Human growth hormone transgene expression increases the biomechanical structural properties of mouse vertebrae
aged rats; biomechanical properties; bone marrow compression; cortical bone; erythroid; fusion genes; growth-hormone; human; mice; Neurosciences & Neurology; Orthopedics; osteoblasts; transgenic mice; vertebrae
Study Design, Caudal vertebrae were obtained from male and female mice from two transgenic lines expressing an erythroid-specific human growth hormone-transgene construct, and gender-matched, age-matched, nontransgenic control mice. Objective. To characterize the effect of human growth hormone transgene expression on the biomechanical structural properties of caudal vertebrae in compression. Summary of Background Data. An increase in trabecular and cortical bone deposition caused by erythroid-specific human growth hormone transgene expression was demonstrated previously. Methods. Compression tests were performed on individual caudal vertebrae (Ca4, Ca5, Ca6) obtained from male and female mice from two transgenic lines (TG420 and TG450) and nontransgenic control mice. Two age groups were evaluated: 12 weeks old and 6 months old. The data were used to obtain axial stiffness, maximum load, and energy to failure. Results. Vertebrae from male TG420 transgenic mice produced significantly larger values for maximum load, energy to failure, and axial stiffness at both 12 weeks and 6 months in comparison with their age-matched nontransgenic male controls. Vertebrae from female TG420 transgenic mice produced similar responses at 6 months. Vertebrae from male TG450 transgenic mice showed significant increases in maximum load and energy to failure at 6 months. In general, the biomechanical properties of vertebrae were significantly larger in the 6-month age group than in the 12-week age group, and this increase was significantly greater in the transgenic mice than in the gender-matched control mice during the same time span. This process was also influenced by transgenic genotype and gender. Conclusions. Erythroid-specific production of human growth hormone in transgenic mice resulted in significant increases in biomechanical properties of their caudal vertebrae in compression. The changes in the biomechanical properties were influenced by genotype, age, and gender.
Steinke B; Patwardhan A G; Havey R M; King D
Spine
1999
1999-01
Journal Article
<a href="http://doi.org/10.1097/00007632-199901010-00002" target="_blank" rel="noreferrer noopener">10.1097/00007632-199901010-00002</a>
Similarities and Differences between Two Modes of Antagonism of the Thyroid Hormone Receptor
androgen receptor; Biochemistry & Molecular Biology; coactivator binding; estrogen receptor; gene-expression; growth-hormone; hepatoma-cell line; hepg2; liver; nuclear receptor; small-molecule inhibitors
Thyroid hormone (T3) mediates diverse physiological functions including growth, differentiation, and energy homeostasis through the thyroid hormone receptors (TR). The TR binds DNA at specific recognition sequences in the promoter regions of their target genes known as the thyroid, hormone response elements (TREs). Gene expression at TREs regulated by TRs is mediated by coregulator recruitment to the DNA bound receptor. This TR-coregulator interaction controls transcription of target genes by multiple mechanisms including covalent histone modifications and chromatin remodeling. Our previous studies identified a beta-aminoketone as a potent inhibitor of the TR-coactivator interaction. We describe here the activity of one of these inhibitors in modulating effects of T3 signaling in comparison to an established ligand-competitive inhibitor of TR, NH-3. The beta-aminoketone was found to reverse thyroid hormone induced gene expression by inhibiting coactivator recruitment at target gene promoters, thereby regulating downstream effects of thyroid hormone. While mimicking the downstream effects of NH-3 at the molecular level, the beta-aminoketone affects only a subset of the thyroid responsive signaling network. Thus antagonists directed to the coregulator binding site have distinct pharmacological properties relative to ligand-based antagonists and may provide complementary activity in vivo.
Sadana P; Hwang J Y; Attia R R; Arnold L A; Neale G; Guy R K
Acs Chemical Biology
2011
2011-10
Journal Article
<a href="http://doi.org/10.1021/cb200092v" target="_blank" rel="noreferrer noopener">10.1021/cb200092v</a>