Lrp5-independent activation of Wnt signaling by lithium chloride increases bone formation and bone mass in mice.
One of the well characterized cell biologic actions of lithium is the inhibition of glycogen synthase kinase-3beta 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.
Clément-Lacroix
Philippe
P
Prostrakan Pharmaceuticals, 102 Route de Noisy, 93230 Romainville, France.
Ai
Minrong
M
Morvan
Frederic
F
Roman-Roman
Sergio
S
Vayssière
Béatrice
B
Belleville
Cecille
C
Estrera
Kenneth
K
Warman
Matthew L
ML
Baron
Roland
R
Rawadi
Georges
G
D000704:Analysis of Variance; D000818:Animals; D001837:Body Weights and Measures; D001842:Bone and Bones / Q000000981:diagnostic imaging; D026502:LDL-Receptor Related Proteins / Q000235:genetics; D018021:Lithium Chloride / Q000494:pharmacology*; D060492:Low Density Lipoprotein Receptor-Related Protein-5; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010012:Osteogenesis / Q000187:drug effects* / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology; D014057:Tomography, X-Ray Computed; D051153:Wnt Proteins / Q000378:metabolism*
D026502:LDL-Receptor Related Proteins; C555482:LRP5 protein, human; D060492:Low Density Lipoprotein Receptor-Related Protein-5; C555483:Lrp5 protein, mouse; D051153:Wnt Proteins; D018021:Lithium Chloride