scholarly journals Methotrexate Toxicity in Growing Long Bones of Young Rats: A Model for Studying Cancer Chemotherapy-Induced Bone Growth Defects in Children

2011 ◽  
Vol 2011 ◽  
pp. 1-8 ◽  
Author(s):  
Chiaming Fan ◽  
Kristen R. Georgiou ◽  
Tristan J. King ◽  
Cory J. Xian
Keyword(s):  
Growth Plate ◽  
Animal Studies ◽  
Bone Growth ◽  
High Dose ◽  
Childhood Cancers ◽  
Paediatric Cancer ◽  
Growth Defects ◽  
Clinical Observations ◽  
Skeletal Defects ◽  
Underlying Mechanisms

The advancement and intensive use of chemotherapy in treating childhood cancers has led to a growing population of young cancer survivors who face increased bone health risks. However, the underlying mechanisms for chemotherapy-induced skeletal defects remain largely unclear. Methotrexate (MTX), the most commonly used antimetabolite in paediatric cancer treatment, is known to cause bone growth defects in children undergoing chemotherapy. Animal studies not only have confirmed the clinical observations but also have increased our understanding of the mechanisms underlying chemotherapy-induced skeletal damage. These models revealed that high-dose MTX can cause growth plate dysfunction, damage osteoprogenitor cells, suppress bone formation, and increase bone resorption and marrow adipogenesis, resulting in overall bone loss. While recent rat studies have shown that antidote folinic acid can reduce MTX damage in the growth plate and bone, future studies should investigate potential adjuvant treatments to reduce chemotherapy-induced skeletal toxicities.

scholarly journals Ceramide inhibition of chondrocyte proliferation and bone growth is IGF-I independent

2006 ◽  
Vol 191 (2) ◽  
pp. 369-377 ◽  
Author(s):  
V E MacRae ◽  
T Burdon ◽  
S F Ahmed ◽  
C Farquharson
Keyword(s):  
Insulin Receptor ◽  
Growth Plate ◽  
Bone Growth ◽  
Inflammatory Diseases ◽  
Thymidine Uptake ◽  
Growth Plate Chondrocytes ◽  
Igf I ◽  
Presence And Absence ◽  
Underlying Mechanisms ◽  
Induced Apoptosis

Proinflammatory cytokines inhibit growth plate development. However, their underlying mechanisms of action are unclear. These effects may be mediated by ceramide, a sphingosine-based lipid second messenger, which is elevated in a number of chronic inflammatory diseases. To test this hypothesis, we determined the effects of C2-ceramide, a cell permeable ceramide analogue, on the growth of the ATDC5 chondrogenic cell line and on cultured fetal mice metatarsals. In ATDC5 cells, C2-ceramide significantly induced apoptosis at both 40 (82%; P < 0.05) and 25 μM (53%; P < 0.05). At 40 μM, C2-ceramide significantly reduced proliferation ([3H]-thymidine uptake/mg protein) (62%; P < 0.05). C2-ceramide did not markedly alter the differentiation state of the cells as judged by the expression of markers of chondrogenesis and differentiation (sox 9, collagen II and collagen X). The IGF-I signalling pathway is the major autocrine/paracrine regulator of bone growth. Both in the presence and absence of IGF-I, C2-ceramide (25 μM) induced an equivalent reduction in proliferation (60%; P < 0.001). Similarly, C2-ceramide (40 μM) induced a 31% reduction in fetal metatarsal growth both in the presence and absence of IGF-I (both P < 0.001). Furthermore, C2-ceramide reduced ADCT5 proliferation in the presence of AG1024, an IGF-I and insulin receptor blocker. Therefore, C2-ceramide-dependent inhibition appears to be independent of IGF-mediated stimulation of bone growth. Indeed, biochemical studies demonstrated that C2-ceramide (25 μM) pretreatment did not alter IGF-I-stimulated phosphorylation of insulin receptor substrate-1, Akt or P44/42 MAP kinase. In conclusion, C2-ceramide inhibits proliferation and induces apoptosis in growth plate chondrocytes through an IGF-I independent mechanism.

scholarly journals The role of estrogen receptor-α and its activation function-1 for growth plate closure in female mice

2012 ◽  
Vol 302 (11) ◽  
pp. E1381-E1389 ◽  
Author(s):  
A. E. Börjesson ◽  
S. H. Windahl ◽  
E. Karimian ◽  
E. E. Eriksson ◽  
M. K. Lagerquist ◽  
...  
Keyword(s):  
Estrogen Receptor ◽  
Growth Plate ◽  
Bone Growth ◽  
High Dose ◽  
Plate Height ◽  
Chondrocyte Proliferation ◽  
Growth Plates ◽  
Longitudinal Bone Growth ◽  
Female Mice

High estradiol levels in late puberty induce growth plate closure and thereby cessation of growth in humans. In mice, the growth plates do not fuse after sexual maturation, but old mice display reduced longitudinal bone growth and high-dose estradiol treatment induces growth plate closure. Estrogen receptor (ER)-α stimulates gene transcription via two activation functions (AFs), AF-1 and AF-2. To evaluate the role of ERα and its AF-1 for age-dependent reduction in longitudinal bone growth and growth plate closure, female mice with inactivation of ERα (ERα−/−) or ERαAF-1 (ERαAF-10) were evaluated. Old (16- to 19-mo-old) female ERα−/− mice showed continued substantial longitudinal bone growth, resulting in longer bones (tibia: +8.3%, P < 0.01) associated with increased growth plate height (+18%, P < 0.05) compared with wild-type (WT) mice. In contrast, the longitudinal bone growth ceased in old ERαAF-10 mice (tibia: −4.9%, P < 0.01). Importantly, the proximal tibial growth plates were closed in all old ERαAF-10 mice while they were open in all WT mice. Growth plate closure was associated with a significantly altered balance between chondrocyte proliferation and apoptosis in the growth plate. In conclusion, old female ERα−/− mice display a prolonged and enhanced longitudinal bone growth associated with increased growth plate height, resembling the growth phenotype of patients with inactivating mutations in ERα or aromatase. In contrast, ERαAF-1 deletion results in a hyperactive ERα, altering the chondrocyte proliferation/apoptosis balance, leading to growth plate closure. This suggests that growth plate closure is induced by functions of ERα that do not require AF-1 and that ERαAF-1 opposes growth plate closure.

scholarly journals Regulation of bone growth via ligand-specific activation of estrogen receptor alpha

2017 ◽  
Vol 232 (3) ◽  
pp. 403-410 ◽  
Author(s):  
Maryam Iravani ◽  
Marie Lagerquist ◽  
Claes Ohlsson ◽  
Lars Sävendahl
Keyword(s):  
Estrogen Receptor ◽  
Side Effects ◽  
Growth Plate ◽  
Bone Growth ◽  
High Dose ◽  
Tall Stature ◽  
Plate Height ◽  
Estrogenic Effects ◽  
Increased Risk ◽  
Risk Of Cancer

Estrogens are well known for their capacity to promote bone maturation and at high doses to induce growth plate closure and thereby stop further growth. High-dose estrogen treatment has therefore been used to limit growth in extremely tall girls. However, recent data suggest that this treatment may have severe side effects, including increased risk of cancer and reduced fertility. We hypothesized that estrogenic effects in bone are mediated via ERα signaling. Twelve-week-old ovariectomized female C57BL/6 mice were subcutaneously injected for 4 weeks with E2 or selective ERα (PPT) or ERβ (DPN) agonists. After killing, tibia and femur lengths were measured, and growth plate morphology was analyzed. E2- and PPT-treated mice had shorter tibiae and femur bones when compared to vehicle-treated controls, whereas animals treated with DPN had similar bone lengths compared to controls. Growth plate height and hypertrophic zone height were reduced in animals treated with E2 or PPT but not in those treated with DPN, supporting that the effect was mediated via ERα. Moreover, PCNA staining revealed suppressed proliferation of chondrocytes in the tibia growth plate in PPT- or E2-treated mice compared to controls. Our data show that estrogenic effects on bone growth and growth plate maturation are mainly mediated via ERα. Our findings may have direct implications for the development of new and more selective treatment modalities of extreme tall stature using selective estrogen receptor modulators that may have low side effects than high-dose E2 treatment.

scholarly journals Growth Hormone and Insulin-Like Growth Factor I Insensitivity of Fibroblasts Isolated from a Patient with an IκBα Mutation

2010 ◽  
Vol 95 (3) ◽  
pp. 1220-1228 ◽  
Author(s):  
Shufang Wu ◽  
Marie J. Walenkamp ◽  
Arjan Lankester ◽  
Martin Bidlingmaier ◽  
Jan M. Wit ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Bone Growth ◽  
Growth Failure ◽  
Heterozygous Mutation ◽  
High Dose ◽  
Gh Secretion ◽  
Igf I ◽  
Mrna And Protein Expression ◽  
Underlying Mechanisms ◽  
Gh Resistance

Abstract Context: NF-κB is a family of transcription factors involved in cell proliferation, differentiation, and apoptosis. Objective: We have recently demonstrated that NF-κB is expressed in the growth plate and it mediates the growth-promoting effects of IGF-I on chondrogenesis and longitudinal bone growth. Humans with defects of the NF-κB pathway exhibit growth failure, which suggests a possible regulatory role for NF-κB in statural growth. We have previously reported a child with ectodermal dysplasia, immunodeficiency, and growth retardation, harboring a heterozygous mutation of IκBα, an essential component of the NF-κB pathway. Since he was found with low IGF-l and IGFBP-3, and elevated GH secretion, an IGF-l generation test was carried out: baseline IGF-l was low and only responded to a high dose of GH. Thus, the diagnosis of GH resistance was made. Results: To assess the underlying mechanisms of his GH resistance, we cultured the patient’s skin fibroblasts with GH and/or IGF-I. While both GH and IGF-l induced cell proliferation and NF-κB activity in controls’ fibroblasts, they had no effect on the patient’s fibroblasts. In the fibroblasts of the patient’s father (who displays mosaicism for the IκBα mutation), GH and IGF-l elicited an attenuated stimulatory effect. In addition, GH stimulated STAT5 phosphorylation and IGF-l mRNA expression in controls ’ and the father’s fibroblasts, while IGF-l induced PI3K activity and mRNA and protein expression of TDAG51, a target gene for IGF-I. In contrast, none of these effects was elicited by GH or IGF-l in the patient’s fibroblasts. Conclusion: Our findings suggest that this patient’s IκBα mutation caused GH and IGF-l resistance which, in turn, contributed to his growth failure.

scholarly journals Roles of MicroRNAs in Osteogenesis or Adipogenesis Differentiation of Bone Marrow Stromal Progenitor Cells

2021 ◽  
Vol 22 (13) ◽  
pp. 7210
Author(s):  
Ya-Li Zhang ◽  
Liang Liu ◽  
Yaser Peymanfar ◽  
Paul Anderson ◽  
Cory J. Xian
Keyword(s):  
Bone Marrow ◽  
Bone Growth ◽  
Target Genes ◽  
Microrna Regulation ◽  
Growth Defects ◽  
Multipotent Cells ◽  
Underlying Mechanisms

Bone marrow stromal cells (BMSCs) are multipotent cells which can differentiate into chondrocytes, osteoblasts, and fat cells. Under pathological stress, reduced bone formation in favour of fat formation in the bone marrow has been observed through a switch in the differentiation of BMSCs. The bone/fat switch causes bone growth defects and disordered bone metabolism in bone marrow, for which the mechanisms remain unclear, and treatments are lacking. Studies suggest that small non-coding RNAs (microRNAs) could participate in regulating BMSC differentiation by disrupting the post-transcription of target genes, leading to bone/fat formation changes. This review presents an emerging concept of microRNA regulation in the bone/fat formation switch in bone marrow, the evidence for which is assembled mainly from in vivo and in vitro human or animal models. Characterization of changes to microRNAs reveals novel networks that mediate signalling and factors in regulating bone/fat switch and homeostasis. Recent advances in our understanding of microRNAs in their control in BMSC differentiation have provided valuable insights into underlying mechanisms and may have significant potential in development of new therapeutics.

scholarly journals Treatment-resistant schizophrenia characterised by dopamine supersensitivity psychosis and efficacy of asenapine

2021 ◽  
Vol 14 (4) ◽  
pp. e242495
Author(s):  
Nagara Takao ◽  
Toshiya Murai ◽  
Hironobu Fujiwara
Keyword(s):  
Animal Studies ◽  
Significant Proportion ◽  
Antipsychotic Treatment ◽  
High Dose ◽  
Receptor Density ◽  
Treatment Resistant ◽  
Psychomotor Activity ◽  
Receptor Blockers ◽  
Dopamine Supersensitivity

Dopamine supersensitivity psychosis (DSP) frequently arises with long-term antipsychotic treatment and accounts for a significant proportion of treatment-resistant schizophrenia. The mechanism underlying DSP is thought to be a compensatory increase in dopamine receptor density in the striatum caused by long-term antipsychotic treatment. Previous animal studies have reported that antipsychotics increase serotonin 5-HT2A receptor density in the striatum and that 5-HT2A receptor blockers suppress dopamine-sensitive psychomotor activity, which may be linked to the pathophysiology of DSP. In this paper, we describe a patient who was hospitalised with treatment-resistant schizophrenia. Following treatment with high-dose antipsychotic polypharmacy for 10 weeks, the patient experienced worsening of psychotic and extrapyramidal symptoms. The patient was then started on second-generation antipsychotic asenapine while other antipsychotics were tapered off, resulting in improvement of these symptoms. Retrospectively, we presumed that the high-dose antipsychotic polypharmacy caused DSP, which was effectively treated by the potent 5-HT2A receptor antagonism of asenapine.

scholarly journals Release of CXCL12 from Apoptotic Skeletal Cells Contributes to Bone Growth Defects Following Dexamethasone Therapy in Rats

2020 ◽  
Vol 35 (8) ◽  
pp. 1612-1613
Author(s):  
Qian Tang ◽  
Yu‐Wen Su ◽  
Chia‐Ming Fan ◽  
Rosa Chung ◽  
Mohammadhossein Hassanshahi ◽  
...  
Keyword(s):  
Bone Growth ◽  
Growth Defects ◽  
Dexamethasone Therapy
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