Receptor activator of NF-?B ligand (RANKL) is a TNF?-type cytokine that is produced by mesenchymal lineage cells such as chondrocytes, osteoblasts and osteocytes, regulated by a number of local inflammatory mediators including TNF?, IL-1 and IL-6 and systemic regulators exemplified by 1,25(OH)2D3 and PTH, and known to play an essential role in bone formation and skeletal remodeling. This cytokine also modulates the immune system and is essential for a pleiotropic collection of additional biologic activities as well. RANKL also plays important underlying roles in bone loss diseases of various etiologies, in chronic inflammatory and autoimmune syndromes and in cancer development and progression. These diverse biological roles support the idea that TNFSF11 (the RANKL gene) is exquisitely regulated, and indeed, our recent work and that of others highlights this hypothesis. Accordingly, a complex set of at least ten upstream distal Tnfsf11 enhancers integrates both factor dependent and cell-specific regulation in osteoblasts as well as T and perhaps B cells. The importance of the Tnfsf11 gene as a basic regulatory paradigm coupled with its significant biological importance in the skeleton and elsewhere prompts the following specific aims.
Aim 1 : To define important epigenetic, structural and functional determinants within the Tnfsf11 locus which are essential for both transcription factor-dependent and cell type-specific expression of RANKL within the skeleton.
Aim 2 : To assess the consequence of individual Tnfsf11 enhancer deletions within the mouse genome on bone cell RANKL expression and regulation and on the skeletal phenotypes that emerge following physiological perturbations associated with age, altered mineral homeostasis, and physiologic state (lactation) in vitro and in vivo. RANKL plays a central role in bone formation during growth, in skeletal remodeling in the adult and in bone repair following fracture. Aberrant expression of RANKL as a result of disturbances in endocrine function, chronic inflammatory diseases such as arthritis or tumor progression are known to result in site-specific bone loss and/or osteoporosis or to produce other aberrant tissue/disease phenotypes. Our present studies are designed to determine components and mechanisms responsible for factor-specific and cell typeselective expression of RANKL in the skeleton and in immune cells in vitro and in vivo. These insights may identify useful therapeutic strategies for controlling RANKL expression, thus ameliorating the bone loss associated with osteoporosis, autoimmune syndromes or other related diseases.

Public Health Relevance

RANKL is a TNF-like factor that plays an important role in skeletal metabolism;aberrant regulation of this factor in numerous disease states can lead to bone loss associated with osteoporosis. The studies herein seek to enhance our understanding of the mechanisms that underlie the expression of this factor such that better and more selective medicines can be created to prevent osteoporosis and perhaps cancer.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK074993-07
Application #
8635344
Study Section
Special Emphasis Panel (ZRG1-MOSS-F (02))
Program Officer
Malozowski, Saul N
Project Start
2006-04-01
Project End
2018-02-28
Budget Start
2014-03-01
Budget End
2015-02-28
Support Year
7
Fiscal Year
2014
Total Cost
$373,341
Indirect Cost
$123,341
Name
University of Wisconsin Madison
Department
Biochemistry
Type
Schools of Earth Sciences/Natur
DUNS #
161202122
City
Madison
State
WI
Country
United States
Zip Code
53715
Obr, Alison E; Grimm, Sandra L; Bishop, Kathleen A et al. (2013) Progesterone receptor and Stat5 signaling cross talk through RANKL in mammary epithelial cells. Mol Endocrinol 27:1808-24
Pike, J Wesley; Meyer, Mark B; Bishop, Kathleen A (2012) Regulation of target gene expression by the vitamin D receptor - an update on mechanisms. Rev Endocr Metab Disord 13:45-55
Bishop, Kathleen A; Coy, Heidi M; Nerenz, Robert D et al. (2011) Mouse Rankl expression is regulated in T cells by c-Fos through a cluster of distal regulatory enhancers designated the T cell control region. J Biol Chem 286:20880-91
Martowicz, Melissa L; Meyer, Mark B; Pike, J Wesley (2011) The mouse RANKL gene locus is defined by a broad pattern of histone H4 acetylation and regulated through distinct distal enhancers. J Cell Biochem 112:2030-45
Pike, J Wesley (2011) Genome-wide principles of gene regulation by the vitamin D receptor and its activating ligand. Mol Cell Endocrinol 347:3-10
Pike, J Wesley; Meyer, Mark B (2010) The vitamin D receptor: new paradigms for the regulation of gene expression by 1,25-dihydroxyvitamin D(3). Endocrinol Metab Clin North Am 39:255-69, table of contents
Meyer, Mark B; Goetsch, Paul D; Pike, J Wesley (2010) Genome-wide analysis of the VDR/RXR cistrome in osteoblast cells provides new mechanistic insight into the actions of the vitamin D hormone. J Steroid Biochem Mol Biol 121:136-41
Pike, J Wesley; Meyer, Mark B; Martowicz, Melissa L et al. (2010) Emerging regulatory paradigms for control of gene expression by 1,25-dihydroxyvitamin D3. J Steroid Biochem Mol Biol 121:130-5
Bishop, Kathleen A; Meyer, Mark B; Pike, J Wesley (2009) A novel distal enhancer mediates cytokine induction of mouse RANKl gene expression. Mol Endocrinol 23:2095-110
Nerenz, Robert D; Martowicz, Melissa L; Pike, J Wesley (2008) An enhancer 20 kilobases upstream of the human receptor activator of nuclear factor-kappaB ligand gene mediates dominant activation by 1,25-dihydroxyvitamin D3. Mol Endocrinol 22:1044-56

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