Enoxacin Directly Inhibits Osteoclastogenesis without Inducing Apoptosis

Toro, Edgardo J.; Zuo, Jian; Ostrov, David A.; Catalfamo, Dana L.; Bradaschia-Corrêa, Vivian; Arana‐Chavez, Victor E.; Caridad, Aliana R.; Neubert, John K.; Wronski, Thomas J.; Wallet, Shannon M.; Holliday, L. Shannon

doi:10.1074/jbc.m111.280511

Cited by 40 publications

(62 citation statements)

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“…Enoxacin functioned by altering vesicular trafficking patterns in osteoclasts (Toro et al, 2012b). In the present study, we show that a bisphosphonate derivative of enoxacin, bis-enoxacin (BE) (Herczegh et al, 2002), also has anti-resorptive bis-enoxacin Inhibits bone resorption and Orthodontic tooth Movement activity in vitro and inhibits orthodontic tooth movement (OTM), an osteoclast-dependent process, in a rat model.…”

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confidence: 81%

“…The enzyme TRAP5b was expressed, but not proteolytically processed to the active form (Toro et al, 2012b). To determine whether lack of TRAP activity after BE treatment was due to the same mechanism, we immunoblotted RANKLstimulated Raw 264.7 extracts from cells that had been treated with vehicle or 50 μM BE and probed them with an .…”

Section: Resultsmentioning

confidence: 99%

“…Caspase-3 assays were performed as described previously (Toro et al, 2012b) with a caspase-3 assay kit (catalog No. APT131; Millipore, Temecula, CA, USA).…”

Section: Caspase-3 Assay For Apoptosismentioning

confidence: 99%

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Bis-enoxacin Inhibits Bone Resorption and Orthodontic Tooth Movement

et al. 2013

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Enoxacin inhibits binding between the B-subunit of vacuolar H + -ATPase (V-ATPase) and microfilaments, and also between osteoclast formation and bone resorption in vitro. We hypothesized that a bisphosphonate derivative of enoxacin, bis-enoxacin (BE), which was previously studied as a bone-directed antibiotic, might have similar activities. BE shared a number of characteristics with enoxacin: It blocked binding between the recombinant B-subunit and microfilaments and inhibited osteoclastogenesis in cell culture with IC 50 s of about 10 µM in each case. BE did not alter the relative expression levels of various osteoclast-specific proteins. Even though tartrate-resistant acid phosphatase 5b was expressed, proteolytic activation of the latent pro-enzyme was inhibited. However, unlike enoxacin, BE stimulated caspase-3 activity. BE bound to bone slices and inhibited bone resorption by osteoclasts on BE-coated bone slices in cell culture. BE reduced the amount of orthodontic tooth movement achieved in rats after 28 days. Analysis of these data suggests that BE is a novel anti-resorptive molecule that is active both in vitro and in vivo and may have clinical uses. Abbreviations: BE, bis-enoxacin; V-ATPase, vacuolar H + -ATPase; TRAP, tartrate-resistant acid phosphatase; αMEM D10, minimal essential media, alpha modification with 10% fetal bovine serum; SDS-PAGE, sodium dodecyl sulfate-polyacrylamide gel electrophoresis; RANKL, receptor activator of nuclear factor kappa B-ligand; NFATc1, nuclear factor of activated T-cells; ADAM, a disintegrin and metalloprotease domain; OTM, orthodontic tooth movement.

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confidence: 81%

Section: Resultsmentioning

confidence: 99%

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Bis-enoxacin Inhibits Bone Resorption and Orthodontic Tooth Movement

et al. 2013

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“…Forty-eight Sprague-Dawley rats were randomly divided into eight groups as follows: 1) polybacterial infection with P. gingivalis, T. denticola, and T. forsythia ; 2) polybacterial infection plus treatment with BE (5 mg · kg −1 · d −1 ); 23 3) polybacterial infection plus treatment with BE (25 mg · kg −1 · d −1 ); 23 4) polybacterial infection plus treatment with ALN (1 mg · kg −1 · d −1 ); 30 5) polybacterial infection plus treatment with ALN (10 mg · kg −1 · d −1 ); 30 6) polybacterial infection plus treatment with ENX (5 mg · kg −1 · d −1 ); 21,23 7) polybacterial infection plus treatment with DOX (5 mg/d); 31 and 8) shaminfected and untreated controls. A daily subcutaneous injection of these treatments was administered for 6 weeks after 6 weeks of initial infection.…”

Section: Methodsmentioning

confidence: 99%

Periodontitis in Rats Induces Systemic Oxidative Stress That Is Controlled by Bone‐Targeted Antiresorptives

Oktay

Chukkapalli

Rivera‐Kweh

et al. 2015

Journal of Periodontology

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Background Periodontitis is a chronic, polymicrobial inflammatory disease that degrades connective tissue and alveolar bone and results in tooth loss. Oxidative stress has been linked to the onset of periodontal tissue breakdown and systemic inflammation, and the success of antiresorptive treatments will rely on how effectively they can ameliorate periodontal disease–induced oxidative stress during oral infection. Methods Rats were infected with polybacterial inoculum consisting of Porphyromonas gingivalis, Treponema denticola, and Tannerella forsythia, as an oral lavage every other week for 12 weeks. Daily subcutaneous injections of enoxacin, bisenoxacin, alendronate, or doxycycline were administered for 6 weeks after 6 weeks of polybacterial infection in rats. The serum levels of oxidative stress parameters and antioxidant enzymes, including glutathione peroxidase, superoxide dismutase, and catalase, were evaluated in each of the infected, treated, and sham-infected rats. Results Rats infected with the periodontal pathogens displayed a five-fold increase in the oxidative stress index compared with controls as a result of increased levels of serum oxidants and decreases in total antioxidant activity. The overall decrease in antioxidant activity occurred despite increases in three important antioxidant enzymes, suggesting an imbalance between antioxidant macromolecules/small molecules production and antioxidant enzyme levels. Surprisingly, the bone-targeted antiresorptives bis-enoxacin and alendronate inhibited increases in oxidative stress caused by periodontitis. Bis-enoxacin, which has both antiresorptive and antibiotic activities, was more effective than alendronate, which acts only as an antiresorptive. Conclusion To the best of the authors’ knowledge, this is the first study to demonstrate that the increased oxidative stress induced by periodontal infection in rats can be ameliorated by bone-targeted antiresorptives.

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“…Primary mouse cell culture of bone marrow-derived macrophages (BMM) were isolated from the long bones of 5-week-old C57BL/6 mice, as described previously [25]. Briefly, cells were isolated from the femur and tibiae bone marrow and cultured in a T75 flask ina-MEM supplemented with 10% (v/v) FBS, 1% (w/v) penicillin/streptomycin, and 10 ng/mL M-CSF for 24 h. Nonadherent cells were then removed, and the adherent cells were cultured in an incubator maintained at 37 8C with a 5% CO 2 (v/v) atmosphere for a further 3-4 days until cells were fully confluent.…”

Section: Bone Marrow-derived Macrophage Isolation and Osteoclast Culturementioning

confidence: 99%

Myricetin prevents titanium particle-induced osteolysis in vivo and inhibits RANKL-induced osteoclastogenesis in vitro

Wang

Tian

et al. 2015

Biochemical Pharmacology

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Enoxacin Directly Inhibits Osteoclastogenesis without Inducing Apoptosis

Abstract: Background: Enoxacin inhibits vacuolar Hϩ -ATPase binding to microfilaments and bone resorption.

Cited by 40 publications

References 59 publications

Bis-enoxacin Inhibits Bone Resorption and Orthodontic Tooth Movement

Bis-enoxacin Inhibits Bone Resorption and Orthodontic Tooth Movement

Periodontitis in Rats Induces Systemic Oxidative Stress That Is Controlled by Bone‐Targeted Antiresorptives

Myricetin prevents titanium particle-induced osteolysis in vivo and inhibits RANKL-induced osteoclastogenesis in vitro

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