Novel bisphosphonates with antiresorptive effect in bone mineralization and osteoclastogenesis

Savino, Salvatore; Toscano, Annamaria; Purgatorio, Rosa; Profilo, Emanuela; Laghezza, Antonio; Tortorella, Paolo; Angelelli, Mariacristina; Cellamare, Saverio; Scala, Rosa; Tricarico, Domenico; Marobbio, C; Perna, Filippo Maria; Tortorella, Paolo; Agamennone, Mariangela; Dimiccoli, Vincenzo; Tolomeo, Anna; Scilimati, Antonio

doi:10.1016/j.ejmech.2018.08.044

Cited by 23 publications

(30 citation statements)

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“…On differentiated MC3T3-E1 cell line, ZOL, RIS, and ALE were capable of inducing significant osteoblastogenesis and mineralization in the nanomolar concentration range (3 × 10 −8 to 5 × 10 −8 M). In our previous work, these concentrations were effective in inducing mineralization in cell lines [6]. At 5 × 10 −8 M, ZOL was the most effective drug in inducing mineralization, which increased by +136.08% ± 21.48% compared to controls (number of replicates = 5) as determined by Student t -test ( p < 0.05).…”

Section: Resultsmentioning

confidence: 72%

“…At micromolar concentrations, ZOL and other BPs show antiproliferative effects associated with the inhibition of intracellular target/s, such as the human recombinant enzymes h FPPS and/or h GGPPS [6]. Here, we showed that, in preosteoblast-like cells MC3T3-E1, the BPs under investigation were equally capable of reducing intracellular dehydrogenase activity.…”

Section: Discussionmentioning

confidence: 79%

“…This assay was performed to evaluate cells’ capability to mineralize, that is, their ability to create calcium deposits or nodules after the expression of a mature osteoblast phenotype, as previously described [6]. Briefly, the cells (1 × 10 6 cells/mL/well) were cultured in the mineralization medium using 12- and 24-well plates in the presence of different concentrations of the drug solution for approximately 10–15 days under standard conditions.…”

Section: Methodsmentioning

confidence: 99%

“…Since BPs can avidly bind to exposed bone mineral, their highest concentration is likely to be in the osteoclast-mediated resorption lacunae. Consequently, BPs are internalized by osteoclasts, where they act as potent inhibitors of farnesyl pyrophosphate synthase, a key enzyme of the mevalonate pathway, involved in bone resorption, affecting osteoclast morphology and finally inducing their apoptosis [5,6].…”

Section: Introductionmentioning

confidence: 99%

“…For example, third-generation bisphosphonates (i.e., zoledronic acid) can inhibit growth, migration, and matrix-associated invasion of breast cancer cells [3]. In vitro, human prostate cancer PC3 cells and human osteosarcoma MG63 cells treated with zoledronic acid, alendronate, or risedronate [6] show attenuated proliferation.…”

Section: Introductionmentioning

confidence: 99%

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Zoledronic Acid Modulation of TRPV1 Channel Currents in Osteoblast Cell Line and Native Rat and Mouse Bone Marrow-Derived Osteoblasts: Cell Proliferation and Mineralization Effect

Scala

Maqoud

Angelelli

et al. 2019

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Bisphosphonates (BPs) reduce bone pain and fractures by balancing the osteoblast/osteoclast ratio. The behavior of ion channels in the presence of BPs is not known. To investigate this, the effect of zoledronic acid BP (ZOL) (3 × 10−8 to 5 × 10−4 M) treatment, on ion channels, cell proliferation, and mineralization, has been investigated on preosteoclast-like cells, RAW264.7, preosteoblast-like cells MC3T3-E1, and rat/mouse native bone marrow-derived osteoblasts. In whole-cell patch clamp on cell line- and bone marrow-derived osteoblasts, ZOL potentiated outward currents. On RAW264.7, ZOL (10−4 M)-evoked current was reduced by the Kv channel blocker tetraethylammonium hydrochloride (TEA), but not by the selective TRPV1-channel antagonist capsazepine. On MC3T3-E1 cells and bone marrow-derived osteoblasts, ZOL-evoked current (5 × 10−8 to 10−4 M) was reduced by capsazepine, whereas the selective TRPV1-channel agonist capsaicin potentiated the control current. In the cell proliferation assay, 72 h incubation of RAW264.7 and MC3T3-E1 cells with ZOL reduced proliferation, with IC50 values of 2.62 × 10−7 M and 2.02 × 10−5 M, respectively. Mineralization of MC3T3-E1 cells and bone marrow-derived osteoblasts was observed in the presence of capsaicin and ZOL (5 × 10−8–10−7 M); ZOL effects were antagonized by capsazepine. In summary, the ZOL-induced activation of TRPV1 channel mediates the mineralization of osteoblasts and counterbalances the antiproliferative effects, increasing the IC50. This mechanism is not operative in osteoclasts lacking the TRPV1 channel.

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Section: Resultsmentioning

confidence: 72%

Section: Discussionmentioning

confidence: 79%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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