Overexpression of human hydroxysteroid (17beta) dehydrogenase 2 induces disturbance in skeletal development in young male mice.
ABSTRACT To understand the function of human hydroxysteroid (17beta) dehydrogenase 2 (HSD17B2) in the peripheral tissues in vivo, we studied the bone development in transgenic male mice ubiquitously expressing human HSD17B2. Bones of HSD17B2TG and WT males (26 days and 2 and 6 mo old) were analyzed by pQCT and histomorphometry, and data were correlated with serum testosterone (T), IGF-I, and osteocalcin concentrations. At the age of 26 days, the body weight of HSD17B2TG males was significantly lower, and the lengths of the tibia and femur of the HSD17B2TG males were significantly shorter. Histomorphometric and pQCT analyses showed lower trabecular and cortical BMD, a markedly smaller area of cortical bone at both of the diaphyses, and a smaller percentage of trabecular bone volume and thickness in the HSD17B2TG males. The data suggested slower osteoblast differentiation and a slower bone formation rate of femoral diaphysis on the periosteum but faster on the endocortical surface in HSD17B2TG males. The altered bone parameters were correlated with low serum T, IGF-I, and osteocalcin concentrations at the prepubertal age. Interestingly, after puberty, the bone parameters analyzed in the adult HSD17B2TG males were mostly normal, consistent with the normal body weight and normalized serum concentrations of IGF-I and T. In conclusion, HSD17B2TG males presented with growth retardation and a decreased bone formation rate at prepubertal age. These changes were associated with lower serum IGF-I, osteocalcin, and T concentrations. It is concluded that the enforced constitutive expression of HSD17B2 disturbs the coordinated action of IGF-I and sex steroids essential for pubertal bone growth.
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ABSTRACT: Null mutant mice for retinoic acid receptor gamma 2 (RAR gamma 2) or all RAR gamma isoforms were generated. RAR gamma 2 mutants appeared normal, whereas RAR gamma mutants exhibited growth deficiency, early lethality, and male sterility due to squamous metaplasia of the seminal vesicles and prostate. These defects were previously observed in vitamin A-deficient animals and could be prevented by RA administration, demonstrating that RAR gamma mediates some of the retinoid signal in vivo. Congenital defects included Harderian gland agenesis, tracheal cartilage malformations, and homeotic transformations along the rostral axial skeleton, establishing a direct link between RA and patterning of the axial skeleton. We also show that in utero RA-induced lumbosacral truncations are mediated by RAR gamma. The observed RAR gamma null phenotype suggests a high degree of functional redundancy among the RARs. The variable penetrance of some of the observed defects is discussed in light of this redundancy and stochastic variation of gene activity.Cell 06/1993; 73(4):643-58. · 31.96 Impact Factor
Article: Growth at puberty.[show abstract] [hide abstract]
ABSTRACT: Somatic growth and maturation are influenced by a number of factors that act independently or in concert to modify an individual's genetic potential. The secular trend in height and adolescent development is further evidence for the significant influence of environmental factors on an individual's genetic potential for linear growth. Nutrition, including energy and specific nutrient intake, is a major determinant of growth. Paramount to normal growth is the general health and well-being of an individual; in fact, normal growth is a strong testament to the overall good health of a child. More recently the effect of physical activity and fitness on linear growth, especially among teenage athletes, has become a topic of interest. Puberty is a dynamic period of development marked by rapid changes in body size, shape, and composition, all of which are sexually dimorphic. One of the hallmarks of puberty is the adolescent growth spurt. Body compositional changes, including the regional distribution of body fat, are especially large during the pubertal transition and markedly sexually dimorphic. The hormonal regulation of the growth spurt and the alterations in body composition depend on the release of the gonadotropins, leptin, the sex-steroids, and growth hormone. It is very likely that interactions among these hormonal axes are more important than their main effects, and that alterations in body composition and the regional distribution of body fat actually are signals to alter the neuroendocrine and peripheral hormone axes. These processes are merely magnified during pubertal development but likely are pivotal all along the way from fetal growth to the aging process.Journal of Adolescent Health 01/2003; 31(6 Suppl):192-200. · 2.97 Impact Factor
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ABSTRACT: Ovariectomy in young, growing rodents results in decreased trabecular bone mineral density (BMD) and increased radial growth of the cortical bone. Both of these effects are reversed by treatment with estrogen. The aim of the present study was to determine the physiological role of estrogen receptor-beta (ERbeta) on bone structure and bone mineral content (BMC). The BMC was increased in adult (11 weeks old), but not prepubertal (4 weeks old), female ERbeta(-/-) mice compared with wild-type (WT) mice. This increase in BMC in females was not due to increased trabecular BMD, but to an increased cross-sectional cortical bone area associated with a radial bone growth. Male ERbeta(-/-) mice displayed no bone abnormalities compared with WT mice. Ovariectomy decreased the trabecular BMD to the same extent in adult female ERbeta(-/-) mice as in WT mice. The expression levels of osteoblast-associated genes - alpha1(I) collagen, alkaline phosphatase, and osteocalcin mRNAs - were elevated in bone from adult ERbeta(-/-) females compared with WT mice. These observations provide a possible explanation for the increased radial bone growth seen in female mutants, suggesting a repressive function for ERbeta in the regulation of bone growth during female adolescence. In summary, ERbeta is essential for the pubertal feminization of the cortical bone in female mice but is not required for the protective effect of estrogens on trabecular BMD.Journal of Clinical Investigation 11/1999; 104(7):895-901. · 12.81 Impact Factor