Cellular mechanisms for methotrexate chemotherapy-induced bone growth defects

Chen, Xian; Cool, Johanna C.; Scherer, Michaela; Macsai, Carmen E.; Fan, Chiaming; Covino, Mark; Foster, Bruce K.

doi:10.1016/j.bone.2007.07.021

Cited by 82 publications

(169 citation statements)

References 30 publications

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“…Interestingly, the in vivo effect of Eto on proliferation of growth plate chondrocytes observed in the current study is consistent with in vitro findings in a previous work which reported dose-dependent inhibition of colony formation and cell cycle progression of rat tibial growth plate chondrocytes exposed to Eto in culture. 29 Previously, it has also been shown that different anti-metabolites appear to have different effects in the growth plate, with 5-fluorouracil (5-FU) being able to induce apoptosis and suppress proliferation and with methotrexate being able to induce apoptosis but having minor effects on proliferation in the growth plate, [13][14]16 In this current study, effects on cell proliferation and apoptosis in the growth plate were also obvious with the combination use of the two drugs. Although combination of Cyc and Eto produced more profound adverse effects in body weight gain than the individual usage as shown previously, 30 no obvious additive or synergistic effects of these two drugs together on the growth plate were observed in our current study.…”

Section: Discussionmentioning

confidence: 55%

“…[19][20][21] Similarly, some studies have demonstrated that some other individual chemotherapy drugs impair bone growth mechanisms and bone growth directly, including DNA-damaging agents cisplatin and doxorubicin and anti-metabolites 5-FU and methotrexate. [13][14]16,[36][37] …”

Section: Discussionmentioning

confidence: 99%

“…Previous evidence has suggested that the effects of chemotherapy on bone growth may be independent of the hypothalamic-pituitary axis. 15 Our recent studies have demonstrated that anti-metabolites 5-fluorurosil [13][14] and methotrexate 16 can damage bone growth mechanisms directly, inhibiting proliferation and inducing apoptosis in growth plate chondrocytes and metaphyseal bone cells. However, effects of other chemotherapy drugs on bone growth mechanisms remain less clear, and this project aimed to investigate effects of acute treatment with an alkylating agent cyclophosphamide (Cyc) and/or a topoisomerase inhibitor etoposide (Eto) on growth plate cartilage and metaphyseal bone.…”

Section: Introductionmentioning

confidence: 99%

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Effects of etoposide and cyclophosphamide acute chemotherapy on growth plate and metaphyseal bone in rats

Chen¹,

Cool²,

Gangelen³

et al. 2007

Cancer Biology & Therapy

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Section: Discussionmentioning

confidence: 55%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Effects of etoposide and cyclophosphamide acute chemotherapy on growth plate and metaphyseal bone in rats

Chen¹,

Cool²,

Gangelen³

et al. 2007

Cancer Biology & Therapy

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“…An apparent decrease in the number of osteocytes was observed and some of them showed apoptotic nuclei. Xian et al attributed the reduction of collagen fibers in the bony cortex to reduction of osteocytes proliferation and induction of osteocytes apoptosis through the Fas/Fas-L death receptor pathway induced by MTX treatment [31] .…”

Section: Discussionmentioning

confidence: 99%

“…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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The morphogenesis of porcine femoral head mammillary processes: A structural mechanism of biomechanical stability

Perrone

Williams

2021

The Anatomical Record

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The capital femoral physis is a growth plate located between the head of the femur and femoral neck, which forms a temporary joint where growth plate cartilage is converted to bone by endochondral ossification. The bone‐cartilage‐bone interface develops a unique radial pattern of interdigitating mammillary processes that interlock the femoral head with the metaphysis, increasing biomechanical stability. The arrangement of these mammillary processes may not be a random occurrence and likely serves to provide mechanical mechanisms to enhance biomechanical stability. In this study, we provide a qualitative and quantitative analysis of porcine femoral head mammillary processes and focus on the analysis of six key points of development: the epiphyseal tubercle, epiphyseal cupping, growth plate slope angles, expansion of the epiphyseal subchondral bone plate, epiphyseal elongation, and the emergence of smaller, radially arranged mammillary processes. We introduce a metric of surface roughness analysis to quantify mammillary processes and apply it to analyze the development of the observed radial pattern of peripheral mammillary processes from birth to adolescence. We hypothesized that these processes develop to form a radial pattern with some degree of periodicity beginning relatively early in development of the joint and increase in prominence with age and weight of the animal. These findings may have important implications in the early diagnosis and treatment of the hip disorder slipped capital femoral epiphysis (SCFE). Underdevelopment of femoral head mammillary processes may reduce joint stability and could be a risk factor in SCFE.

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Cellular mechanisms for methotrexate chemotherapy-induced bone growth defects

Cited by 82 publications

References 30 publications

Effects of etoposide and cyclophosphamide acute chemotherapy on growth plate and metaphyseal bone in rats

Effects of etoposide and cyclophosphamide acute chemotherapy on growth plate and metaphyseal bone in rats

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

The morphogenesis of porcine femoral head mammillary processes: A structural mechanism of biomechanical stability

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