WLS/GPR177 is specifically required for Wnt signaling, a key pathway in osteoblast differentiation and function and that has been the focus of our research for more than a decade. Specifically, deletion of WLS makes any cell incapable of secreting any Wnt protein. This competitive renewal will test whether the actions of WLS within cells of the osteoblast lineage affect bone mass. This builds on our work examining the importance of the Wnt receptors, Lrp5 and Lrp6, in establishing and maintaining normal bone mass within the osteoblast lineage. Two single nucleotide polymorphisms (SNPs) located within an intron of the GPR177/Wntless gene (WLS) on human chromosome 1p31.3 are associated with significant reductions in bone mineral density (BMD) in the lumbar spine and femoral neck. While these studies identify WLS as a candidate gene in establishing and maintaining BMD, the results need to be validated and a molecular mechanism determined to put the information into biological context. A key step is to identify the cell type(s) in which the gene product functions o impact BMD. We will do this by creating genetically engineered mouse models in which Wls deficiency is restricted to specific cell types.
Two specific aims will test the overarching hypothesis that WLS/GPR177 functions within osteoblasts to control bone formation and/or homeostasis.
Specific Aim 1 will focus on examining Wls function in differentiated osteoblasts.
Sub aims will include characterizing the phenotypes associated with Osteocalcin-cre- mediated conditional deletion of Wls in osteoblasts, assessing the function in Wls in osteoblasts of skeletally mature mice by using a tamoxifen-inducible cre (Col1a1-cre), and crossing mice with high bone mass due to an Lrp5 mutation to those lacking Wls to examine the resulting phenotype.
Aim 2 will examine the role of Wls within osteochondral progenitors by using Dermo1-cre mediate Wls deletion. In addition, differentiation of Wls- deficient and control primary calvarial osteoblasts will be compared to assess mechanisms which underlie the deficiencies in bone mass we have seen in our preliminary studies examining mice with targeted deletions of Wls in the osteoblast lineage.
WLS/GPR177 is specifically required for Wnt signaling, a key pathway in osteoblast differentiation and function and that has been the focus of our research for more than a decade. Specifically, deletion of WLS makes any cell incapable of secreting any Wnt protein. This competitive renewal will test whether the actions of WLS within cells of the osteoblast lineage affect bone mass. This builds on our work examining the importance of the Wnt receptors, Lrp5 and Lrp6, in establishing and maintaining normal bone mass within the osteoblast lineage.
|Williams, Bart O; Warman, Matthew L (2017) CRISPR/CAS9 Technologies. J Bone Miner Res 32:883-888|
|Williams, Bart O (2016) Genetically engineered mouse models to evaluate the role of Wnt secretion in bone development and homeostasis. Am J Med Genet C Semin Med Genet 172C:24-6|
|Schumacher, Cassie A; Joiner, Danese M; Less, Kennen D et al. (2016) Characterization of genetically engineered mouse models carrying Col2a1-cre-induced deletions of Lrp5 and/or Lrp6. Bone Res 4:15042|
|Burgers, Travis A; Vivanco, Juan F; Zahatnansky, Juraj et al. (2016) Mice with a heterozygous Lrp6 deletion have impaired fracture healing. Bone Res 4:16025|
|Weivoda, Megan M; Ruan, Ming; Hachfeld, Christine M et al. (2016) Wnt Signaling Inhibits Osteoclast Differentiation by Activating Canonical and Noncanonical cAMP/PKA Pathways. J Bone Miner Res 31:65-75|
|Zhong, Zhendong A; Peck, Anderson; Li, Shihong et al. (2015) (99m)TC-Methylene diphosphonate uptake at injury site correlates with osteoblast differentiation and mineralization during bone healing in mice. Bone Res 3:15013|
|Zhong, Zhendong A; Zahatnansky, Juraj; Snider, John et al. (2015) Wntless spatially regulates bone development through ?-catenin-dependent and independent mechanisms. Dev Dyn 244:1347-55|
|Rudnicki, Michael A; Williams, Bart O (2015) Wnt signaling in bone and muscle. Bone 80:60-66|
|Collins, Caitlyn J; Vivanco, Juan F; Sokn, Scott A et al. (2015) Fracture healing in mice lacking Pten in osteoblasts: a micro-computed tomography image-based analysis of the mechanical properties of the femur. J Biomech 48:310-7|
|Cheng, Su-Li; Ramachandran, Bindu; Behrmann, Abraham et al. (2015) Vascular smooth muscle LRP6 limits arteriosclerotic calcification in diabetic LDLR-/- mice by restraining noncanonical Wnt signals. Circ Res 117:142-56|
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