Differential effects of high fat diet and diet-induced obesity on skeletal acquisition in female C57BL/6J vs. FVB/NJ Mice.

The effects of obesity on bone metabolism are complex, and may be mediated by consumption of a high fat diet and/or by obesity-induced metabolic dysregulation. To test the hypothesis that both high fat (HF) diet and diet-induced metabolic disease independently decrease skeletal acquisition, we compared effects of HF diet on bone mass and microarchitecture in two mouse strains: diet-induced obesity (DIO)-susceptible C57BL/6J (B6) and DIO-resistant FVB/NJ (FVB). At 3 wks of age we weaned 120 female FVB and B6 mice onto normal (N, 10% Kcal/fat) or HF diet (45% Kcal/fat) and euthanized them at 6, 12 and 20 weeks of age (N = 10/grp). Outcomes included body mass; percent fat and whole-body bone mineral density (WBBMD, g/cm2) via DXA; cortical and trabecular bone architecture at the midshaft and distal femur via µCT; and marrow adiposity via histomorphometry. In FVB HF, body mass, percent body fat, WBBMD and marrow adiposity did not differ vs. N, but trabecular bone mass was lower at 6 wks of age only (p < 0.05), cortical bone geometric properties were lower at 12 wks only, and bone strength was lower at 20 wks of age only in HF vs. N (p < 0.05). In contrast, B6 HF had higher body mass, percent body fat, and leptin vs. N. B6 HF also had higher WBBMD (p < 0.05) at 9 and 12 wks of age but lower distal femur trabecular bone mass at 12 wks of age, and lower body mass-adjusted cortical bone properties at 20 wks of age compared to N (p < 0.05). Marrow adiposity was also markedly higher in B6 HF vs. N. Overall, HF diet negatively affected bone mass in both strains, but was more deleterious to trabecular bone microarchitecture and marrow adiposity in B6 than in FVB mice. These data suggest that in addition to fat consumption itself, the metabolic response to high fat diet independently alters skeletal acquisition in obesity.

Sclerostin antibody inhibits skeletal deterioration in mice exposed to partial weight-bearing.

Whereas much is known regarding the musculoskeletal responses to full unloading, little is known about the physiological effects and response to pharmacological agents in partial unloading (e.g. Moon and Mars) environments. To address this, we used a previously developed ground-based model of partial weight-bearing (PWB) that allows chronic exposure to reduced weight-bearing in mice to determine the effects of murine sclerostin antibody (SclAbII) on bone microstructure and strength across different levels of mechanical unloading. We hypothesize that treatment with SclAbII would improve bone mass, microarchitecture and strength in all loading conditions, but that there would be a greater skeletal response in the normally loaded mice than in partially unloaded mice suggesting the importance of combined countermeasures for exploration-class long duration spaceflight missions. Eleven-week-old female mice were assigned to one of four loading groups: normal weight-bearing controls (CON) or weight-bearing at 20% (PWB20), 40% (PWB40) or 70% (PWB70) of normal. Mice in each group received either SclAbII (25mg/kg) or vehicle (VEH) via twice weekly subcutaneous injection for 3 weeks. In partially-unloaded VEH-treated groups, leg BMD decreased -5 to -10% in a load-dependent manner. SclAbII treatment completely inhibited bone deterioration due to PWB, with bone properties in SclAbII-treated groups being equal to or greater than those of CON, VEH-treated mice. SclAbII treatment increased leg BMD from +14 to +18% in the PWB groups and 30 ± 3% in CON (p< 0.0001 for all). Trabecular bone volume, assessed by µCT at the distal femur, was lower in all partially unloaded VEH-treated groups vs. CON-VEH (p< 0.05), and was 2-3 fold higher in SclAbII-treated groups (p< 0.001). Midshaft femoral strength was also significantly higher in SclAbII vs. VEH-groups in all-loading conditions. These results suggest that greater weight bearing leads to greater benefits of SclAbII on bone mass, particularly in the trabecular compartment. Altogether, these results demonstrate the efficacy of sclerostin antibody therapy in preventing astronaut bone loss during terrestrial solar system exploration.

Jet injection of a monoclonal antibody: A preliminary study.

Monoclonal antibodies (mAbs) represent a major group of biotherapeutics. The high concentration and volume of drug administered together with a shift to administration via the subcutaneous route have generated interest in alternative delivery technologies. The feasibility of using a novel, highly controllable jet injection technology to deliver a mAb is presented. The effect of delivery parameters on protein structure were evaluated and compared with delivery using a conventional needle and syringe. Injection of mAb into a rat model showed that jet injection using the device resulted in more rapid absorption and longer duration of exposure.

Maternal perinatal diet induces developmental programming of bone architecture.

Maternal high-fat (HF) diet can alter offspring metabolism via perinatal developmental programming. This study tests the hypothesis that maternal HF diet also induces perinatal programming of offspring bone mass and strength. We compared skeletal acquisition in pups from C57Bl/6J mice fed HF or normal diet from preconception through lactation. Three-week-old male and female pups from HF (HF-N) and normal mothers (N-N) were weaned onto normal diet. Outcomes at 14 and 26 weeks of age included body mass, body composition, whole-body bone mineral content (WBBMC) via peripheral dual-energy X-ray absorptiometry, femoral cortical and trabecular architecture via microcomputed tomography, and glucose tolerance. Female HF-N had normal body mass and glucose tolerance, with lower body fat (%) but higher serum leptin at 14 weeks vs. N-N (P<0.05 for both). WBBMC was 12% lower at 14 weeks and 5% lower at 26 weeks, but trabecular bone volume fraction was 20% higher at 14 weeks in female HF-N vs. N-N (P<0.05 for all). Male HF-N had normal body mass and mildly impaired glucose tolerance, with lower body fat (%) at 14 weeks and lower serum leptin at 26 weeks vs. N-N (P<0.05 for both). Serum insulin was higher at 14 weeks and lower at 26 weeks in HF-N vs. N-N (P<0.05). Trabecular BV/TV was 34% higher and cortical bone area was 6% higher at 14 weeks vs. N-N (P<0.05 for both). These data suggest that maternal HF diet has complex effects on offspring bone, supporting the hypothesis that maternal diet alters postnatal skeletal homeostasis.

Volume reduction mammaplasty.

I present an operation for breast reduction in which a prosthesis-shaped mass of breast tissue is removed through a transverse inframammary incision. No skin is removed. With time the breast tissue and skin shrink. No skin markings are required. There is very little interference with blood or nerve supply to the skin, areola, and nipple. The breast appears normal postoperatively.