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Projects

Williams Laboratory

Wnt signaling in normal bone development

Mutations in the Wnt receptor Lrp5 have been causally linked to alterations in human bone development. We have characterized a mouse strain deficient in Lrp5 and have shown that it recapitulates the low-bone-density phenotype seen in human patients who have a Lrp5 deficiency. We have further shown that mice carrying mutations in both Lrp5 and the related Lrp6 protein have even more-severe defects in bone density. To test whether Lrp5 deficiency causes changes in bone density due to aberrant signaling through β-catenin, we created mice carrying an osteoblast-specific deletion of β-catenin (OC-Cre;β-cateninflox/flox mice). We are addressing how other genetic alterations linked to Wnt/β-catenin signaling affect bone development and osteoblast function. We have generated mice with conditional alleles of Lrp6 and Lrp5 that can be inactivated via Cre-mediated recombination and demonstrated that both Lrp5 and Lrp6 function within osteoblasts to regulate normal bone development and homeostasis. We have also created mice that lack the ability to secrete Wnts from osteoblasts and shown that these mice also have extremely low bone mass, establishing that the mature osteoblast is an important source of Wnts for establishing and maintaining normal bone mass. We are also examining the effects on normal bone development and homeostasis of chemical inhibitors of the enzyme porcupine, which is required for the secretion and activity of all Wnts. Given that such inhibitors are currently in human clinical trials for treatment of several tumor types, their side effects related to the lowering bone mass be evaluated.

Wnt signaling in mammary development and cancer

We also are addressing the relative roles of Lrp5 and Lrp6 in Wnt1-induced mammary carcinogenesis. A deficiency in Lrp5 dramatically inhibits the development of mammary tumors, and a germline deficiency for Lrp5 or Lrp6 results in delayed mammary development. Because Lrp5-deficient mice are viable and fertile, we have focused our initial efforts on these mice. We also have found that Lrp6 plays a key role in mammary development, and we are focusing on the mechanisms underlying this role. We are particularly interested in how these pathways may regulate the proliferation of normal mammary progenitor cells, as well as of tumor-initiating cells.

Wnt signaling in prostate development and cancer

Two hallmarks of advanced prostate cancer are the development of skeletal osteoblastic metastasis and the ability of the tumor cells to become independent of androgen for survival. We have created mice with a prostate-specific deletion of the Apc gene. These mice develop fully penetrant prostate hyperplasia by four months of age, and these tumors progress to frank carcinomas by seven months. We have found that these tumors initially regress under androgen ablation but show signs of androgen-independent growth some months later.

Genetically engineered mouse models of bone disease

We have also focused on developing mouse models of osteoarthritis and of fracture repair. In addition, we are interested in identifying novel genes that play key roles in skeletal development and maintenance of bone mass. For example, current work is focused on the role of galectin-3, a member of the lectin family, in this context.