Osteogenesis imperfecta (OI) is one of the most common skeletal dysplasias. Most cases are caused by either qualitative or quantitative defects in type I collagen. We previously identified the pathogenic mechanism of recessively inherited OI caused by CRTAP and P3H1 mutations, components of a collagen prolyl 3-hydroxylation complex. We also identified mutations in the signaling molecules PEDF, IFITM5, and WNT1 causing recessive OI. Importantly, our WNT1 finding identified the first specific WNT ligand involved in a human skeletal dysplasia. Surprisingly, WNT1 is best known for its functions in neural crest and cerebellar development, while its essential function in bone was a surprise. Hence, there are many unanswered questions regarding WNT1-related OI: 1) What are the tissue-specific requirements of WNT1 in bone? 2) Which signaling pathways mediate WNT1 function in bone? 3) Can therapeutics that target Wnt signaling show differential efficacy in distinct OI types? 4) What other Wnt-signaling pathway genes contribute to OI and/or low bone mass? The goals of Project 1 are to understand the functions of WNT1 in bone development and homeostasis; to identify the pathogenic mechanisms by which mutations in WNT1 lead to OI; to test the potential of anti-sclerostin antibody treatment for WNT1-related vs. other types of OI; and to identify novel genes in the WNT and collagen modification pathway leading to OI. Our preliminary data show that Wnt1 mutant mice (swaying) exhibit spontaneous fractures and reduced bone mass. Moreover, overexpression of Wnt1 increases osteoblast differentiation and activates mTORC1 signaling in vitro. We hypothesize that Wnt1 expressed in osteocytes contributes to bone homeostasis by regulating mTORC1 signaling in osteoblasts. We will test this hypothesis by accomplishing the following specific aims:
Aim 1. What are the tissue and cell- specific contributions of Wnt1 to skeletal development and homeostasis? Aim 2. What are the downstream signaling pathways that mediate Wnt1 functions in skeletal development and homeostasis? Aim 3. What are the effects of Wnt-targeted therapies in different forms of OI? Aim 4. Are there rare forms of OI that identify new and essential components of collagen processing and/or Wnt signaling in bone?

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
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Baylor College of Medicine
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