Graduate Thesis Or Dissertation
 

The role of leptin in normal and pathological bone resorption

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https://ir.library.oregonstate.edu/concern/graduate_thesis_or_dissertations/h128nj20z

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  • Particles generated from wear of prosthesis joint bearing surfaces induce inflammation and promote pathological periprosthetic osteoclast-mediated bone resorption (osteolysis). Obesity increases the risk of prosthesis failure. However, despite being morbidly obese, leptin-deficient ob/ob mice are resistant to osteolysis. These findings suggest that leptin exerts effects that act to increase particle-induced osteolysis. Leptin is an adipokine produced primarily by adipose tissue and circulates in concentrations relative to total body adiposity. Leptin exerts effects on the skeleton, the immune system, and other organ systems. Elevation in the circulating concentration of leptin may act to increase particle-induced osteolysis through its actions on bone and the immune system. Studies were conducted to: 1) determine the dose-response effects of circulating leptin on bone in leptin-deficient ob/ob mice, 2) determine if leptin acts to increase particle- induced osteolysis in ob/ob mice, and 3) determine if elevation in the concentration of circulating leptin acts to increase particle-induced osteolysis in wild-type (WT) mice. To determine the dose-response effects of leptin on bone, vehicle or leptin (0.1 μg/d, 0.3 μg/d, 1.0 μg/d, 3.5 μg/d, and 10 μg/d) were administered continuously to ob/ob mice (n=8/group) by s.c. osmotic pump for 2 weeks. Leptin treatment acted to increase the rate of bone formation. Effects were first detected with the delivery of 0.3 μg/d. This dosage induced circulating concentrations of ~0.8 ng/ml. This finding provides evidence that leptin exerts skeletal actions at low circulating concentrations in mice. To confirm that ob/ob mice are resistent to particle-induced osteolysis, ob/ob and WT mice were randomized to no-treatment and particle treatment groups (N=8–10/group). Polyethylene particles (2.5 mg) were suspended in 95% ethanol and implanted over the calvarial periosteum to induce osteolysis. All mice were sacrificed 2 weeks after implantation. Calvarial bone volume was quantified by μCT and osteolysis was scored blinded from 0 (no osteolysis) to 4 (severe osteolysis). Calvaria from particle-treated ob/ob mice had a lower osteolysis score and greater bone volume than particle-treated WT mice. These findings confirm that ob/ob mice are resistant to particle-induced osteolysis. To determine if leptin acts to increase particle-induced osteolysis in ob/ob mice, ob/ob mice were randomized to 3 treatment groups: 1) no-treatment (n=8), 2) particles (n=8), and 3) particles + leptin (osmotic pump, 6 μg/d, n=6). Particles were implanted on top of the calvaria and particle-induced osteolysis was assessed as described above. Calvaria from particles + leptin-treated ob/ob mice had a greater osteolytic score and lower bone volume than particle-treated ob/ob mice. These findings demonstrate that leptin acts to increase particle-induced osteolysis in ob/ob mice. To determine if elevation in circulating leptin acts in WT mice to increase particle- induced osteolysis, WT mice were randomized to 4 treatment groups (N=16/group): 1) no-treatment, 2) particles, 3) particles + leptin (osmotic pump, 10 μg/d), and 4) particles + pair-fed to leptin treatment. Particles were implanted on top of the calvaria and particle-induced osteolysis was assessed as described above. At sacrifice circulating leptin was 61% greater in particles + leptin-treated mice than in particle-treated mice. However, there were no differences in calvaria osteolysis score and in bone volume between the particles + leptin and particle-treated mice. These findings demonstrate that small increases in circulating leptin do not increase particle-induced osteolysis in WT mice. The findings of these studies provide evidence that: 1) leptin acts in ob/ob mice to exert skeletal effects at low circulating concentrations; 2) ob/ob mice are resistant to particle- induced osteolysis as a consequence of leptin deficiency; and 3) small elevations in the concentration of circulating leptin do not act to further increase osteolysis in WT mice. Further studies will be required to determine the skeletal effects of obesity-induced hyperleptinemia on normal bone metabolism and particle-induced osteolysis.
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