Identification of Extracellular Wnt Inhibitors for Novel Synergistic Anabolic Action on the Skeleton

Abstract

The Wnt pathway has been an obvious target for designing skeletal therapies, mainly based on the high-bone-mass phenotypes in patients with activating mutations in the Wnt co-receptors Lrp5 and Lrp6, or with inactivating mutations in the Lrp5/6 inhibitor Sost. An attractive property of the Wnt pathway is that it stimulates anabolic action in bone cells. The powerful anabolic potential of manipulating Wnt signaling in bone has been demonstrated by the recent FDA approval of sclerostin antibody (Scl-mAb) EvenityTM (Romosozumab) for the treatment of osteoporosis. However, an increased risk of cardiovascular events was reported, triggering the FDA to issue a ‘black box warning’ requirement for romosozumab. One potential solution to lower the risk of adverse events is to reduce the medication dose. Reducing the dose of Scl-mAb, while maintaining the anabolic potential of the drug, will likely provide a safer and more cost-effective strategy to harness Wnt for fracture prevention. Here, we found that dual inhibition of sclerostin and Dkk1 produced extremely potent synergistic bone anabolic effects in the cancellous compartment, using both genetic and pharmacological models. Further, much lower total doses of dual antibody treatment, given at optimized proportions, generated equivalent trabecular bone anabolic effects as Scl-mAb alone. On the contrary, we looked for other candidates that might potentiate the cortical effects of sclerostin inhibition. We found that either Sostdc1 or Notum deletion results in high bone mass, specifically in the cortical compartment, with little to no effect in the cancellous compartment. Inhibition/deletion of Sostdc1 or Notum alone had no detectable effects (Sostdc1) or mild (Notum) cortical effects, but suppression of either target while co-supressing/deleting Sost improved bone mass disproportionately. In summary, these findings highlight the potential therapeutic role that combinational inhibition of different Wnt inhibitors generates, resulting in synergistic bone anabolic action in different/select skeletal compartments.