Leptin potentiates bone loss at skeletal sites distant from focal inflammation in female ob/ob mice.

Abstract

Leptin increases focal inflammation and osteolysis induced by polyethylene particles in leptin-deficient ob/ob mice suggesting the adipokine, an important immune modulator, contributes to orthopedic implant failure. Focal inflammation leads to bone loss at distant skeletal sites, and it is plausible that leptin also contributes to this response. We tested this possibility in 6-week-old female ob/ob mice (6-8/group) by evaluating bone architecture, turnover, and gene expression 12 days following surgical placement of polyethylene particles over calvaria. Particle treatment had minimal effect on bone mass, density, or cancellous bone architecture in femur and 5th lumbar vertebra (LV). However, compared to controls, particle treatment altered tibial expression levels of 32/84 genes related to bone metabolism. Subcutaneous infusion of leptin (6 µg/d) to mice following placement of polyethylene particles over calvaria (combination treatment) resulted in cancellous bone loss in distal femur metaphysis and LV and in the differential expression of 34/84 genes, 15 of which overlapped with particle treatment. Notably, combination treatment, but not particle treatment, resulted in increased expression of genes strongly associated with bone turnover and response to inflammation. Leptin treatment alone (0.1-10 µg/day) did not result in bone loss in femur or LV in the ob/ob mice. These findings suggest that leptin exaggerates the detrimental effects of particle-induced inflammation on bone turnover balance, leading to systemic bone loss.