAK, CD44, and MFR. These data suggest that Pisidium coreanum inhibits osteoclast differentiation by negatively regulating the fusion of mononuclear osteoclast precursors. Thus, our data demonstrate the ability of Pisidium coreanum to effectively prevent estrogen-deficient osteoporosis through inhibition of multinucleated osteoclast formation.

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Artemisia capillaris Alleviates Bone Loss by Stimulating Osteoblast Mineralization and Suppressing Osteoclast Differentiation and Bone Resorption

The American Journal of Chinese Medicine ◽

10.1142/s0192415x16500944 ◽

2016 ◽

Vol 44 (08) ◽

pp. 1675-1691 ◽

Cited By ~ 4

Author(s):

Chung-Jo Lee ◽

Ki-Shuk Shim ◽

Jin Yeul Ma

Keyword(s):

Bone Resorption ◽

Bone Loss ◽

Osteoclast Differentiation ◽

Water Extract ◽

Osteoclast Formation ◽

Bone Diseases ◽

Osteoporotic Bone ◽

Nuclear Factor ◽

Artemisia Capillaris

Artemisia capillaris has been used to treat jaundice and relieve high liver-heat in traditional medicine. In this study, we found that the administration of a water extract from A. capillaris (WEAC) to the receptor activator of nuclear factor kappa-B ligand (RANKL)-induced bone loss model significantly prevents osteoporotic bone loss, increasing bone volume/trabecular volume by 22% and trabecular number by 24%, and decreasing trabecular separation by 29%. WEAC stimulated in vitro osteoblast mineralization from primary osteoblasts in association with increasing expression of osterix, nuclear factor of activated T cells cytoplasmic 1, and activator protein-1, as well as phosphorylation of extracellular signal-regulated kinase. In contrast to the anabolic effect of WEAC, WEAC significantly suppressed in vitro osteoclast formation from bone marrow macrophages by inhibiting the RANKL signaling pathways and bone resorption by downregulating the expression of resorption markers. Therefore, this study demonstrated that WEAC has a beneficial effect on bone loss through the regulation of osteoblast mineralization, as well as osteoclast formation and bone resorption. These results suggest that A. capillaris may be a promising herbal candidate for therapeutic agents to treat or prevent osteoporotic bone diseases.

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Berberine Suppresses RANKL-Induced Osteoclast Differentiation by Inhibiting c-Fos and NFATc1 Expression

The American Journal of Chinese Medicine ◽

10.1142/s0192415x19500228 ◽

2019 ◽

Vol 47 (02) ◽

pp. 439-455 ◽

Cited By ~ 3

Author(s):

Sang-Yong Han ◽

Yun-Kyung Kim

Keyword(s):

Bone Loss ◽

Osteoclast Differentiation ◽

Osteoclast Formation ◽

Bone Diseases ◽

Mrna Levels ◽

Nuclear Factor ◽

Activated T Cells ◽

Murine Bone Marrow

Osteoporosis is a common disorder of bone remodeling, marked by excessive osteoclast formation. Recent studies indicated that berberine (BBR) is a potential natural drug for the treatment of various bone diseases. However, it still needs to be further studied for the treatment of osteoporosis. The current study investigated the inhibitory effects of BBR on receptor activator of nuclear factor-[Formula: see text]B ligand (RANKL)-induced osteoclast differentiation in vitro and in vivo. Cell-based assays were performed using osteoclasts generated in cultures of murine bone marrow-derived macrophages (BMMs) treated with RANKL and M-CSF. The effects of BBR on in vivo lipopolysaccharide (LPS)-mediated bone loss were evaluated using ICR mice. BBR significantly inhibited TRAP-positive osteoclast formation induced by RANKL. BBR also inhibited RANKL-induced Akt, p38 and ERK phosphorylation and I[Formula: see text]B degradation, and suppressed RANKL-induced expression of c-Fos and nuclear factor of activated T cells c1 (NFATc1), which is a key transcription factors for osteoclast formation. BBR reduced the mRNA levels of osteoclast markers, including TRAP, osteoclast-associated receptor (OSCAR), cathepsin K, and ATPase H[Formula: see text] transporting V0 subunit d2 (ATP6v0d2). Moreover, BBR prevented LPS-mediated bone loss in vivo. We suggest BBR as a natural compound that can be a potential therapeutic agent for osteoclast-related bone diseases.

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Anti-Osteoporotic Effects of Combined Extract of Lycii Radicis Cortex and Achyranthes japonica in Osteoblast and Osteoclast Cells and Ovariectomized Mice

Nutrients ◽

10.3390/nu11112716 ◽

2019 ◽

Vol 11 (11) ◽

pp. 2716 ◽

Cited By ~ 3

Author(s):

Eunkuk Park ◽

Jeonghyun Kim ◽

Subin Yeo ◽

Eunguk Lim ◽

Chun Whan Choi ◽

...

Keyword(s):

Bone Loss ◽

Osteoclast Differentiation ◽

Osteoporotic Bone ◽

Osteoblastic Cell ◽

Mouse Bone Marrow ◽

Osteoblastic Cell Line ◽

Ovariectomized Mice ◽

Achyranthes Japonica

Osteoporosis is characterized by low bone density and quality with high risk of bone fracture. Here, we investigated anti-osteoporotic effects of natural plants (Lycii Radicis Cortex (LRC) and Achyranthes japonica (AJ)) in osteoblast and osteoclast cells in vitro and ovariectomized mice in vivo. Combined LRC and AJ enhanced osteoblast differentiation and mineralized bone-forming osteoblasts by the up-regulation of bone metabolic markers (Alpl, Runx2 and Bglap) in the osteoblastic cell line MC3T3-E1. However, LRC and AJ inhibited osteoclast differentiation of monocytes isolated from mouse bone marrow. In vivo experiments showed that treatment of LRC+AJ extract prevented OVX-induced trabecular bone loss and osteoclastogenesis in an osteoporotic animal model. These results suggest that LRC+AJ extract may be a good therapeutic agent for the treatment and prevention of osteoporotic bone loss.

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Anti-c-fms Antibody Prevents Osteoclast Formation and Bone Resorption in Co-Culture of Osteoblasts and Osteoclast Precursors In Vitro and in Ovariectomized Mice

International Journal of Molecular Sciences ◽

10.3390/ijms21176120 ◽

2020 ◽

Vol 21 (17) ◽

pp. 6120

Author(s):

Yasuhiko Nara ◽

Hideki Kitaura ◽

Saika Ogawa ◽

Wei-Ren Shen ◽

Jiawei Qi ◽

...

Keyword(s):

Bone Resorption ◽

Bone Structure ◽

Osteoclast Differentiation ◽

Osteoclast Formation ◽

Osteoclast Precursor ◽

Antibody Treatment ◽

Osteoporosis Therapy ◽

Osteoclast Precursors ◽

Ovariectomized Mice

Osteoporosis morphology is characterized by bone resorption and decreases in micro-architecture parameters. Anti-osteoporosis therapy targets osteoclasts because bone resorption is a unique function of osteoclasts. Anti-c-fms antibodies against the receptor for macrophage colony-stimulating factor (M-CSF) inhibit osteoclast formation and bone resorption in vitro and in vivo. However, the effect of anti-c-fms antibodies on bone resorption in ovariectomized (OVX) mice is unknown. In this study, we evaluated the effect of anti-c-fms antibodies on osteoclast formation and bone resorption in osteoblast–osteoclast precursor co-culture in vitro and in OVX mice. Osteoblast and osteoclast precursor co-cultures treated with anti-c-fms antibodies showed significantly inhibited osteoclast formation, while cultures without anti-c-fms antibody treatment showed osteoclast formation. However, anti-c-fms antibodies did not change the receptor activator of nuclear factor kappa-B ligand (RANKL) or osteoprotegrin (OPG) expression during osteoblast and osteoclast differentiation in vitro. These results indicate that anti-c-fms antibodies directly affected osteoclast formation from osteoclast precursors in co-culture. OVX mice were treated with intraperitoneal injections of anti-c-fms antibody. The trabecular bone structure of the femur was assessed by micro-computer tomography. The anti-c-fms antibody inhibited osteoclast formation and bone loss compared with PBS-treated OVX mice. These results indicate potential for the therapeutic application of anti-c-fms antibodies for postmenopausal osteoporosis.

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Protective Effect of Ciclopirox against Ovariectomy-Induced Bone Loss in Mice by Suppressing Osteoclast Formation and Function

International Journal of Molecular Sciences ◽

10.3390/ijms22158299 ◽

2021 ◽

Vol 22 (15) ◽

pp. 8299

Author(s):

Hye Jung Ihn ◽

Jiwon Lim ◽

Kiryeong Kim ◽

Sang-Hyeon Nam ◽

Soomin Lim ◽

...

Keyword(s):

Bone Loss ◽

Type I Collagen ◽

Osteoclast Differentiation ◽

Osteoclast Formation ◽

Bone Diseases ◽

Mitogen Activated Protein Kinase ◽

Type I ◽

And Function

Postmenopausal osteoporosis is closely associated with excessive osteoclast formation and function, resulting in the loss of bone mass. Osteoclast-targeting agents have been developed to manage this disease. We examined the effects of ciclopirox on osteoclast differentiation and bone resorption in vitro and in vivo. Ciclopirox significantly inhibited osteoclast formation from primary murine bone marrow macrophages (BMMs) in response to receptor activator of nuclear factor kappa B ligand (RANKL), and the expression of genes associated with osteoclastogenesis and function was decreased. The formation of actin rings and resorption pits was suppressed by ciclopirox. Analysis of RANKL-mediated early signaling events in BMMs revealed that ciclopirox attenuates IκBα phosphorylation without affecting mitogen-activated protein kinase activation. Furthermore, the administration of ciclopirox suppressed osteoclast formation and bone loss in ovariectomy-induced osteoporosis in mice and reduced serum levels of osteocalcin and C-terminal telopeptide fragment of type I collagen C-terminus. These results indicate that ciclopirox exhibits antiosteoclastogenic activity both in vitro and in vivo and represents a new candidate compound for protection against osteoporosis and other osteoclast-related bone diseases.

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Monocrotaline Suppresses RANKL-Induced Osteoclastogenesis In Vitro and Prevents LPS-Induced Bone Loss In Vivo

Cellular Physiology and Biochemistry ◽

10.1159/000491892 ◽

2018 ◽

Vol 48 (2) ◽

pp. 644-656 ◽

Cited By ~ 4

Author(s):

Cheng-Ming Wei ◽

Yi-Ji Su ◽

Xiong Qin ◽

Jia-Xin Ding ◽

Qian Liu ◽

...

Keyword(s):

Critical Role ◽

Osteoclast Differentiation ◽

Osteoclast Formation ◽

Bone Diseases ◽

Marker Genes ◽

Tartrate Resistant Acid Phosphatase ◽

Dependent Manner ◽

And Function

Background/Aims: Extensive osteoclast formation plays a critical role in bone diseases, including rheumatoid arthritis, periodontitis and the aseptic loosening of orthopedic implants. Thus, identification of agents that can suppress osteoclast formation and bone resorption is important for the treatment of these diseases. Monocrotaline (Mon), the major bioactive component of crotalaria sessiliflora has been investigated for its anti-cancer activities. However, the effect of Mon on osteoclast formation and osteolysis is not known. Methods: The bone marrow macrophages (BMMs) were cultured with M-CSF and RANKL followed by Mon treatment. Then the effects of Mon on osteoclast differentiation were evaluated by counting TRAP (+) multinucleated cells. Moreover, effects of Mon on hydroxyapatite resorption activity of mature osteoclast were studied through resorption areas measurement. The involved potential signaling pathways were analyzed by performed Western blotting and quantitative real-time PCR examination. Further, we established a mouse calvarial osteolysis model to measure the osteolysis suppressing effect of Mon in vivo. Results: In this study, we show that Mon can inhibit RANKL-induced osteoclast formation and function in a dose-dependent manner. Mon inhibits the expression of osteoclast marker genes such as tartrate-resistant acid phosphatase (TRAP) and cathepsin K. Furthermore, Mon inhibits RANKL-induced the activation of p38 and JNK. Consistent with in vitro results, Mon exhibits protective effects in an in vivo mouse model of LPS-induced calvarial osteolysis. Conclusion: Taken together our data demonstrate that Mon may be a potential prophylactic anti-osteoclastic agent for the treatment of osteolytic diseases caused by excessive osteoclast formation and function.

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Biological Effects of β-Glucans on Osteoclastogenesis

Molecules ◽

10.3390/molecules26071982 ◽

2021 ◽

Vol 26 (7) ◽

pp. 1982

Author(s):

Wataru Ariyoshi ◽

Shiika Hara ◽

Ayaka Koga ◽

Yoshie Nagai-Yoshioka ◽

Ryota Yamasaki

Keyword(s):

Bone Resorption ◽

Bone Marrow Cells ◽

Biological Effects ◽

Osteoclast Differentiation ◽

Treatment Strategies ◽

Alcaligenes Faecalis ◽

Osteoclast Formation ◽

Osteoclast Precursors

Although the anti-tumor and anti-infective properties of β-glucans have been well-discussed, their role in bone metabolism has not been reviewed so far. This review discusses the biological effects of β-glucans on bone metabolisms, especially on bone-resorbing osteoclasts, which are differentiated from hematopoietic precursors. Multiple immunoreceptors that can recognize β-glucans were reported to be expressed in osteoclast precursors. Coordinated co-stimulatory signals mediated by these immunoreceptors are important for the regulation of osteoclastogenesis and bone remodeling. Curdlan from the bacterium Alcaligenes faecalis negatively regulates osteoclast differentiation in vitro by affecting both the osteoclast precursors and osteoclast-supporting cells. We also showed that laminarin, lichenan, and glucan from baker’s yeast, as well as β-1,3-glucan from Euglema gracilisas, inhibit the osteoclast formation in bone marrow cells. Consistent with these findings, systemic and local administration of β-glucan derived from Aureobasidium pullulans and Saccharomyces cerevisiae suppressed bone resorption in vivo. However, zymosan derived from S. cerevisiae stimulated the bone resorption activity and is widely used to induce arthritis in animal models. Additional research concerning the relationship between the molecular structure of β-glucan and its effect on osteoclastic bone resorption will be beneficial for the development of novel treatment strategies for bone-related diseases.

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Osteoclast and osteoblast response to strontium-doped struvite coatings on titanium for improved bone integration

Biomedical Engineering / Biomedizinische Technik ◽

10.1515/bmt-2019-0265 ◽

2020 ◽

Vol 0 (0) ◽

Author(s):

Claus Moseke ◽

Katharina Wimmer ◽

Markus Meininger ◽

Julia Zerweck ◽

Cornelia Wolf-Brandstetter ◽

...

Keyword(s):

Bone Ingrowth ◽

Osteoclast Differentiation ◽

Inhibitory Effect ◽

Osteoclast Formation ◽

Strontium Nitrate ◽

Bone Implant ◽

Electrochemically Deposited ◽

Bone Integration ◽

Titanium Substrates

AbstractTo develop implants with improved bone ingrowth, titanium substrates were coated with homogeneous and dense struvite (MgNH4PO4·6H2O) layers by means of electrochemically assisted deposition. Strontium nitrate was added to the coating electrolyte in various concentrations, in order to fabricate Sr-doped struvite coatings with Sr loading ranging from 10.6 to 115 μg/cm2. It was expected and observed that osteoclast activity surrounding the implant was inhibited. The cytocompatibility of the coatings and the effect of Sr-ions in different concentrations on osteoclast formation were analyzed in vitro. Osteoclast differentiation was elucidated on morphological, biochemical as well as on gene expression level. It could be shown that moderate concentrations of Sr2+ had an inhibitory effect on osteoclast formation, while the growth of osteoblastic cells was not negatively influenced compared to pure struvite surfaces. In summary, the electrochemically deposited Sr-doped struvite coatings are a promising approach to improve bone implant ingrowth.

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Kalkitoxin Reduces Osteoclast Formation and Resorption and Protects against Inflammatory Bone Loss

International Journal of Molecular Sciences ◽

10.3390/ijms22052303 ◽

2021 ◽

Vol 22 (5) ◽

pp. 2303

Author(s):

Liang Li ◽

Ming Yang ◽

Saroj Kumar Shrestha ◽

Hyoungsu Kim ◽

William H. Gerwick ◽

...

Keyword(s):

Bone Loss ◽

Transmembrane Protein ◽

Osteoclast Differentiation ◽

Mapk Signaling ◽

Osteoclast Formation ◽

Bone Diseases ◽

Tartrate Resistant Acid Phosphatase ◽

Nuclear Factor ◽

Mineral Density ◽

Multinucleated Cells

Osteoclasts, bone-specified multinucleated cells produced by monocyte/macrophage, are involved in numerous bone destructive diseases such as arthritis, osteoporosis, and inflammation-induced bone loss. The osteoclast differentiation mechanism suggests a possible strategy to treat bone diseases. In this regard, we recently examined the in vivo impact of kalkitoxin (KT), a marine product obtained from the marine cyanobacterium Moorena producens (previously Lyngbya majuscula), on the macrophage colony-stimulating factor (M-CSF) and on the receptor activator of nuclear factor κB ligand (RANKL)-stimulated in vitro osteoclastogenesis and inflammation-mediated bone loss. We have now examined the molecular mechanism of KT in greater detail. KT decreased RANKL-induced bone marrow-derived macrophages (BMMs) tartrate-resistant acid phosphatase (TRAP)-multinucleated cells at a late stage. Likewise, KT suppressed RANKL-induced pit area and actin ring formation in BMM cells. Additionally, KT inhibited several RANKL-induced genes such as cathepsin K, matrix metalloproteinase (MMP-9), TRAP, and dendritic cell-specific transmembrane protein (DC-STAMP). In line with these results, RANKL stimulated both genes and protein expression of c-Fos and nuclear factor of activated T cells (NFATc1), and this was also suppressed by KT. Moreover, KT markedly decreased RANKL-induced p-ERK1/2 and p-JNK pathways at different time points. As a result, KT prevented inflammatory bone loss in mice, such as bone mineral density (BMD) and osteoclast differentiation markers. These experiments demonstrated that KT markedly inhibited osteoclast formation and inflammatory bone loss through NFATc1 and mitogen-activated protein kinase (MAPK) signaling pathways. Therefore, KT may have potential as a treatment for destructive bone diseases.

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Capsaicin, a TRPV1 Ligand, Suppresses Bone Resorption by Inhibiting the Prostaglandin E Production of Osteoblasts, and Attenuates the Inflammatory Bone Loss Induced by Lipopolysaccharide

ISRN Pharmacology ◽

10.5402/2012/439860 ◽

2012 ◽

Vol 2012 ◽

pp. 1-6 ◽

Cited By ~ 11

Author(s):

Megumi Kobayashi ◽

Kenta Watanabe ◽

Satoshi Yokoyama ◽

Chiho Matsumoto ◽

Michiko Hirata ◽

...

Keyword(s):

Bone Resorption ◽

Bone Loss ◽

Transient Receptor Potential ◽

Interleukin 1 ◽

Osteoclast Differentiation ◽

Bone Diseases ◽

Prostaglandin E ◽

Transient Receptor Potential Vanilloid ◽

Cox 2

Capsaicin, a transient receptor potential vanilloid type 1 (TRPV1) ligand, regulates nerve-related pain-sensitive signals, inflammation, and cancer growth. Capsaicin suppresses interleukin-1-induced osteoclast differentiation, but its roles in bone tissues and bone diseases are not known. This study examined the effects of capsaicin on inflammatory bone resorption and prostaglandin E (PGE) production induced by lipopolysaccharide (LPS) in vitro and on bone mass in LPS-treated mice in vivo. Capsaicin suppressed osteoclast formation, bone resorption, and PGE production induced by LPS in vitro. Capsaicin suppressed the expression of cyclooxygenase-2 (COX-2) and membrane-bound PGE synthase-1 (mPGES-1) mRNAs and PGE production induced by LPS in osteoblasts. Capsaicin may suppress PGE production by inhibiting the expression of COX-2 and mPGES-1 in osteoblasts and LPS-induced bone resorption by TRPV1 signals because osteoblasts express TRPV1. LPS treatment markedly induced bone loss in the femur in mice, and capsaicin significantly restored the inflammatory bone loss induced by LPS in mice. TRPV1 ligands like capsaicin may therefore be potentially useful as clinical drugs targeting bone diseases associated with inflammatory bone resorption.

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