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United States Department of Agriculture

Agricultural Research Service

Research Project: BONE METABOLISM IN OBESITY Title: Alpha-1 antitrypsin reduces ovariectomy-induced bone loss in mice

Authors
item Cao, Jay
item Gregoire, Brian
item Sun, Li -
item Song, Sihong -

Submitted to: Annals of the New York Academy of Sciences
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: December 14, 2011
Publication Date: February 4, 2012
Repository URL: http://handle.nal.usda.gov/10113/56919
Citation: Cao, J.J., Gregoire, B.R., Song, S. 2012. Alpha-1 antitrypsin reduces ovariectomy-induced bone loss in mice. Annals of the New York Academy of Sciences. doi: 10.111/j.1749-6632.2011.06370.x.

Interpretive Summary: We investigated whether alpha-1 antitrypsin (AAT), a multifunctional protein with proteinase inhibitor and anti-inflammatory activities, mitigates bone loss induced by estrogen deficiency, a state with increased production of proinflammatory cytokines. We found that ovariectomy decreased wet uterus weight, caused significant bone loss, and increased serum leptin concentrations in mice compared to sham. AAT injection (2 mg/mouse, every 3 days for 30 days) increased tibial trabecular bone volume/total volume and trabecular thickness compared to phosphate buffered saline (PBS) injection in ovariectomized mice. Ovariectomized mice with AAT treatment had higher uterus weight, lower serum osteocalcin levels, fewer bone marrow TRAP-positive osteoclasts and less expression of calcitonin receptor in bone than that in PBS-injected mice. We conclude that AAT mitigates ovariectomy-induced bone loss in mice possibly through inhibiting osteoclast activity and bone resorption and AAT can be a potential agent to prevent bone loss in humans.

Technical Abstract: Alpha-1antitrypsin (AAT) is a multifunctional protein with proteinase inhibitor and anti-inflammatory activities. Recent studies showed that AAT has therapeutic effect for diseases associated with inflammation, such as type 1 diabetes and arthritis. Proinflammatory cytokines are primary mediators of bone loss in postmenopausal women due to the decreased estrogen production. To determine whether AAT mitigates bone loss induced by estrogen deficiency, thirty-eight female C57BL/6J mice (7-wk-old), were either ovariectomized or sham-operated. Ovariectomized animals were randomly assigned to AAT-injected (n=13; 2 mg/mouse, every 3 days for 30 days) or phosphate buffered saline (PBS)-injected group (n=12), while sham-operated mice (Sham; n=13) were injected with PBS and used as controls. Ovariectomy resulted in decreased wet uterus weight (P<0.01), significant bone loss, increased serum leptin concentrations, and higher body weight (P<0.01) compared to sham. AAT treatment increased tibial trabecular bone volume/total volume and trabecular thickness compared to PBS treatment in ovariectomized mice (P<0.01). Ovariectomized mice with AAT treatment had higher uterus weight (P<0.01), lower serum osteocalcin levels (P<0.05), fewer bone marrow TRAP-positive osteoclasts (P<0.05) and less expression of calcitonin receptor in bone (P<0.01) than that in PBS-injected mice. These data demonstrate that AAT reduces ovariectomy-induced bone loss in mice possibly through inhibiting osteoclast activity and bone resorption. Our results indicated new functions of AAT and imply an novel application of AAT for the treatment of osteoporosis.

Last Modified: 12/20/2014
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