Inhibition of bone resorption by α-difluoromethylornithine may not be mediated by polyamine depletion

Lucas, Rita C.; Seidenfeld, Jerome; Krieger, Nancy S.; Stern, Paula H.

doi:10.1002/jbmr.5650040615

Cited by 4 publications

(1 citation statement)

References 21 publications

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“…Tamoxifen has been shown to inhibit prostaglandin synthesis in vitro [41], and it was previously reported that prostaglandin E, a potent bone resorbing agent, increases in bone after immobilisation [42]. Tamoxifen has also been shown to regulate the expression of genes that control polyamine biosynthesis [36], and polyamine inhibitors have been shown to inhibit parathyroid hormone-mediated bone resorption [26]. Induction of transforming growth factor-beta by tamoxifen has also been reported [20].…”

Section: Introductionmentioning

confidence: 99%

Biochemical and immunohistochemical investigations on bone formation and remodelling in ovariectomised rats with tamoxifen citrate administration

Baloğlu

Özkorkmaz

2019

Folia Morphol

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Background: Osteoporosis results with the imbalance between osteoblastic formation and osteoclastic resorption, resulting in susceptibility to bone fractures. Ovariectomy leads to osteoporosis by triggering alterations in bone formation and structure. Tamoxifen as an anti-oestrogen is used for adjuvant therapy especially in metastatic diseases and known to have a bone mass protective effect after ovariectomy. Materials and methods: An animal model of ovariectomy induced osteoporosis after tamoxifen citrate administration was studied via biochemical and immunohistochemical methods. Female Wistar albino rats (n = 45), selected according to their oestrous cycle, were divided into three groups; I -control, II -ovariectomy, III -ovariectomy + tamoxifen. Following ovariectomy, tamoxifen citrate (10 mg/kg) was given intraperitoneally daily for 8 weeks. At the end of the period, animals were sacrificed under anaesthesia, blood samples were taken to measure oestrogen, calcium, and alkaline phosphate. Tibia bone samples were fixed in formalin solution and decalcified with 5% ethylene-diamine tetra acetic acid. After the routine histological follow up, samples were embedded in paraffin and cut with a microtome for semi-thin sections. Primary antibodies osteonectin and osteopontin were applied to sections and examined under light microscope. Results: As a consequence, when oestrogen and calcium data were compared there was a decrease in ovariectomy group with an increase in alkaline phosphatase. In ovariectomy + tamoxifen group, these values were close to the control group. Osteonectin was observed to promote bone formation by influencing collagen fibre formation, extracellular matrix development, osteoblast differentiation and the capacity to affect osteoclast activity. Conclusions: It has been suggested that osteopontin, the cytokine and cell binding protein, stimulates cellular signalling pathways, induces bone remodelling and acts in osteoporosis. (Folia Morphol 2019; 78; 4: 789-797)

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Section: Introductionmentioning

confidence: 99%

Biochemical and immunohistochemical investigations on bone formation and remodelling in ovariectomised rats with tamoxifen citrate administration

Baloğlu

Özkorkmaz

2019

Folia Morphol

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A clinical-stage Nrf2 activator suppresses osteoclast differentiation via the iron-ornithine axis

Dong,

Kang,

Peng

et al. 2024

Cell Metabolism

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Developmental toxicity studies of 2-(difluoromethyl)-dl-ornithine (DFMO) in rats and rabbits

Kirchner

Mercieca²,

Crowell³

et al. 1999

Toxicological Sciences

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DFMO, an irreversible inhibitor of ornithine decarboxylase (ODC), is under development as a chemopreventive drug against cancers with pronounced proliferative phases. In support of human clinical trials, preclinical developmental toxicity studies were conducted in pregnant rats and rabbits. Rats were treated during GD 6-17, and fetuses were obtained by C-section on GD 20. Rabbits were treated during GD 7-20, and fetuses were obtained by C-section on GD 29. The dose range-finding study in rats (5/group at 0, 50, 125, 300, 800, or 1000 mg/kg/day) revealed maternal toxicity at doses > or = 800 mg/kg/day (decreased body weights and food consumption) and developmental toxicity at doses > or = 300 mg/kg/day (increased early resorptions and reduced fetal body weights). In the main study, rats (25/group) received 0, 30, 80, or 200 mg/kg/day. Developmental toxicity in the absence of maternal toxicity was observed at 200 mg/kg/day as significantly decreased fetal weights and increased incidence of litters with skeletal variations of 14th rudimentary rib, 14th full rib, and/or 27th presacral vertebrae. There were no treatment-related fetal skeletal malformations or external or visceral anomalies at any dose level. The dose range-finding study in rabbits (5/group at 0, 30, 60, 120, 240, or 500 mg/kg/day) revealed developmental toxicity at doses > or = 60 mg/kg/day (increased resorptions and reduced fetal body weights) in the absence of maternal toxicity. In the main study, rabbits (20/group) received 0, 15, 45, or 135 mg/kg/day. Developmental toxicity in the absence of maternal toxicity was observed at 135 mg/kg/day as nonsignificantly increased early resorptions, decreased implantation sites, decreased viable fetuses, and reduced fetal weights. There were no external, visceral, or skeletal anomalies at any dose level. Thus, in the main developmental toxicity studies, DFMO produced developmental but not maternal toxicity at 200 and 135 mg/kg/day in rats and rabbits, respectively. Accordingly, in rats, the maternal no-observable-effect level (NOEL) was 200 mg/kg/day and the fetal NOEL was 80 mg/kg/day; while in rabbits the maternal NOEL was 135 mg/kg/day and the fetal NOEL was 45 mg/kg/day. These fetal NOELs are several-fold higher than the dose level currently used in Phase II and III clinical trials (approximately 13 mg/kg).

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Inhibition of bone resorption by α-difluoromethylornithine may not be mediated by polyamine depletion

Cited by 4 publications

References 21 publications

Biochemical and immunohistochemical investigations on bone formation and remodelling in ovariectomised rats with tamoxifen citrate administration

Biochemical and immunohistochemical investigations on bone formation and remodelling in ovariectomised rats with tamoxifen citrate administration

A clinical-stage Nrf2 activator suppresses osteoclast differentiation via the iron-ornithine axis

Developmental toxicity studies of 2-(difluoromethyl)-dl-ornithine (DFMO) in rats and rabbits

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