Mechanisms of WNT Signaling In Bone

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 DESCRIPTION (provided by applicant): Wnt signaling has emerged as a major target pathway for developing novel bone anabolic agents. Although promising therapeutics has entered clinical trials, our understanding about how Wnt signaling promotes bone anabolism remains incomplete. Nonetheless, a fundamental understanding of the mechanism is critical for rational design of the next generation of therapies. We have previously discovered that Wnt signaling reprograms cellular metabolism during osteoblast differentiation. In particular, Wnt stimulates both aerobic glycolysis and glutaminolysis. We have further demonstrated that the increase in glutaminolysis fulfills both energetic and biosynthetic needs of osteoblasts. Moreover, redirecting glycolysis away from lactate production with a small molecule diminishes Wnt-induced bone formation. However, it remains unknown how the glycolytic switch favoring lactate production contributes to bone anabolism in response to Wnt. Here we test the central hypothesis that Wnt-induced aerobic glycolysis promotes bone formation through stimulation of glutaminolysis. We test the hypothesis in three specific aims. Aim 1 genetically tests the effect of Ldha deletion on osteosclerosis caused by a mutation of Lrp5 in mice. Aim 2 specifically examines the relationship between glycolysis and glutaminolysis in both bone explants and primary cell cultures. Finally, in Aim 3 we will determine the efficacy of Ldha overexpression in promoting bone formation in both an ossicle implant model and transgenic mice. Successful completion of the proposal is expected to pave a new avenue for developing bone-enhancing drugs.