Lrp5-Independent Activation of Wnt Signaling by Lithium Chloride Increases Bone Formation and Bone Mass in Mice

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 102; no. 48; pp. 17406 - 17411
• Main Authors: Philippe Clément-Lacroix, Minrong Ai, Frederic Morvan, Sergio Roman-Roman, Béatrice Vayssière, Cecille Belleville, Kenneth Estrera, Warman, Matthew L., Baron, Roland, Georges Rawadi, Prockop, Darwin J.
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 29.11.2005; National Acad Sciences
• Subjects: Adipocytes; Analysis of Variance; Animals; Biological Sciences; Body Weights and Measures; Bone and Bones - diagnostic imaging; Bone formation; Bone marrow cells; Bone metabolism; Bones; Genetics; LDL-Receptor Related Proteins - genetics; Lithium; Lithium Chloride - pharmacology; Low Density Lipoprotein Receptor-Related Protein-5; Mesenchymal stem cells; Mice; Mice, Inbred C57BL; Mice, Knockout; Osteoblasts; Osteogenesis - drug effects; Osteogenesis - physiology; Osteoporosis; Rodents; Signal transduction; Signal Transduction - drug effects; Signal Transduction - physiology; Stromal cells; Tomography, X-Ray Computed; Wnt Proteins - metabolism
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.0505259102

One of the well characterized cell biologic actions of lithium is the inhibition of glycogen synthase kinase-3/3 and the consequent activation of canonical Wnt signaling. Because deficient Wnt signaling has been implicated in disorders of reduced bone mass, we tested whether lithium could improve bone mass in mice. We gavage-fed lithium chloride to 8-week-old mice from three different strains$(Lrp5^{-/-}$, SAMP6, and C57BL/6) and assessed the effect on bone metabolism after 4 weeks of therapy.$Lrp5^{-/-}$mice lack the Wnt coreceptor low-density lipoprotein receptor-related protein 5 and have markedly reduced bone mass. Lithium, which is predicted to act downstream of this receptor, restored bone metabolism and bone mass to near wild-type levels in these mice. SAMP6 mice have accelerated osteoporosis due to inadequate osteoblast renewal. Lithium significantly improved bone mass in these mice and in wild-type C57BL/6 mice. We found that lithium activated canonical Wnt signaling in cultured calvarial osteoblasts from$Lrp5^{-/-}$mice ex vivo and that lithium-treated mice had increased expression of Wnt-responsive genes in their bone marrow cells in vivo. These data lead us to conclude that lithium enhances bone formation and improves bone mass in mice and that it may do so via activation of the canonical Wnt pathway. Lithium has been used safely and effectively for over half a century in the treatment of bipolar illness. Prospective studies in patients receiving lithium should determine whether it also improves bone mass in humans.