Secreted Wnt Signaling Inhibitors in Disuse-Induced Bone Loss

Abstract : To investigate whether antagonizing secreted inhibitors of Wnt signaling is a viable approach for combating the bone loss that normally accompanies neuromuscular paralysis, we have conducted several paralysis experiments in mice that address the potential role of sclerostin inhibition in preventing paralysis-induced bone loss. In the first series, adult female mice were subjected to unilateral Botox-induced muscle paralysis of the lower limb via Botox (20 U/kg) injection into the right lower limb musculature. We performed this treatment in 2 types of mice: Wild type (Sost+/+) and Sost knock-out mice (Sost-/-). Despite the equal loss in muscle mass induced by Botox, Sost+/+ mice lost a significant percentage of their initial lower-limb aBMD and BMC over the experimental period, whereas bone mass in Sost-/- mice actually increased significantly (2-4%; p0.05) over the same period. Similar effects were seen for BV/TV, trabecular thickness, and trabecular bone mineral content (Tb.BMC) in the distal femur. We also investigated the osteopenic effects of Botox-induced muscle paralysis in WT mice that were given neutralizing antibody to sclerostin. Botox injection into the right limb musculature of vehicle-treated mice resulted in an 8.4% decrease (p0.001) in femoral aBMD, whereas mice given Scl-AbIII after Botox injection exhibited an 8.0% increase in femoral aBMD in the paralyzed limb. In summary, these data suggest that sclerostin inhibition is a useful approach for overcoming the bone loss that normally occurs with disuse. We are also investigating the efficacy of Dkk1 neutralization (and genetic deletion) for preventing disuse induced bone loss. Those studies are still underway.