The genetic basis of human height : the role of estrogen

摘要: Height is a complex physical trait that displays strong heritability. Adult height related to length of the long bones, which determined by growth at epiphyseal plate. Longitudinal bone occurs via process endochondral ossification, where forms over differentiating cartilage template Estrogen plays major role in regulating longitudinal and responsible for inducing pubertal spurt fusion However, mechanism estrogen promotes poorly understood. It has been hypothesised functions regulate plate stimulating chondrocyte apoptosis, angiogenesis cell invasion Another theory suggested exposure exhausts proliferative capacity chondrocytes, accelerates senescence, leading fusion. The overall objective this study was gain greater understanding molecular mechanisms behind estrogen-mediated attainment examining gene regulation chondrocytes some these genes normal inheritance. With heritability so well established, initial hypothesis genetic variation candidate associated with would be involved adult variation. height-related FGFR3, CBFA1, ER CBFA1 were screened novel polymorphisms using denaturing HPLC RFLP analysis. In total, 24 identified. Two SNPs (rs3757323 C>T rs1801132 G>C) strongly male displayed an 8 cm 9 difference between homozygous genotypes, respectively. TC haplotype 6 decrease remarkably, no carriers identified tall subjects. No significant associations found or VDR genes. plate, proliferation, matrix synthesis hypertrophy are all contributors growth. As such both final attainment, another exerted its effects influencing proliferation mediating expression marker examination regulated chondrocyte-like cells aimed identify potential regulators fusion, may further elucidate cessation linear While did not dramatically alter SW1353 line, experiments several Sixteen examined response concentrations ranging from 10-12 M 10-8 varying time points. Of analysed, IHH, collagen II X readily detectable PTHrP, GHR, ER, BMP6, SOX9 TGF1 mRNAs showed treatments. MMP13, BCL-2 BAX significantly decreased. Interestingly, majority expressed hypertrophic zone also known systemic GH secretion local action. At level, inhibit action negatively signalling. treated increases MMP9 mRNA (4.4-fold) MMP13 (64-fold) cells. Increases detected their respective proteins. Treatment AG490, established JAK2 inhibitor, blocked mediated stimulation expression. application attenuated GH-stimulated levels, but affect levels. Investigation signalling revealed have high levels activated GH, estrogen, AG490 other inhibitors phosphorylation. treatment decreased ERK2 signalling, although stimulate phosphorylation above control expression, transcription factor activate MMP13. Finally, increased SOCS3 mRNA, suggesting JAK/STAT modulation GH-mediated MMP represents potentially investigation required order precise This provided additional evidence factors determination height. Newly only contribute our basis human height, useful association studies traits. indicated modifies primarily region Furthermore, synergistic incorporating ability attenuate on revealing pathways modulate even arthritis.