Leptin modulates both resorption and formation while preventing disuse-induced bone loss in tail-suspended female rats.
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 kappaB-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.
Martin
Aline
A
Institut National de la Santé et de la Recherche Médicale E0366, University Hospital, Boulevard Pasteur, 42055 Saint-Etienne Cedex2, France.
de Vittoris
Raphaël
R
David
Valentin
V
Moraes
Ricardo
R
Bégeot
Martine
M
Lafage-Proust
Marie-Hélène
MH
Alexandre
Christian
C
Vico
Laurence
L
Thomas
Thierry
T
D000818:Animals; D001483:Base Sequence; D001846:Bone Development / Q000502:physiology*; D001862:Bone Resorption / Q000503:physiopathology*; D003345:Corticosterone / Q000097:blood; D017931:DNA Primers; D005260:Female; D020738:Leptin / Q000235:genetics / Q000494:pharmacology*; D016133:Polymerase Chain Reaction; D051381:Rats; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013623:Tail; D016474:Weight-Bearing
D017931:DNA Primers; D020738:Leptin; D003345:Corticosterone