Overexpression of Human Hydroxysteroid (17β) Dehydrogenase 2 Induces Disturbance in Skeletal Development in Young Male Mice

Abstract

ABSTRACT:To understand the function of human hydroxysteroid (17␤) 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.

Heavy Metal Lead Exposure, Osteoporotic-like Phenotype in an Animal Model, and Depression of Wnt Signaling

“…Data on human bone outcomes and Pb are limited. However, Khalil et al (2008) reported that elevated BLLs are associated with an increased risk of falls and nonspine fractures, further validating this concern. Moreover, osteoporotic patients have a decreased capacity for healing of fractures.…”

17β-Hydroxysteroid dehydrogenases (17β-HSDs) as therapeutic targets: Protein structures, functions, and recent progress in inhibitor development

“…Surprisingly, the HSD17B2TG mice did not show a significant rise in the tumor incidence which was expected according to the protective hypothesis for 17␤-HSD2. In a second study the same group showed that the over-expression of human 17␤-HSD2 led to disturbances in the skeletal development of male mice [124]. Studies with the HSD17B2TG suggested a sex-steroid independent role for 17␤-HSD2 besides its steroid converting function.…”

“…Studies with the HSD17B2TG suggested a sex-steroid independent role for 17␤-HSD2 besides its steroid converting function. To clarify this point a mouse bearing two genetic alterations was generated, ubiquitously expressing both human 17␤-HSD1 and human 17␤-HSD2 [124]. Using this "bi-TG mouse" the involvement of 17␤-HSD2 in sex steroid independent pathways could be proven.…”

Sex Steroid-Dependent and -Independent Action of Hydroxysteroid (17β) Dehydrogenase 2: Evidence from Transgenic Female Mice

“…Data in our recent studies applying TG mice expressing human HSD17B2 suggested that most marked physiological changes observed, such as growth retardation, delayed eye opening, and disrupted germ cell development, were not due to altered sex steroid action (24,33). The phenotypes observed together with the rescuing studies performed in male mice suggested that one putative explanation for the observed changes in the mice could be the alteration of retinoid and IGF action (33,34). Similarly, the phenotype of HSD17B2 knockout mice was not considered to be caused by altered estrogen or P action (25).…”