Estrogen receptor (ER) a is a member of the nuclear receptor superfamily. Upon binding to 17b-estradiol (E2), ERa undergoes conformational changes and modulates the transcription of target genes.1) The magnitude of this estrogen-induced response depends on the initial concentration of ERa 2) and is modulated by numerous regulatory proteins.3) Furthermore, the differential regulation of coactivator activity modulates ER signal transduction pathways via direct or indirect interactions.4) Despite considerable progress, the exact mechanism of E2-induced transcriptional activation has yet to be elucidated.Down-regulation of ERa in response to estrogen is one of the earliest and most distinct functional readouts of estrogen binding and was first observed more than four decades ago. 5)Although the transcriptional mechanism of autoregulation is not fully understood, studies have shown that ligand-mediated protein degradation via 26S proteasome is involved. 6)The ubiquitin proteasome system has been implicated in cellcycle control, signal transduction, and transcription.7) The somewhat paradoxical correlation between receptor turnover and transcriptional activation of estrogen target genes raises the possibility that ER down-regulation is intimately related to ERa-mediated transactivation. 8) Lonard et al. 9) showed that the ubiquitin-proteasome function is required for ERa to serve as a transcriptional activator. In addition, they showed that protein interactions with ERa coactivator-binding surfaces are important for ligand-mediated ER down-regulation, suggesting that receptor and coactivator turnover contributes to ERa transcriptional activity. However, a different experimental system found that these two phenomena are distinct responses.9,10) Thus, further studies, using various experimental systems, are required.ER is also degraded in response to stimuli other than estrogens.11,12) We and others have reported that under hypoxic conditions, ER is degraded via a proteasome-dependent pathway. 13,14) Hypoxia plays an important role in normal physiological processes and development as well as in tumorigenesis.15) Hypoxia-inducible factor-1 (HIF-1), a heterodimer composed of the HIF-1a subunit and the aryl hydrocarbon receptor nuclear translocator b-subunit, is a key transcription factor that regulates the expression of various genes involved in the physiological response to changes in cellular oxygen tension. For example, HIF-1 modulates erythropoietin expression during erythropoiesis; glucose transporter-1, aldolase A, enolase 1, and lactate dehydrogenase expression during glycolysis; vascular endothelial growth factor expression during vasculogenesis; and nitric oxide synthase and hemoxigenase expression during vasodilation.16) We previously demonstrated that HIF-1a is sufficient to induce proteasomedependent ER down-regulation, which involves interactions between these proteins.13) In addition, hypoxia-induced HIF1a can activate ERa in the absence of a estrogenic ligand. Here we used the proteasome inhibitor MG132 t...
to treatment (p¼0.001); effect size 0.76. There was a statistically significant increase in HOOS of 12.4 at 52 weeks (p<0.0005); effect size 0.76 when comparing the treatment and control groups. The UCLA activity score showed an increase of 0.66 (p¼0.019); effect size 0.43 in favour of the treatment group at 52 weeks. The EQ5D summary index increased by 0.85 (p¼0.005); effect size 0.76 at 52 weeks when moving from the control group to the treatment group. Hip flexion (increase of 17.9, p<0.0005) and hip extension (increase of 5.7, p¼.004) also showed a marked improvement between the treatment group and the control group. Muscle strength improved more in the intervention group but was not statistically significant. Eighty percent (32 of 40) of the intervention group fully met their self-selected goal compared to 55% (22 of 40) of the control group. Conclusions: A simple tailored exercise programme resulted in marked increases in hip range of motion and self reported function than the previous conventional rehabilitation programme. A change in the emphasis of post-operative rehabilitation could improve outcome for patients after hip resurfacing arthroplasty
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