Mechanistic investigation into Frizzled-2 signaling for treatment of Osteogenesis Imperfecta

Abstract
Osteogenesis imperfecta (OI) is a group of genetically and phenotypically heterogeneous connective tissue
disorders that results in low bone mass, bone deformity, and bone fractures. OI has an estimated prevalence
of 1 in 15,000 births. Disruptions in multiple processes such as collagen synthesis, collagen posttranslational
modification, signaling defects and intracellular trafficking lead to OI. The primary focus of medical therapy has
been to increase bone mass and reduce fracture risk through medical and surgical treatment. The mainstay of
treatment in this population is bisphosphonates, which reduces bone loss by suppressing bone turnover.
However, these drugs can only delay bone loss without fully preventing it. We've shown that modulation of the
Wnt/Frizzled2 signaling pathway can in increase bone mass in wild type mice. My objective in this project is to
test whether the Wnt/Frizzled2 signaling pathway can be used to treat both skeletal features of a dominant and
recessive form OI, reduce cerebellar dysfunction in the Wnt1sw/sw mouse model and investigate how modulation
in the Wnt/Frizzled2 signaling pathway increases bone mass. Our preliminary studies indicate this modulate
increases bone mass in a dominant (Col1a2tm1.1Mcbr) and recessive model of OI (Crtap-/-). In other preliminary
studies, I found that modulating the Wnt/Frizzled2 pathway increases downstream activation of the mTORC1
signaling pathway. The central hypothesis is that modulation of the Wnt/Frizzled2 signaling pathway
increases bone mass through activation of downstream targets of the mTORC1 signaling pathway. We plan to
test our hypothesis in the following ways: characterize the skeletal in two OI mouse models after treatment with
a modulated Wnt/Frizzled2 signaling molecule, assess the changes in the extraskeletal phenotype in the
Wnt1sw/sw mouse model and investigate the role of Wnt/Frizzled2 signaling in mTORC1 pathway in vivo and in
vitro on bone mass and cellular proliferation and function, respectively. By assessing these aims, we will
elucidate the role of Wnt/Frizzled2 signaling in bone formation and gain insight on how downstream activation
of the mTORC1 signaling pathway alters bone formation.

Grant Number: 5F31HD112171-03
NIH Institute/Center: NIH
Principal Investigator: Mary Adeyeye