Li Sun

Diet-induced obesity alters bone remodeling leading to decreased femoral trabecular bone mass in mice

Obesity‐derived body mass may be detrimental to bone health through not well‐defined mechanisms. In this study we determined changes in bone structure and serum cytokines related to bone metabolism in diet‐induced obese mice. Mice fed a high‐fat diet (HFD) had higher serum tartrate‐resistant acid phosphatase (TRAP) and leptin but lower osteocalcin concentrations than those fed the normal‐fat diet. The HFD increased multinucleated TRAP‐positive osteoclasts in bone marrow compared to the control diet. Despite being much heavier, mice fed the HFD had lower femoral bone volume, trabecular number, and connectivity density and higher trabecular separation than mice on the control diet. These findings suggest that obesity induced by a HFD increases bone resorption that may blunt any positive effects of increased body weight on bone.

Restoration of bone mass in hpg mouse by preoptic area grafting.

Abstract:u2002 Hereditary hypogonadism in the hpg mouse, caused by a deletion mutation in the gonadotropin‐releasing hormone (GnRH) gene, is associated with sterility, absent ovarian development, and undetectable circulating sex steroids. Eight‐month‐old female hpg mice had a significantly reduced bone mineral density (BMD) at the lumbar spine, femur, and tibia. In addition, the mice showed significant reductions in liver and kidney weight, with virtually nonexistent ovaries. Successfully transplanted hpg mice with preoptic area grafts contained GnRH‐positive neurons, consistent with our previous experience, and the host median eminence was innervated by GnRH immunoreactive fibers. A return of reproductive function was evident from increased ovarian weight and vaginal cornification. Of note was that grafted hpg mice showed a complete reversal to baseline of their BMD measured at all three sites. This establishes that the low bone mass that occurs in old hpg mice can be fully and rapidly ameliorated by preoptic area grafting.

Alpha-1 antitrypsin reduces ovariectomy-induced bone loss in mice

Proinflammatory cytokines are primary mediators of bone loss in estrogen deficiency. This study determined whether alpha‐1 antitrypsin (AAT), a multifunctional protein with proteinase inhibitor and anti‐inflammatory activities, mitigates bone loss induced by estrogen deficiency. Mice were either sham‐operated or ovariectomized and injected with either AAT or phosphate buffered saline (PBS). Ovariectomy resulted in decreased wet uterus weight, significant bone loss, increased serum leptin concentrations, and higher body weight compared to sham. AAT injection increased tibial trabecular bone volume/total volume and trabecular thickness compared to PBS injection in ovariectomized mice. Ovariectomized mice with AAT treatment had higher uterus weight, lower serum osteocalcin levels, fewer bone marrow tartrate‐resistant acid phosphatase–positive osteoclasts, and less expression of calcitonin receptor in bone than that in PBS‐injected mice. These data demonstrate that AAT mitigates ovariectomy‐induced bone loss in mice possibly through inhibiting osteoclast activity and bone resorption.

The Cellular and Molecular Aspects of Immunosuppressant Osteoporosis

The advent of immunosuppressant agents that prevent organ rejection and prolong life has revolutionized the field of organ transplantation. However, these drugs possess numerous side effects, including bone loss that results in osteoporosis and fracture. This chapter will focus on the mechanism of action of the major immunosuppressants used clinically. These include glucocorticoids, the calcineurin inhibitors (cyclosporin A [CsA] and tacrolimus [FK506]), rapamycin, and several others, such as azathiaprine and mycophenolate mofetil (MMF). We will describe in vitro and in vivo studies that have elucidated their action on bone.