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.
|Zhong, Zhendong; Ethen, Nicole J; Williams, Bart O (2014) WNT signaling in bone development and homeostasis. Wiley Interdiscip Rev Dev Biol 3:489-500|
|Yang, Jing; Mowry, Laura E; Nejak-Bowen, Kari Nichole et al. (2014) ?-catenin signaling in murine liver zonation and regeneration: a Wnt-Wnt situation! Hepatology 60:964-76|
|Williams, Bart O (2014) Insights into the mechanisms of sclerostin action in regulating bone mass accrual. J Bone Miner Res 29:24-8|
|Lim, Won Hee; Liu, Bo; Cheng, Du et al. (2014) Wnt signaling regulates pulp volume and dentin thickness. J Bone Miner Res 29:892-901|
|Lim, W H; Liu, B; Cheng, D et al. (2014) Wnt signaling regulates homeostasis of the periodontal ligament. J Periodontal Res 49:751-9|
|Riddle, Ryan C; Diegel, Cassandra R; Leslie, Julie M et al. (2013) Lrp5 and Lrp6 exert overlapping functions in osteoblasts during postnatal bone acquisition. PLoS One 8:e63323|
|Burgers, Travis A; Williams, Bart O (2013) Regulation of Wnt/*-catenin signaling within and from osteocytes. Bone 54:244-9|
|Burgers, Travis A; Hoffmann, Martin F; Collins, Caitlyn J et al. (2013) Mice lacking pten in osteoblasts have improved intramembranous and late endochondral fracture healing. PLoS One 8:e63857|
|Joiner, Danese M; Ke, Jiyuan; Zhong, Zhendong et al. (2013) LRP5 and LRP6 in development and disease. Trends Endocrinol Metab 24:31-9|
|Joiner, D M; Less, K D; Van Wieren, E M et al. (2013) Heterozygosity for an inactivating mutation in low-density lipoprotein-related receptor 6 (Lrp6) increases osteoarthritis severity in mice after ligament and meniscus injury. Osteoarthritis Cartilage 21:1576-85|
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