Chondroitin sulfate-e enhances osteoblast differentiation and inhibits osteoclast differentiation in vitro

Bone ◽  
2009 ◽  
Vol 44 ◽  
pp. S314
Author(s):  
T. Miyazaki ◽  
S. Miyauchi ◽  
A. Tawada ◽  
T. Anada ◽  
S. Matsuzaka ◽  
...  
Keyword(s):  
Chondroitin Sulfate ◽  
Osteoblast Differentiation ◽  
Osteoclast Differentiation ◽  
Chondroitin Sulfate E

Oversulfated chondroitin sulfate-E binds to BMP-4 and enhances osteoblast differentiation

2008 ◽  
Vol 217 (3) ◽  
pp. 769-777 ◽  
Author(s):  
Tatsuya Miyazaki ◽  
Satoshi Miyauchi ◽  
Akira Tawada ◽  
Takahisa Anada ◽  
Satoshi Matsuzaka ◽  
...  
Keyword(s):  
Chondroitin Sulfate ◽  
Osteoblast Differentiation ◽  
Chondroitin Sulfate E ◽  
Oversulfated Chondroitin Sulfate

scholarly journals In vitro activation of the contact (Hageman factor) system of plasma by heparin and chondroitin sulfate E

Blood ◽  
1984 ◽  
Vol 63 (6) ◽  
pp. 1453-1459 ◽  
Author(s):  
Y Hojima ◽  
CG Cochrane ◽  
RC Wiggins ◽  
KF Austen ◽  
RL Stevens
Keyword(s):  
Bone Marrow ◽  
Mast Cells ◽  
Connective Tissue ◽  
Chondroitin Sulfate ◽  
Mouse Bone Marrow ◽  
Hageman Factor ◽  
In Vitro Activation ◽  
Chondroitin Sulfate E ◽  
Charged Macromolecules

Abstract A large number of negatively charged macromolecules, including DNA, glycosaminoglycans, and proteoglycans, were tested as possible activators of the contact (Hageman factor) system in vitro. Activation was assessed by conversion of prekallikrein to kallikrein, as determined by amidolytic assay and by cleavage of 125I-Hageman factor into 52,000- and 28,000-dalton fragments. Of particular interest to these studies, heparin proteoglycan and glycosaminoglycan from rat peritoneal mast cells, and squid chondroitin sulfate E, which is representative of the glycosaminoglycan from cultured mouse bone marrow derived mast cells, induced the reciprocal activation between Hageman factor and prekallikrein. In addition, naturally occurring heparin glycosaminoglycans from pig mucosa, bovine lung, and rat mast cells also induced activation. In contrast, native connective tissue matrix glycosaminoglycans and proteoglycans from several sources were inactive, although when one such chondroitin sulfate was further sulfated in vitro, it gained activity. When the negative charge of the activating agents was blocked by the addition of hexadimethrine bromide, the cleavage of 125I-Hageman factor in the presence of prekallikrein was prevented. The active negatively charged macromolecules induced cleavage of 125I-high molecular weight kininogen in normal plasma but not in Hageman factor-deficient or prekallikrein- deficient plasmas. Reconstitution of prekallikrein-deficient plasma with purified prekallikrein restored the kininogen cleavage upon addition of the active proteoglycans. These results suggest that both heparin from connective tissue mast cells and highly sulfated chondroitin sulfate E from cultured mouse bone marrow derived mast cells (which are considered synonomous with mucosal mast cells) could activate the contact system of plasma subsequent to an activation secretion response.

Chondroitin Sulfate-E Binds to Both Osteoactivin and Integrin αVβ3 and Inhibits Osteoclast Differentiation

2015 ◽  
Vol 116 (10) ◽  
pp. 2247-2257 ◽  
Author(s):  
Tatsuya Miyazaki ◽  
Satoshi Miyauchi ◽  
Takahisa Anada ◽  
Akira Tawada ◽  
Osamu Suzuki
Keyword(s):  
Chondroitin Sulfate ◽  
Osteoclast Differentiation ◽  
Integrin Αvβ3 ◽  
Chondroitin Sulfate E

scholarly journals Effects of Sparganii Rhizoma on Osteoclast Formation and Osteoblast Differentiation and on an OVX-Induced Bone Loss Model

2022 ◽  
Vol 12 ◽  
Author(s):  
Sungyub Lee ◽  
Minsun Kim ◽  
Sooyeon Hong ◽  
Eom Ji Kim ◽  
Jae-Hyun Kim ◽  
...  
Keyword(s):  
Bone Loss ◽  
Postmenopausal Osteoporosis ◽  
Osteoblast Differentiation ◽  
Osteoclast Differentiation ◽  
Bone Morphogenetic Protein 2 ◽  
Tartrate Resistant Acid Phosphatase ◽  
Activated T Cells ◽  
Western Blots ◽  
Loss Model

Postmenopausal osteoporosis is caused by an imbalance between osteoclasts and osteoblasts and causes severe bone loss. Osteoporotic medicines are classified into bone resorption inhibitors and bone formation promoters according to the mechanism of action. Long-term use of bisphosphonate and selective estrogen receptor modulators (SERMs) can cause severe side effects in postmenopausal osteoporosis patients. Therefore, it is important to find alternative natural products that reduce osteoclast activity and increase osteoblast formation. Sparganii Rhizoma (SR) is the dried tuberous rhizome of Sparganium stoloniferum Buchanan-Hamilton and is called “samreung” in Korea. However, to date, the effect of SR on osteoclast differentiation and the ovariectomized (OVX)-induced bone loss model has not been reported. In vitro, tartrate-resistant acid phosphatase (TRAP) staining, western blots, RT-PCR and other methods were used to examine the effect of SR on osteoclast differentiation and osteoblasts. In vivo, we confirmed the effect of SR in a model of OVX-induced postmenopausal osteoporosis. SR inhibited osteoclast differentiation and decreased the expression of TNF receptor-associated factor 6 (TRAF6), nuclear factor of activated T cells 1 (NFATc1) and c-Fos pathway. In addition, SR stimulates osteoblast differentiation and increased protein expression of the bone morphogenetic protein 2 (BMP-2)/SMAD signaling pathway. Moreover, SR protected against bone loss in OVX-induced rats. Our results appear to advance our knowledge of SR and successfully demonstrate its potential role as a osteoclastogenesis-inhibiting and osteogenesis-promoting herbal medicine for the treatment of postmenopausal osteoporosis.

scholarly journals Eudebeiolide B Inhibits Osteoclastogenesis and Prevents Ovariectomy-Induced Bone Loss by Regulating RANKL-Induced NF-κB, c-Fos and Calcium Signaling

2020 ◽  
Vol 13 (12) ◽  
pp. 468
Author(s):  
Mi-Hwa Kim ◽  
Hyung-Jin Lim ◽  
Seon Gyeong Bak ◽  
Eun-Jae Park ◽  
Hyun-Jae Jang ◽  
...  
Keyword(s):  
Bone Loss ◽  
Calcium Signaling ◽  
Osteoblast Differentiation ◽  
Transmembrane Protein ◽  
Osteoclast Differentiation ◽  
Mouse Bone Marrow ◽  
Nuclear Factor ◽  
Mineral Density ◽  
Activated T Cells

Eudebeiolide B is a eudesmane-type sesquiterpenoid compound isolated from Salvia plebeia R. Br., and little is known about its biological activity. In this study, we investigated the effects of eudebeiolide B on osteoblast differentiation, receptor activator nuclear factor-κB ligand (RANKL)-induced osteoclastogenesis in vitro and ovariectomy-induced bone loss in vivo. Eudebeiolide B induced the expression of alkaline phosphatase (ALP) and calcium accumulation during MC3T3-E1 osteoblast differentiation. In mouse bone marrow macrophages (BMMs), eudebeiolide B suppressed RANKL-induced osteoclast differentiation of BMMs and bone resorption. Eudebeiolide B downregulated the expression of nuclear factor of activated T-cells 1 (NFATc1) and c-fos, transcription factors induced by RANKL. Moreover, eudebeiolide B attenuated the RANKL-induced expression of osteoclastogenesis-related genes, including cathepsin K (Ctsk), matrix metalloproteinase 9 (MMP9) and dendrocyte expressed seven transmembrane protein (DC-STAMP). Regarding the molecular mechanism, eudebeiolide B inhibited the phosphorylation of Akt and NF-κB p65. In addition, it downregulated the expression of cAMP response element-binding protein (CREB), Bruton’s tyrosine kinase (Btk) and phospholipase Cγ2 (PLCγ2) in RANKL-induced calcium signaling. In an ovariectomized (OVX) mouse model, intragastric injection of eudebeiolide B prevented OVX-induced bone loss, as shown by bone mineral density and contents, microarchitecture parameters and serum levels of bone turnover markers. Eudebeiolide B not only promoted osteoblast differentiation but inhibited RANKL-induced osteoclastogenesis through calcium signaling and prevented OVX-induced bone loss. Therefore, eudebeiolide B may be a new therapeutic agent for osteoclast-related diseases, including osteoporosis, rheumatoid arthritis and periodontitis.

scholarly journals Anti-Osteoporotic Effects of Kukoamine B in Osteoblast and Osteoclast Cells and Ovariectomized Mice

2017 ◽  
Author(s):  
Eunkuk Park ◽  
Jeonghyun Kim ◽  
Mun-Chang Kim ◽  
Subin Yeo ◽  
Jieun Kim ◽  
...  
Keyword(s):  
Osteoblast Differentiation ◽  
Osteoclast Differentiation ◽  
Osteoblastic Differentiation ◽  
Nodule Formation ◽  
Mouse Bone Marrow ◽  
Mineral Density ◽  
Bone Mineral Density Loss ◽  
Ovariectomized Mice

Osteoporosis is an abnormal bone remodeling condition characterized by decreased bone density, which leads to high risks of broken bones. Previous studies have demonstrated that Lycii Radicis Cortex (LRC) extract inhibits bone loss in ovariectomized (OVX) mice by enhancing the osteoblast differentiation. A bioactive compound, Kukoamine B (KB), was identified from a fractionation of LRC extract as a candidate component responsible for an anti-osteoporotic effect. This study investigated the anti-osteoporotic effects of KB using in vitro and in vivo osteoporosis models. KB treatment significantly increased the osteoblastic differentiation and mineralized nodule formation of osteoblastic MC3T3-E1 cells, while it significantly decreased the osteoclast differentiation of primary-cultured monocytes derived from mouse bone marrow. The effects of KB on osteoblastic and osteoclastic differentiations under more physiological conditions were also examined. In the co-culture of MC3T3-E1 cells and monocytes, KB promoted osteoblast differentiation but did not affect osteoclast differentiation. For the in vivo experiments, KB significantly inhibited OVX-induced bone mineral density loss and restored the impaired bone structural properties in osteoporosis model mice. These results suggest that KB may be a potential therapeutic candidate for the treatment of osteoporosis.

scholarly journals Anti-Osteoporotic Effects of Kukoamine B Isolated from Lycii Radicis Cortex Extract on Osteoblast and Osteoclast Cells and Ovariectomized Osteoporosis Model Mice

2019 ◽  
Vol 20 (11) ◽  
pp. 2784 ◽  
Author(s):  
Eunkuk Park ◽  
Jeonghyun Kim ◽  
Mun-Chang Kim ◽  
Subin Yeo ◽  
Jieun Kim ◽  
...  
Keyword(s):  
Osteoblast Differentiation ◽  
Osteoclast Differentiation ◽  
Bioactive Compound ◽  
Osteoblastic Differentiation ◽  
Nodule Formation ◽  
Mouse Bone Marrow ◽  
Mineral Density ◽  
Bone Mineral Density Loss

Osteoporosis is an abnormal bone remodeling condition characterized by decreased bone density, which leads to high risks of fracture. Previous study has demonstrated that Lycii Radicis Cortex (LRC) extract inhibits bone loss in ovariectomized (OVX) mice by enhancing osteoblast differentiation. A bioactive compound, kukoamine B (KB), was identified from fractionation of an LRC extract as a candidate component responsible for an anti-osteoporotic effect. This study investigated the anti-osteoporotic effects of KB using in vitro and in vivo osteoporosis models. KB treatment significantly increased the osteoblastic differentiation and mineralized nodule formation of osteoblastic MC3T3-E1 cells, while it significantly decreased the osteoclast differentiation of primary-cultured monocytes derived from mouse bone marrow. The effects of KB on osteoblastic and osteoclastic differentiations under more physiological conditions were also examined. In the co-culture of MC3T3-E1 cells and monocytes, KB promoted osteoblast differentiation but did not affect osteoclast differentiation. In vivo experiments revealed that KB significantly inhibited OVX-induced bone mineral density loss and restored the impaired bone structural properties in osteoporosis model mice. These results suggest that KB may be a potential therapeutic candidate for the treatment of osteoporosis.

scholarly journals Blockade of Mer By the Small Molecule Inhibitor R992 Inhibits Multiple Myeloma and Its Associated Bone Disease By Restoring the Perturbed Bone Homeostasis

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 1922-1922 ◽  
Author(s):  
Janik Engelmann ◽  
Isabel Ben Batalla ◽  
Hanna Taipaleenmäki ◽  
Kristoffer Riecken ◽  
Victoria Gensch ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Disease ◽  
Osteoblast Differentiation ◽  
Biological Effects ◽  
Osteoclast Differentiation ◽  
Bone Homeostasis ◽  
Mineral Density ◽  
Trabecular Thickness ◽  
Dose Dependent

Abstract Despite many therapeutic advances in recent years Multiple Myeloma (MM) still remains incurable in the majority of the patients. In addition, MM patients suffer significantly from co-morbidities including bone pain and renal insufficiency. Therefore, the development of novel treatments is warranted. The TAMR family consists of Tyro3, Axl and Mer which represent evolving targets in cancer. We demonstrated that the role of TAMR is non-redundant in hematologic malignancies, with Axl exerting an important function in AML, but not in MM, where Mer represents a novel target. Therefore, we tested the therapeutic potential of the Mer-inhibitor R992, which has an 8-fold selectivity over Tyro3 and a 13-fold selectivity over Axl in preclinical MM models (Rigel, San Francisco, USA). R992 exerted a dose-dependent growth inhibition of U266, JJN3 and RPMI8226 cells in vitro (n=3, *p<0.001). Mechanistically, Mer blockade inhibited proliferation in 5-bromo-2′-deoxyuridine assays and induced apoptosis as shown by increased numbers of Annexin V+ cells (n=3,*p<0.05 and *p<0.001, respectively). To delineate signaling pathways mediating the biological effects of Mer blockade in MM cells we investigated key mediators of MM cell proliferation and survival. Here, we found reduced phosphorylation of Akt upon Mer inhibition with R992. Furthermore, R992 inhibited mitogen-activated protein kinase (MAPK) pathways Erk and p38. Subsequently, we investigated whether inhibition of Mer signaling increases chemosensitivity of MM cells. Combination treatment of R992 with bortezomib and cyclophosphamide demonstrated that Mer inhibition significantly increased sensitivity of MM cells to these established MM therapies. Oral administration of 60mg/kg R992 BID to mice significantly reduced tumor burden in the U266 systemic myeloma mouse model. The λ light chain concentration and the CD138+ MM cell load was reduced 2-fold in R992 treated mice compared to placebo-treated mice 8 weeks after injection (n=5/5, *p<0.05 and n=4/5, *p<0.05, respectively). Importantly, treatment with R992 resulted in a significant prolongation of overall survival by 15 days in the U266 model (median OS 73 vs. 88 days (n=13/12, *p<0.05). In addition, treatment with R992 prolonged survival in the more aggressive JJN3 model (median OS 24 vs. 27 days, n=9/7, *p<0.005). For further phenotyping of the effects of R992 we performed microcomputed tomography (µCT) and histological analysis of the tibias in the U266 model. µCT analysis of proximal tibia metaphyses revealed, that bone volume and bone mineral density (BMD) were significantly increased by R992 (n=7/7, *p<0.05). Moreover, analysis of the metaphyseal spongiosa showed that R992 could retard myeloma-mediated destruction of trabecular bone area measured by increased trabecular number and increased trabecular thickness (n=7/7, *p<0.05). Interestingly, R992 could also enlarge the metaphyseal diameter due to thickened cortical bone. Vice versa, overexpression of the Mer ligands Gas6 and Pros1 in U266 and JJN3 cells led to increased osteoclast and decreased osteoblast differentiation in vitro and more rapid and destructive myeloma bone disease in vivo. These data suggest that the expression of Mer ligands represent thus far unrecognized mediators of MM-induced perturbed bone homeostasis. To directly assess the effect of R992 on osteoclasts, we treated osteoclast cultures with R992 and observed an inhibition of osteoclast differentiation by R992 alone and in co-culture with myeloma cells. Western blot analysis confirmed, that Mer phosphorylation was reduced by R992, whereas the phosphorylation of Tyro3 was not altered. Concomitantly, phosphorylation of p38 and activation of non-canonical NFκB pathway showed a dose dependent reduction after Mer blockade. Interestingly, R992 led also to increased osteoblast differentiation and could restore myeloma mediated osteoblast inhibition in co-cultures of MM cells and osteoblasts. In summary, our data suggest that Mer blockade leads to inhibition of MM and its associated bone disease. Furthermore, the function of Mer in bone homeostasis promoting osteoclast and inhibiting osteoblast activity leads to the potential application of Mer inhibitors also in osteolytic bone metastases or osteoporosis. Disclosures Darwish: Rigel Pharmaceuticals: Employment. Bhamidipati:Rigel Pharmaceuticals: Employment. Masuda:Rigel Pharmaceuticals: Employment, Equity Ownership. Loges:BerGenBio: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding.

scholarly journals Overexpression of PIK3R1 Promotes Bone Formation by Regulating Osteoblast Differentiation and Osteoclast Formation

2021 ◽  
Vol 2021 ◽  
pp. 1-13
Author(s):  
Haitao Zhu ◽  
Hua Chen ◽  
Degang Ding ◽  
Shui Wang ◽  
Xiaofeng Dai ◽  
...  
Keyword(s):  
Bone Formation ◽  
Signaling Pathway ◽  
Differentially Expressed Genes ◽  
Osteoblast Differentiation ◽  
Osteoclast Differentiation ◽  
Osteoclast Formation ◽  
Differentially Expressed ◽  
Estrogen Signaling ◽  
Mineral Density

In an effort to bolster our understanding of regulation of bone formation in the context of osteoporosis, we screened out differentially expressed genes in osteoporosis patients with high and low bone mineral density by bioinformatics analysis. PIK3R1 is increasingly being nominated as a pivotal mediator in the differentiation of osteoblasts and osteoclasts that is closely related to bone formation. However, the specific mechanisms underlying the way that PIK3R1 affects bone metabolism are not fully elucidated. We intended to examine the potential mechanism by which PIK3R1 regulates osteoblast differentiation. Enrichment analysis was therefore carried out for differentially expressed genes. We noted that the estrogen signaling pathway, TNF signaling pathway, and osteoclast differentiation were markedly associated with ossification, and they displayed enrichment in PIK3R1. Based on western blot, qRT-PCR, and differentiation analysis in vitro, we found that upregulation of PIK3R1 enhanced osteoblastic differentiation, as evidenced by increased levels of investigated osteoblast-related genes as well as activities of ALP and ARS, while it notably decreased levels of investigated osteoclast-related genes. On the contrary, downregulation of PIK3R1 decreased levels of osteoblast-related genes and increased levels of osteoclast-related genes. Besides, in vitro experiments revealed that PIK3R1 facilitated proliferation and repressed apoptosis of osteoblasts but had an opposite impact on osteoclasts. In summary, PIK3R1 exhibits an osteoprotective effect via regulating osteoblast differentiation, which can be represented as a promising therapeutic target for osteoporosis.

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