Bone Abstracts

We previously demonstrated the involvement of Lcn2 in bone loss induced by mechanical unloading. This prompted us to investigate bone phenotype of Lcn2^−/− mice by μCT, which showed an osteopenic phenotype, characterized by 40% lower trabecular bone volume, 50 and 21% lesser trabecular number and thickness, respectively, and 20% higher trabecular separation, compared to WT, while cortical thickness was significantly lower (40%) only in elderly Lcn2^−/− mice. Lcn2^−/− mice showed 30% and 50% lower osteoblast number and surface, and 50% lower bone formation rate, while osteoclast parameters were unremarkable. Consistently, femurs transcriptional levels of Alp, Runx2 and Col1A2 were significantly lower in Lcn2^−/− mice. We found no difference of ALP activity and nodule mineralization in calvaria osteoblast cultures from WT and Lcn2^−/− mice, while less ALP positive colonies were observed in bone marrow-derived Lcn2^−/− cells. Incidentally, we noticed that Lcn2^−/− mice showed higher body weight at all ages evaluated, which prompted us to investigate their energy metabolism. We observed lower serum levels of fasted glucose (60.58±7.48 vs 83.10±18.9 mg/dl, P=0.008), likely due to higher circulating insulin (3.67±0.7 vs 2.25±0.79 ng/ml, P=0.036). Consistently, glucose tolerance was significantly higher in Lcn2^−/− compared to WT mice. Interestingly, while insulin tolerance test was similar at 3 months of age, 12-month-old Lcn2^−/− mice showed 20% lower insulin sensitivity. Finally, the transcriptional expression of the insulin receptor was 30% lower in LCN2^−/− osteoblasts compared to WT, which could explain why, despite the increased levels of insulin, known to be a bone anabolic hormone, Lcn2^−/− mice showed an osteopenic phenotype. This hypothesis was also supported by the observation that the insulin receptor downstream gene, osteocalcin, was significantly reduced in Lcn2^−/− mice (P=0.001). Taken together, these results point to Lcn2 as a key player of the crosstalk between bone and energy metabolism, contributing to the insulin pathway.