The role of strain in the response of rapidly growing young male rat bones to parathyroid hormone.

Human parathyroid hormone (hPTH 1-34) stimulates an anabolic response in human and animal skeletons; however, it is unclear if the effect is strain dependent. To determine if the anabolic response to hPTH (1-34) was dependent upon strain in rats we used 2 outbred strains (Sprague Dawley, Wistar), 2 inbred strains (Fischer 344, Wistar spontaneously hypertensive:SHR), and 2 mutant strains (Zucker obese, Zucker lean) of rats. Male rats, 5 weeks of age, from each strain were treated subcutaneously with 80 microg/kg body weight hPTH (1-34) or vehicle for 12 days. The response to PTH was similar in all strains whereby PTH exerted an anabolic effect on femoral bone mass and cancellous bone histology that was independent of strain differences. Histomorphometric indices of bone volume, mineralized surface and bone formation in lumbar vertebrae increased in all PTH-treated rats. Additionally, femur bone mineral content and bone mineral density measured by dual energy X-ray absorptiometry (DEXA), and ash weight increased in all PTH-treated rats. These increases occurred regardless of strain. In summary, PTH exerted comparable anabolic effects on bone mass, bone mineral density and bone formation in all rat models tested demonstrating that the skeletal responsiveness to PTH was not dependent upon strain.

Bone histomorphometry in three females with Rett syndrome.

The frequent occurrence of osteoporosis in Rett syndrome raises questions about the etiology of this finding. It is unknown whether there is any relationship between low bone mass and the underlying genetic disorder. We recently had an opportunity to study the status of bone remodeling by quantitative bone histomorphometry in three girls ages 9.75, 13.5, and 14 years, with typical Rett syndrome who required scoliosis surgery.Anterior iliac crest bone biopsies were performed 1-2 days after double labeling of the bone surfaces with tetracycline. Samples were processed for plastic embedding, sectioned, stained, and histomorphometry performed in the cancellous bone. The same observer performed all measurements. Bone volume was reduced, surface parameters of formation (osteoid surface) were normal while parameters of resorption (osteoclast surface and number) were decreased. The rate of bone formation was reduced in the first two girls but could not be measured in the third girl due to lack of double labeling. It may be that the slow rate of bone formation seen in each age group impedes the development and accumulation of peak bone mass and contributes to the decreased bone volume associated with Rett syndrome, although the data is limited. This is the first report to document decreased bone volume determined by quantitative bone histomorphometry in patients with Rett syndrome. With the recent identification of MECP2 mutations in Rett syndrome it is quite likely that genetic factors not only play a major role in brain development but may also influence other organ growth including bone formation.

Phenotypic characterization of mice bred for high and low peak bone mass.

In humans, peak bone mineral density (BMD) is a highly heritable trait and a strong determinant of subsequent osteoporotic fracture risk. To identify the genetic factors responsible for variation in peak BMD, investigators have turned to animal models. In this study we examined the heritability of BMD acquisition and characterized differences in skeletal geometry, histomorphometry, and biomechanical competence between two lines of mice artificially selected for extremes of peak whole body BMD. F2 progeny from a cross between C57BL/6 and DBA/2 inbred strains was used as the foundation population to develop lines selected for either high or low BMD. Whole body BMD was measured by dual-energy X-ray absorptiometry (DXA). By the third generation of selection, highest-scoring BMD (HiBMD) mice exhibited 14% greater peak BMD than lowest-scoring BMD (LoBMD) mice. The mean realized heritability of peak BMD was 36%. Femoral shaft cortical area and thickness and vertebral cancellous bone volume (BV) were significantly greater (16-30%) in the HiBMD line compared with the LoBMD line. Mean cancellous bone formation rates (BFRs) were 35% lower in HiBMD mice compared with LoBMD mice. Failure load and stiffness in the femoral shaft, femoral neck, and L6 vertebrae were all substantially greater (by 25-190%) in HiBMD mice. Thus, these divergently selected murine lines serve to illustrate some of the means by which genetic mechanisms can affect skeletal structure and remodeling. Identification of the individual genes influencing peak BMD in this experimental system will likely reveal some of the genetic determinants of overall bone strength.