Biological Effects of β-Glucans on Osteoclastogenesis

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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Dihydroartemisinin prevents breast cancer-induced osteolysis via inhibiting both breast caner cells and osteoclasts

Scientific Reports ◽

10.1038/srep19074 ◽

2016 ◽

Vol 6 (1) ◽

Cited By ~ 20

Author(s):

Ming-Xuan Feng ◽

Jian-Xin Hong ◽

Qiang Wang ◽

Yong-Yong Fan ◽

Chi-Ting Yuan ◽

...

Keyword(s):

Breast Cancer ◽

Bone Resorption ◽

Molecular Mechanisms ◽

Osteoclast Differentiation ◽

Metastatic Breast ◽

Osteoclast Formation ◽

Migration And Invasion ◽

Titanium Particle

Abstract Bone is the most common site of distant relapse in breast cancer, leading to severe complications which dramatically affect the patients’ quality of life. It is believed that the crosstalk between metastatic breast cancer cells and osteoclasts is critical for breast cancer-induced osteolysis. In this study, the effects of dihydroartemisinin (DHA) on osteoclast formation, bone resorption, osteoblast differentiation and mineralization were initially assessed in vitro, followed by further investigation in a titanium-particle-induced osteolysis model in vivo. Based on the proved inhibitory effect of DHA on osteolysis, DHA was further applied to MDA-MB-231 breast cancer-induced mouse osteolysis model, with the underlying molecular mechanisms further investigated. Here, we verified for the first time that DHA suppressed osteoclast differentiation, F-actin ring formation and bone resorption through suppressing AKT/SRC pathways, leading to the preventive effect of DHA on titanium-particle-induced osteolysis without affecting osteoblast function. More importantly, we demonstrated that DHA inhibited breast tumor-induced osteolysis through inhibiting the proliferation, migration and invasion of MDA-MB-231 cells via modulating AKT signaling pathway. In conclusion, DHA effectively inhibited osteoclastogenesis and prevented breast cancer-induced osteolysis.

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Thalidomide Derivative CC-4047 Inhibits Osteoclast Formation by down Regulation of PU.1.

Blood ◽

10.1182/blood.v106.11.629.629 ◽

2005 ◽

Vol 106 (11) ◽

pp. 629-629 ◽

Cited By ~ 1

Author(s):

Suzanne Lentzsch ◽

Gulsum Anderson ◽

Noriyoshi Kurihara ◽

Tadashi Honjo ◽

Judith Anderson ◽

...

Keyword(s):

Bone Marrow ◽

Bone Resorption ◽

Bone Marrow Cells ◽

Osteoclast Differentiation ◽

Inhibitory Effect ◽

Osteoclast Formation ◽

Early Event ◽

Down Regulation ◽

Bone Marrow Cultures

Abstract CC-4047 (Actimid) is an immunomodulatory analog of thalidomide that has stronger anti-myeloma and anti-angiogenic activity than thalidomide, but its effects on human osteoclast lineage are unknown. Early osteoclast progenitors are of hematopoietic origin and progressively differentiate into mature bone resorbing multinucleated osteoclasts. We investigated the effects of CC-4047 and thalidomide on human osteoclastogenesis, using in vitro receptor activator of NFκ-B ligand/M-CSF stimulated culture system of bone marrow cells. Three weeks of treatment of primary bone marrow cultures with 100 μM CC-4047 decreased osteoclast formation accompanied by complete inhibition of bone resorption. Interestingly, osteoclast formation was also inhibited when cultures were treated with CC-4047 only for the first week (90% inhibition). In contrast, inhibitory effect was greatly diminished when the drug was given for only the last week (25% inhibition), indicating that inhibition of osteoclast formation is an early event. The inhibitory effect of CC-4047 on osteoclastogenesis was not induced by cell death, but by a shift of lineage commitment to granulocyte-CFU at the expense of GM-CFU that are osteoclast progenitors. Further studies revealed that this shift is mediated through down regulation of the transcription factor PU.1, which is critical for early osteoclast formation. In contrast to CC-4047, thalidomide was a significantly less potent inhibitor of osteoclast formation and bone resorption. These results provide the first evidence that CC-4047 blocks osteoclast differentiation at the early phase of osteoclastogenesis. Therefore, CC-4047 might be a valuable drug targeting both the tumor and osteoclastic activity in patients with multiple myeloma and potentially other diseases associated with the development of osteolytic lesions.

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IL-33 Inhibits TNF-α-Induced Osteoclastogenesis and Bone Resorption

International Journal of Molecular Sciences ◽

10.3390/ijms21031130 ◽

2020 ◽

Vol 21 (3) ◽

pp. 1130 ◽

Cited By ~ 8

Author(s):

Fumitoshi Ohori ◽

Hideki Kitaura ◽

Saika Ogawa ◽

Wei-Ren Shen ◽

Jiawei Qi ◽

...

Keyword(s):

Bone Resorption ◽

Nuclear Translocation ◽

Bone Marrow Cells ◽

Bone Destruction ◽

Osteoclast Formation ◽

Tartrate Resistant Acid Phosphatase ◽

Ct Reconstruction ◽

Tnf Α

Interleukin (IL)-33 is a member of the IL-1 family, which acts as an alarmin. Several studies suggested that IL-33 inhibited osteoclastogenesis and bone resorption. Tumor necrosis factor-α (TNF-α) is considered a direct inducer of osteoclastogenesis. However, there has been no report regarding the effect of IL-33 on TNF-α-induced osteoclastogenesis and bone resorption. The objective of this study is to investigate the role of IL-33 on TNF-α-induced osteoclastogenesis and bone resorption. In an in vitro analysis of osteoclastogenesis, osteoclast precursors, which were derived from bone marrow cells, were treated with or without IL-33 in the presence of TNF-α. Tartrate-resistant acid phosphatase (TRAP) staining solution was used to assess osteoclast formation. In an in vivo analysis of mouse calvariae, TNF-α with or without IL-33 was subcutaneously administrated into the supracalvarial region of mice daily for 5 days. Histological sections were stained for TRAP, and osteoclast numbers were determined. Using micro-CT reconstruction images, the ratio of bone destruction area on the calvariae was evaluated. The number of TRAP-positive cells induced by TNF-α was significantly decreased with IL-33 in vitro and in vivo. Bone resorption was also reduced. IL-33 inhibited IκB phosphorylation and NF-κB nuclear translocation. These results suggest that IL-33 inhibited TNF-α-induced osteoclastogenesis and bone resorption.

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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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LAMP-2 Is Involved in Surface Expression of RANKL of Osteoblasts In Vitro

International Journal of Molecular Sciences ◽

10.3390/ijms21176110 ◽

2020 ◽

Vol 21 (17) ◽

pp. 6110

Author(s):

Ineke D.C. Jansen ◽

Wikky Tigchelaar-Gutter ◽

Jolanda M. A. Hogervorst ◽

Teun J. de Vries ◽

Paul Saftig ◽

...

Keyword(s):

Bone Marrow ◽

Plasma Membrane ◽

Bone Marrow Cells ◽

Surface Expression ◽

Osteoclast Formation ◽

Long Bone ◽

Mouse Bone Marrow ◽

Osteoclast Precursors

Lysosome associated membrane proteins (LAMPs) are involved in several processes, among which is fusion of lysosomes with phagosomes. For the formation of multinucleated osteoclasts, the interaction between receptor activator of nuclear kappa β (RANK) and its ligand RANKL is essential. Osteoclast precursors express RANK on their membrane and RANKL is expressed by cells of the osteoblast lineage. Recently it has been suggested that the transport of RANKL to the plasma membrane is mediated by lysosomal organelles. We wondered whether LAMP-2 might play a role in transportation of RANKL to the plasma membrane of osteoblasts. To elucidate the possible function of LAMP-2 herein and in the formation of osteoclasts, we analyzed these processes in vivo and in vitro using LAMP-2-deficient mice. We found that, in the presence of macrophage colony stimulating factor (M-CSF) and RANKL, active osteoclasts were formed using bone marrow cells from calvaria and long bone mouse bone marrow. Surprisingly, an almost complete absence of osteoclast formation was found when osteoclast precursors were co-cultured with LAMP-2 deficient osteoblasts. Fluorescence-activated cell sorting FACS analysis revealed that plasma membrane-bound RANKL was strongly decreased on LAMP-2 deficient osteoblasts. These results suggest that osteoblastic LAMP-2 is required for osteoblast-induced osteoclast formation in vitro.

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The Prenyl Group Contributes to Activities of Phytoestrogen 8-Prenynaringenin in Enhancing Bone Formation and Inhibiting Bone Resorption In Vitro

Endocrinology ◽

10.1210/en.2012-2086 ◽

2013 ◽

Vol 154 (3) ◽

pp. 1202-1214 ◽

Cited By ~ 28

Author(s):

Lei-Guo Ming ◽

Xiang Lv ◽

Xiao-Ni Ma ◽

Bao-Feng Ge ◽

Ping Zhen ◽

...

Keyword(s):

Bone Resorption ◽

Mrna Expression ◽

Bone Marrow Cells ◽

Osteoclast Differentiation ◽

Cathepsin K ◽

Active Role ◽

Osteoclast Formation ◽

Calcium Deposition ◽

Tartrate Resistant Acid Phosphatase

Abstract Previous studies have found that 8-prenylflavonoids have a higher osteogenic activity than do flavonoids, which suggested that the 8-prenyl group may play an active role in bone-protective properties. To address this hypothesis, activities of 8-prenylnaringenin (PNG) and naringenin (NG) in osteoblast and osteoclast differentiation and function were compared in vitro. PNG was found to have a stronger ability than NG to improve osteoblast differentiation and osteogenic function in cultured rat calvarial osteoblasts, as demonstrated by levels of alkaline phosphatase activity, osteocalcin, calcium deposition, and the number and area of mineralized bone nodules, as well as mRNA expression of osteogenesis-related genes Bmp-2, OSX, and Runx-2. In addition, although expression of osteoclastogenic inducer receptor activator of nuclear factor kappa-B ligand (RANKL) was not affected, that of osteoclastogenesis inhibitor osteoprotegerin (OPG) and consequently the OPG/RANKL ratio were increased, more potently by PNG than NG. PNG was also found to have a higher potency than NG in inhibiting the osteoclast formation in rabbit bone marrow cells and their resorptive activity, as revealed by lower numbers of osteoclasts formed, lower numbers and areas of bone resorption pits, and lower mRNA expression levels of tartrate-resistant acid phosphatase and cathepsin K. Furthermore, PNG induced apoptosis of mature osteoclasts at a higher degree and at an earlier time than did NG. These results indicate that the 8-prenyl group plays an important role and contributes to the higher bone-protective activity of PNG in comparison with NG.

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Jatrorrhizine Hydrochloride Suppresses RANKL-Induced Osteoclastogenesis and Protects against Wear Particle-Induced Osteolysis

International Journal of Molecular Sciences ◽

10.3390/ijms19113698 ◽

2018 ◽

Vol 19 (11) ◽

pp. 3698 ◽

Cited By ~ 3

Author(s):

Hui Li ◽

Jing Wang ◽

Qiwen Sun ◽

Gang Chen ◽

Shengnan Sun ◽

...

Keyword(s):

Bone Resorption ◽

Therapeutic Potential ◽

Osteoclast Differentiation ◽

Chinese Herb ◽

Major Complication ◽

Wear Particle ◽

Osteoclast Formation ◽

Marker Genes

Wear particle-induced aseptic prosthetic loosening is a major complication associated with total joint arthroplasty (TJA). A growing body of evidence suggests that receptor activator of nuclear factor κ-B ligand (RANKL)-stimulated osteoclastogenesis and bone resorption are responsible for peri-implant loosening. Thus, agents which attenuate excessive osteoclast differentiation and function have been considered to offer therapeutic potential for prolonging the life of TJA implants. Jatrorrhizine hydrochloride (JH), a major protoberberine alkaloid isolated from the traditional Chinese herb Coptis chinensis, has been reported to have antimicrobial, antitumor, and antihypercholesterolemic and neuroprotective activities. However, its effects on osteoclast biology remain unknown. Here, we found that JH inhibited RANKL-induced osteoclast formation and bone resorption in vitro and exerted protection against titanium (Ti) particle-induced osteolysis in vivo. Biochemical analysis demonstrated that JH suppressed RANKL-induced activation of MAPKs (p38 and ERK) which down-regulated the production of NFATc1 and NFATc1-regulated osteoclastic marker genes, such as TRAP, CTR and CTSK. Collectively, our findings suggest that JH may be a promising anti-osteoclastogenesis agent for treating periprosthetic osteolysis or other osteoclast-related osteolytic diseases.

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Immunological Reaction in TNF-α-Mediated Osteoclast Formation and Bone ResorptionIn VitroandIn Vivo

Clinical and Developmental Immunology ◽

10.1155/2013/181849 ◽

2013 ◽

Vol 2013 ◽

pp. 1-8 ◽

Cited By ~ 91

Author(s):

Hideki Kitaura ◽

Keisuke Kimura ◽

Masahiko Ishida ◽

Haruka Kohara ◽

Masako Yoshimatsu ◽

...

Keyword(s):

T Cells ◽

Bone Metabolism ◽

Stromal Cells ◽

Fas Ligand ◽

Bone Marrow Cells ◽

Bone Destruction ◽

Osteoclast Formation ◽

Bone Diseases

Tumor necrosis factor-α(TNF-α) is a cytokine produced by monocytes, macrophages, and T cells and is induced by pathogens, endotoxins, or related substances. TNF-αmay play a key role in bone metabolism and is important in inflammatory bone diseases such as rheumatoid arthritis. Cells directly involved in osteoclastogenesis include macrophages, which are osteoclast precursor cells, osteoblasts, or stromal cells. These cells express receptor activator of NF-κB ligand (RANKL) to induce osteoclastogenesis, and T cells, which secrete RANKL, promote osteoclastogenesis during inflammation. Elucidating the detailed effects of TNF-αon bone metabolism may enable the identification of therapeutic targets that can efficiently suppress bone destruction in inflammatory bone diseases. TNF-αis considered to act by directly increasing RANK expression in macrophages and by increasing RANKL in stromal cells. Inflammatory cytokines such as interleukin- (IL-) 12, IL-18, and interferon-γ(IFN-γ) strongly inhibit osteoclast formation. IL-12, IL-18, and IFN-γinduce apoptosis in bone marrow cells treated with TNF-α in vitro, and osteoclastogenesis is inhibited by the interactions of TNF-α-induced Fas and Fas ligand induced by IL-12, IL-18, and IFN-γ. This review describes and discusses the role of cells concerned with osteoclast formation and immunological reactions in TNF-α-mediated osteoclastogenesisin vitroandin vivo.

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Inhibition of intravacuolar acidification by antisense RNA decreases osteoclast differentiation and bone resorption in vitro

Journal of Cell Science ◽

10.1242/jcs.112.21.3657 ◽

1999 ◽

Vol 112 (21) ◽

pp. 3657-3666 ◽

Cited By ~ 1

Author(s):

T. Laitala-Leinonen ◽

C. Lowik ◽

S. Papapoulos ◽

H.K. Vaananen

Keyword(s):

Bone Marrow ◽

Bone Resorption ◽

Antisense Rna ◽

Osteoclast Differentiation ◽

Osteoclast Formation ◽

Gm Csf ◽

Monocytes And Macrophages ◽

Marrow Cultures ◽

Rat Bone

The role of proton transport and production in osteoclast differentiation was studied in vitro by inhibiting the transcription/translation of carbonic anhydrase II (CA II) and vacuolar H(+)-ATPase (V-ATPase) by antisense RNA molecules. Antisense RNAs targeted against CA II, or the 16 kDa or 60 kDa subunit of V-ATPase were used to block the expression of the specific proteins. A significant decrease in bone resorption rate and TRAP-positive osteoclast number was seen in rat bone marrow cultures and fetal mouse metacarpal cultures after antisense treatment. Intravacuolar acidification in rat bone marrow cells was also significantly decreased after antisense treatment. The CA II antisense RNA increased the number of TRAP-positive mononuclear cells, suggesting inhibition of osteoclast precursor fusion. Antisense molecules decreased the number of monocytes and macrophages, but increased the number of granulocytes in marrow cultures. GM-CSF, IL-3 and IL-6 were used to stimulate haematopoietic stem cell differentiation. The 16 kDa V-ATPase antisense RNA abolished the stimulatory effect of GM-CSF, IL-3 and IL-6 on TRAP-positive osteoclast formation, but did not affect the formation of monocytes and macrophages after IL-3 treatment, or the formation of granulocytes after IL-6 treatment. These results suggest that CA II and V-ATPase are needed, not only for the actual resorption, but also for osteoclast formation in vitro.

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