Bisphosphonates

Fleisch, H.; Reszka, Alfred A.; Rodan, Gideon A.; Rogers, Michael J.

doi:10.1016/b978-012098652-1.50180-3

Cited by 17 publications

(16 citation statements)

References 208 publications

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“…Herein, we found that other bisphosphonates, etidronate, tiludronate, or alendronate did not enhance the VEGF synthesis induced by PGF 2␣ , suggesting that the enhancement by incadronate is not a common effect of bisphosphonates but a specific effect of incadronate. It has been shown that cycloheptylamino side chain is specific to incadronate (12). Therefore, it is likely that the unique effect of incadronate is attributed to the structural specificity.…”

Section: Effects Of Incadronate On the Phosphorylation Of Mek1/2 And mentioning

confidence: 99%

“…Nitrogen-containing bisphosphonates, including incadronate, are recognized to inhibit both farnesyl diphosphate synthase and squalene synthase in osteoclasts (12). These enzymes play pivotal roles in the mevalonate/cholesterol biosynthetic pathway.…”

Section: Effects Of Incadronate On the Phosphorylation Of Mek1/2 And mentioning

confidence: 99%

“…We herein presented that incadronate truly up-regulated the cloprostenolincreased VEGF level in mouse plasma in vivo. It is well known that bisphosphonates mainly bind bone tissue (12), whereas cloprostenol is distributed to the whole body and acts through the activation of FP receptor. Therefore, our present findings strongly suggest that incadronate truly affects osteoblasts and enhances the PGF 2␣ -induced VEGF synthesis in vivo.…”

Section: Effects Of Incadronate On the Phosphorylation Of Mek1/2 And mentioning

confidence: 99%

“…Bisphosphonates, stable analogues of pyrophosphate, have been developed as potent inhibitors of bone resorption and effective tools for the treatment of various metabolic bone diseases associated with increased osteoclastic bone resorption such as Paget's disease, tumoral bone disease, and osteoporosis (12). Inhibition of osteoclast recruitment, osteoclastic adhesion to bone surface, and osteoclast activity is known to be the main mechanism of the anti-bone-resorptive actions of bisphosphonates (12).…”

mentioning

confidence: 99%

“…Inhibition of osteoclast recruitment, osteoclastic adhesion to bone surface, and osteoclast activity is known to be the main mechanism of the anti-bone-resorptive actions of bisphosphonates (12). On the other hand, at least some of the effects of bisphosphonates on osteoclast development and function are proposed to be mediated through the actions to osteoblasts (12). It has been reported that ibandronate and alendronate induce the synthesis of an inhibitor of osteoclastic bone resorption in osteoblastic cell line CRP 10/30 (13).…”

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confidence: 99%

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Incadronate Amplifies Prostaglandin F2α-induced Vascular Endothelial Growth Factor Synthesis in Osteoblasts

Tokuda

Harada

Hirade

et al. 2003

Journal of Biological Chemistry

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We have previously reported that prostaglandin F 2␣ (PGF 2␣ ) activates p44/p42 mitogen-activated protein kinase (MAPK) through protein kinase C (PKC) in osteoblast-like MC3T3-E1 cells. In the present study, we investigated the mechanism of vascular endothelial growth factor (VEGF) synthesis induced by PGF 2␣ and the effect of incadronate on the VEGF synthesis in these cells. PGF 2␣ significantly stimulated the VEGF synthesis in a dose-dependent manner between 1 pM and 10 M. Cycloheximide reduced the PGF 2␣ effect. PGF 2␣ increased the levels of mRNA for VEGF. Cloprostenol, a PGF 2␣ -sensitive receptor agonist, potently induced the VEGF synthesis. Indomethacin, an inhibitor of cyclooxygenase, significantly reduced the PGF 2␣ -induced VEGF synthesis. Bisindolylmaleimide, an inhibitor of PKC, reduced the PGF 2␣ -induced VEGF synthesis. The VEGF synthesis induced by PGF 2␣ was significantly attenuated in the PKC down-regulated cells. PGF 2␣ elicited the translocation of PKC␤I from cytosol to membrane fraction. PD98059 or U0126, inhibitors of MEK, suppressed the VEGF synthesis induced by PGF 2␣ . Farnesyltransferase inhibitor failed to affect the PGF 2␣ -induced VEGF synthesis. Incadronate enhanced the synthesis of VEGF induced by PGF 2␣ . NaF-induced VEGF synthesis was also amplified by incadronate. PD98059 suppressed the enhancement by incadronate of PGF 2␣ -induced VEGF synthesis. Incadronate markedly enhanced the phosphorylation of Raf-1, MEK1/2, and p44/p42 MAPK induced by PGF 2␣ or 12-O-tetradecanoylphorbol-13-acetate, a PKC activator. Incadronate significantly enhanced the cloprostenol-increased level of VEGF concentration in mouse plasma in vivo. These results strongly suggest that PGF 2␣ stimulates VEGF synthesis through the PKC-dependent activation of p44/p42 MAPK in osteoblasts and that the incadronate enhances the VEGF synthesis at the point between PKC and Raf-1.Bone metabolism is mainly regulated by two functional cells, osteoblasts and osteoclasts; the former is responsible for bone formation, and the latter for bone resorption (1). Accumulating evidence indicates that bone-resorptive agents such as parathyroid hormone and 1,25-(OH) 2 vitamin D 3 up-regulate RANKL (receptor activator of nuclear factor B) expression through their specific receptors on osteoblasts, suggesting that osteoblasts play pivotal roles in the regulation of bone resorption (2). The bone remodeling results from the coupling bone resorption by activated osteoclasts with subsequent deposition of new matrix by osteoblasts. During the process, capillary endothelial cells provide the microvasculature, and osteoblasts and osteoprogenitor cells, which proliferate locally and differentiate into osteoblasts, migrate into the resorption lacuna.

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Section: Effects Of Incadronate On the Phosphorylation Of Mek1/2 And mentioning

confidence: 99%

Section: Effects Of Incadronate On the Phosphorylation Of Mek1/2 And mentioning

confidence: 99%

Section: Effects Of Incadronate On the Phosphorylation Of Mek1/2 And mentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Incadronate Amplifies Prostaglandin F2α-induced Vascular Endothelial Growth Factor Synthesis in Osteoblasts

Tokuda

Harada

Hirade

et al. 2003

Journal of Biological Chemistry

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Polymeric Matrices for the Controlled Release of Phosphonate Active Agents for Medicinal Applications

Papathanasiou

Demadis

2015

Handbook of Polymers for Pharmaceutical Technologies

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Selectivity in Bone Targeting with Multivalent Dendritic Polyanion Dye Conjugates

Gröger

Kerschnitzki

Weinhart

et al. 2013

Adv Healthcare Materials

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Targeting bone with anionic macromolecules is a potent approach for the development of novel diagnostics and therapeutics for bone related diseases. A highly efficient modular synthesis of dendritic polyglycerol (dPG) polyanion dye conjugates, namely, sulfates, sulfonates, carboxylates, phosphates, phosphonates, and bisphosphonates via click chemistry is presented. By investigating the microarchitecture of stained bone sections with confocal laser scanning microscopy, the bisphosphonate, phosphonate, and phosphate functionalized polymers are identified as strongly penetrating compounds, whereas sulfates, sulfonates, and carboxylates reveal a weaker binding to hydroxyapatite (HA) but a more pronounced affinity toward collagen. In a quantitative HA binding assay, the affinity of the dPG sulfonate, sulfate, and carboxylate toward collagen and the exceptional high HA affinity of the phosphorous containing polyelectrolytes are validated. This shows the potential of dendritic polyphosphates and phosphonates as alternatives to the commonly employed bisphosphonate modification. In cytotoxicity studies with murine fibroblasts, the conjugates have no significant effect on the cell viability at 10(-5) m. All polyanions are taken up into the cells within 24 h. The presented synthetic approach allows versatile extensions for preparing conjugates for selective bone imaging applications, tissue engineering, and drug delivery.

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Bisphosphonates

Cited by 17 publications

References 208 publications

Incadronate Amplifies Prostaglandin F2α-induced Vascular Endothelial Growth Factor Synthesis in Osteoblasts

Incadronate Amplifies Prostaglandin F2α-induced Vascular Endothelial Growth Factor Synthesis in Osteoblasts

Polymeric Matrices for the Controlled Release of Phosphonate Active Agents for Medicinal Applications

Selectivity in Bone Targeting with Multivalent Dendritic Polyanion Dye Conjugates

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