Folinic acid attenuates methotrexate chemotherapy‐induced damages on bone growth mechanisms and pools of bone marrow stromal cells

Chen, Xian; Cool, Johanna C.; Scherer, Michaela; Fan, Chiaming; Foster, Bruce K.

doi:10.1002/jcp.21274

Cited by 41 publications

(79 citation statements)

References 38 publications

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“…Consistent with a multiplicity of functions for OPN, it is involved specifically in both the forming and resorption of bone. That is why its suppression causes defects in process of bone remodeling (Fan et al, 2016) In The result of present work came in line with the study of Xian et al (2008) who found that MTX had no obvious effects on apoptosis but only some moderate damaging effects on proliferation of osteoblasts and preosteoblasts in bone with moderate changes in osteoblastic cell density along trabecular surface in comparing to 5-FU.…”

Section: Results:-supporting

confidence: 88%

Evaluation of Toxic Effects of Chemotherapeutic Drugs on Normal Jaw Bones Using Osteopontin: An Experimental Study.

Farag¹,

Hassabou²,

Din³

et al. 2018

IJAR

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Background: Chemotherapy does not differentiate between rapidly dividing cancer cells and normal cells that divide at higher rates as bone forming cells. Methotrexate and 5-fluorouracil are chemotherapeutic drugs with high potentiality to damage bone forming cells by blocking their DNA synthesis which leads to their suppression and in turn impaired bone formation mainly by dysregulation of Runx2 and osterix associated with osteoblastic cell differentiation. Aim: Compare the toxic effects of methotrexate and 5-flurouracil on normal bone cells. Material and methods: A total of 30 rats were divided into three groups. Group I was control group, Group II was given a single 20 mg/kg intraperitoneal dose of MTX and Group III was given a single 150 mg/kg intraperitoneal dose of 5-FU. Four days later, the rats were euthanized and their mandibles were dissected, immediately fixed in 10% formalin, processed and prepared for histopathological and immunohistochemical examinations using osteopontin. Statistical analysis was performed using ANOVA test where P values < 0.05 were statistically significant. Results: Variable degenerative effects on the bone forming cells were observed where such effects were higher in 5-FU group compared to the MTX group. Positive osteopontin expression and higher number of bone formative cells were detected in the control group followed by MTX group then the 5-FU group. Low osteopontin expression was correlated with decreased number of bone cells and subsequent decreased jaw bone density and formation. Conclusion: 5-FU is more cytotoxic to the normal bone forming cells than MTX.

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Section: Results:-supporting

confidence: 88%

Evaluation of Toxic Effects of Chemotherapeutic Drugs on Normal Jaw Bones Using Osteopontin: An Experimental Study.

Farag¹,

Hassabou²,

Din³

et al. 2018

IJAR

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“…Also, MTX therapy might lead to overall reduction of trabecular bone volume [36] . Experimental studies of MTX induced bone defects revealed that apart from the reduced osteoblast number and trabecular bone volume; there was a significant increase in marrow adiposity [31,37] .…”

Section: Discussionmentioning

confidence: 99%

The Protective Role of Simvastatin on Methotrexate-Induced Bone Injury in Adult Albino Rat

Elsaid

Sadek

2017

Egyptian Journal of Histology

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Background: Methotrexate (MTX) is a folic acid antagonist and chemotherapeutic agent widely used in cancer treatment. It is used as first line therapy in treatment of rheumatoid arthritis (RA). MTX was known to cause bone defects in the form of reduced mineral density (BMD) and bone fractures. Simvastatin (SIM) is widely used for cardiovascular diseases. Aim of Work: To investigate the possible protective role of SIM on MTX induced bone injury in rats. Material and Methods: Forty adult male albino rats were divided into four groups; Control group, SIM-treated group, MTX group and MTX + SIM group. MTX was given by subcutaneous injection as 0.65 mg/kg/day for two separate 5 days. SIM was administered orally as 25 mg/kg/day one month prior to and during the MTX course. At the end of the experiment, blood samples were collected for levels of osteocalcin (OSC) and alkaline phosphatase (ALP). All rats were sacrificed and specimens from their femurs were examined. Results: examination of MTX group showed marked thinning of the periosteum, and widening of bone marrow spaces. There was an apparent decrease in the number of osteocytes, together with an apparent increase in the number of osteoclasts. There was a significant decrease in the serum level of OSC together with a highly significant increase in the serum level of ALP in the MTX group as compared to the control group. On administration of SIM with MTX, there was marked improvement in most of the histological and serological parameters. Conclusion: SIM could be used as a protective measure for MTX-induced bone defects.

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“…EO supplementation significantly preserved the osteoblast density especially on day 3 after H 2 O ϩ 5-FU administration and prevented 5-FU-induced higher osteoclast density in the metaphysis. Although the mechanisms for EO-induced preservation of osteoblast density remain to be studied, it is known that a constant supply of osteoblasts is required for normal bone formation and homeostasis, and any significant reduction in osteoblast numbers and activity can result in reduced bone formation and lead to osteoporosis (8,49,51). Although the underlying mechanisms for EO's antiosteoclastic effects remain to be defined, consistent with its effects in suppressing 5-FU-induced osteoclastogenesis, our gene expression studies suggest that EO supplementation can suppress the induction of proinflammatory cytokines, particularly TNF␣ and osteoclast receptors RANK and OSCAR, which were upregulated by (53).…”

Section: Discussionmentioning

confidence: 99%

“…Stained sections were used for morphometric measurements of growth plate total heights, heights of primary spongiosa, and bone volume of primary and secondary spongiosa metaphyseal bone using image analysis software AnalySIS (Olympus). Briefly, the entire height of the growth plate along an axis oriented 90°to the transverse of the growth plate and parallel to the longitudinal axis of the tibial bone was measured (12,48,49,51,52). Similarly, the average primary spongiosa zonal height at the metaphysis was also obtained using the same software (12,48,49,51,52).…”

Section: Methodsmentioning

confidence: 99%

“…Briefly, the entire height of the growth plate along an axis oriented 90°to the transverse of the growth plate and parallel to the longitudinal axis of the tibial bone was measured (12,48,49,51,52). Similarly, the average primary spongiosa zonal height at the metaphysis was also obtained using the same software (12,48,49,51,52). At both primary (0.1 mm above the primary-secondary transitional line) and secondary spongiosa (1 mm below the transitional line), total areas were measured and all trabecular cores traced, and the data were used to work out the ratio of bone volume to total tissue volume (BV/TV%), as described (12,48,49,51,52).…”

Section: Methodsmentioning

confidence: 99%

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Dietary emu oil supplementation suppresses 5-fluorouracil chemotherapy-induced inflammation, osteoclast formation, and bone loss

Nadhanan

Abimosleh

et al. 2012

American Journal of Physiology-Endocrinology and Metabolism

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Raghu Nadhanan R, Abimosleh SM, Su YW, Scherer MA, Howarth GS, Xian CJ. Dietary emu oil supplementation suppresses 5-fluorouracil chemotherapy-induced inflammation, osteoclast formation, and bone loss. Am J Physiol Endocrinol Metab 302: E1440 -E1449, 2012. First published March 20, 2012; doi:10.1152/ajpendo.00587.2011Cancer chemotherapy can cause osteopenia or osteoporosis, and yet the underlying mechanisms remain unclear, and currently, no preventative treatments are available. This study investigated damaging effects of 5-fluorouracil (5-FU) on histological, cellular, and molecular changes in the tibial metaphysis and potential protective benefits of emu oil (EO), which is known to possess a potent anti-inflammatory property. Female dark agouti rats were gavaged orally with EO or water (1 ml·day Ϫ1 ·rat Ϫ1 ) for 1 wk before a single ip injection of 5-FU (150 mg/kg) or saline (Sal) was given. The treatment groups were H2O ϩ Sal, H2O ϩ 5-FU, EO ϩ 5-FU, and EO ϩ Sal. Oral gavage was given throughout the whole period up to 1 day before euthanasia (days 3, 4, and 5 post-5-FU). Histological analysis showed that H2O ϩ 5-FU significantly reduced heights of primary spongiosa on days 3 and 5 and trabecular bone volume of secondary spongiosa on days 3 and 4. It reduced density of osteoblasts slightly and caused an increase in the density of osteoclasts on trabecular bone surface on day 4. EO supplementation prevented reduction of osteoblasts and induction of osteoclasts and bone loss caused by 5-FU. Gene expression studies confirmed an inhibitory effect of EO on osteoclasts since it suppressed 5-FU-induced expression of proinflammatory and osteoclastogenic cytokine TNF␣, osteoclast marker receptor activator of nuclear factor-B, and osteoclast-associated receptor. Therefore, this study demonstrated that EO can counter 5-FU chemotherapy-induced inflammation in bone, preserve osteoblasts, suppress osteoclast formation, and potentially be useful in preventing 5-FU chemotherapy-induced bone loss.receptor activator of nuclear factor-B ligand; tumor necrosis factor-␣; anti-inflammatory ANTI-CANCER CHEMOTHERAPY can cause significant adverse effects on tissues, including the bone, in both pediatric and adult cancer patients (25). Short stature, low bone mass or osteoporosis, and/or fractures are some skeletal side effects that are due to chemotherapy among pediatric patients and adult survivors (32, 38, 46). Experimental studies in rats have also shown that drugs such as methotrexate (MTX), cisplatin, doxorubicin, etoposide, cyclophosphamide, and 5-fluorouracil (5-FU) can cause a reduction in bone growth and bone mass (50 -52). 5-FU is an antimetabolite drug commonly used to treat adult patients suffering from colorectal and breast cancer, whereas in children 5-FU is used to treat childhood solid tumours (27, 36). 5-FU inhibits thymidylate synthase, an enzyme required to synthesize thymine nucleotide, which is important for synthesis of DNA and RNA (27). In an acute 5-FU chemotherapy model in rats, reduced primary spongiosa heigh...

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Folinic acid attenuates methotrexate chemotherapy‐induced damages on bone growth mechanisms and pools of bone marrow stromal cells

Cited by 41 publications

References 38 publications

Evaluation of Toxic Effects of Chemotherapeutic Drugs on Normal Jaw Bones Using Osteopontin: An Experimental Study.

Evaluation of Toxic Effects of Chemotherapeutic Drugs on Normal Jaw Bones Using Osteopontin: An Experimental Study.

The Protective Role of Simvastatin on Methotrexate-Induced Bone Injury in Adult Albino Rat

Dietary emu oil supplementation suppresses 5-fluorouracil chemotherapy-induced inflammation, osteoclast formation, and bone loss

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