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Leptin Modulates both Resorption and Formation while Preventing Disuse-Induced Bone Loss in Tail-Suspended Female Rats

Institut National de la Santé et de la Recherche Médicale (INSERM) E0366 (A.M., R.d.V., V.D., M.-H.L.-P., C.A., L.V., T.T.), University Hospital, 42055 St-Etienne, France; and INSERM Unité 418 (R.M., M.B.), 69005 Lyon, France

Address all correspondence and requests for reprints to: Prof. Thierry Thomas, Institut National de la Santé et de la Recherche Médicale E0366, University Hospital, Boulevard Pasteur, 42055 Saint-Etienne Cedex2, France. E-mail: thierry.thomas{at}univ-st-etienne.fr.

In vitro studies have demonstrated leptin-positive effects on the osteoblast lineage and negative effects on osteoclastogenesis. Therefore, we tested the hypothesis that leptin may prevent tail-suspension-induced bone loss characterized by an uncoupling pattern of bone remodeling, through both mechanisms. Female rats were randomly tail-suspended or not and treated either with ip administration of leptin or vehicle for 3, 7, and 14 d. As measured by dual energy x-ray absorptiometry, tail-suspension induced a progressive decrease in tibia-metaphysis bone mineral density, which was prevented by leptin. Histomorphometry showed that this was related to the prevention of the transient increase in osteoclast number observed with suspension at d 7. These effects could be mediated by the receptor activator of nuclear factor B-ligand (RANKL)/osteoprotegerin (OPG) pathway since we observed using direct RT-PCR, a suspension-induced increase in RANKL gene expression in proximal tibia at d 3, which was counterbalanced by leptin administration with a similar 3-fold increase in OPG expression and a RANKL to OPG ratio close to nonsuspended conditions. In addition, leptin prevented the decrease in bone formation rate induced by tail-suspension at d 14. The latter could be related to the role of leptin in mediating the reciprocal differentiation between adipocytes and osteoblasts, because leptin concurrently blunted the disuse-induced increase in bone marrow adipogenesis. In summary, these data suggest that peripheral administration of leptin could prevent disuse-induced bone loss through, first, a major inhibitory effect on bone resorption and, second, a delayed effect preventing the decrease in bone formation.

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