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2015 Scientific Report

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Van Andel Research

Van Andel Research Institute | Scientific Report 2015 Research Interests Our laboratory is interested in understanding how alterations in the Wnt signaling pathway cause human disease. Wnt signaling is an evolutionarily conserved process that functions in the differentiation of most tissues within the body. Given its central role in growth and differentiation, it is not surprising that alterations in the pathway are among the most common events associated with human cancer. In addition, several other human diseases, including osteoporosis, cardiovascular disease, and diabetes, have been linked to altered regulation of this pathway. A specific focus of our work is characterizing the role of Wnt signaling in bone formation. Our interest is not only from the perspective of normal bone development, but also in trying to understand whether aberrant Wnt signaling plays a role in the predisposition of some common tumor types (for example, prostate, breast, lung, and renal tumors) to metastasize to and grow in bone. The long-term goal of this work is to provide insights useful in developing strategies to lessen the morbidity and mortality associated with skeletal metastasis. 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 -catenin, we created mice carrying an osteoblast-specific deletion of -catenin (OC-Cre;-catenin flox/flox mice). We are addressing how other genetic alterations linked to Wnt/-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 which 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 of chemical inhibitors of the enzyme porcupine on normal bone development and homeostasis, 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 of bone mass must be evaluated. Wnt signaling in mammary development and cancer We are also 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 have also 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. 36

Williams 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. Recent Publications Collins, C.J., J.F. Vivanco, S. Sokn, B. Williams, T. Burgers, and H.L. Ploeg. In press. Fracture healing in mice lacking Pten in osteoblasts: a micro-computed tomography image-based analysis of the mechanical properties of the femur. Journal of Orthopaedic Research. Lim, W.H., B. Liu, D. Cheng, B.O. Williams, S.J. Mah, and J.A. Helms. In press. Wnt signaling regulates homeostasis of the periodontal ligament. Journal of Periodontal Research. Scholten, D.J., II, C.M. Timmer, J. Peacock, D.W. Pelle, B. Williams, and M.R. Steensma. In press. Hypoxia-mediated down-regulation of Wnt/-catenin signaling is a viable target for chemoresistance in human osteosarcoma cells. PLoS One. Zhong, Zhendong, Nicole J. Ethen, and Bart O. Williams. In press. WNT signaling in bone development and homeostasis. Wiley Interdisciplinary Reviews: Developmental Biology. Hoffmann, F. Michael, Travis Burgers, James J. Mason, Bart O. Williams, Debra L. Sietsema, and Clifford B. Jones. 2014. Biomechanical evaluation of fracture fixation constructs using a variable-angle locked periprosthetic femur plate system. Injury 45(7): 1035–1041. Joiner, Danese M., Kennen D. Less, Emily M. Van Wieren, Yu-Wen Zhang, Daniel Hess, and Bart O. Williams. 2014. Accelerated and increased joint damage in young mice with global inactivation of mitogen-inducible gene 6 (Mig-6) after ligament and meniscus injury. Arthritis Research and Therapy 16(2): R81. Kabiri, Zahra, Gediminas Greicius, Babita Madan, Steffan Biechele, Zhendong Zhong, Hamed Zaribafzadeh, Edison, Jamal Aliyed, Yonghui Wu, et al. 2014. Stroma provides an intestinal stem cell niche in the absence of epithelial Wnts. Development 141(11): 2206–2215. Lim, Won Hee, Bo Liu, Du Cheng, Daniel J. Hunter, Zhendong Zhong, Daniel M. Ramos, Bart O. Williams, Paul T. Sharpe, Claire Bardet, et al. 2014. Wnt signaling regulates pulp volume and dentin thickness. Journal of Bone and Mineral Research 29(4): 892–901. Staal, Ben, Bart O. Williams, Frank Beier, George F. Vande Woude, and Yu-Wen Zhang. 2014. Cartilage-specific deletion of Mig-6 results in osteoarthritis-like disorder with excessive articular chrondrocyte proliferation. Proceedings of the National Academy of Sciences U.S.A. 111(7): 2590–2595. 37

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