An important area of research is the identification and characterization of key molecules and pathways that promote bone formation, de novo. Currently the most promising anabolic agent used for the systemic treatment of osteoporosis is parathyroid hormone (PTH) and recently it has been shown that sclerostin (sost), a negative regulator of bone formation, is a direct target of PTH, suggesting that sost regulation may play an important role in PTH-dependent bone formation. This is of great biomedical importance since loss of Sost in humans causes two severe bone dysplasias: sclerosteosis (MIM 269500) and Van Buchem (VB) disease (MIM 239100), both characterized by hyperostosis and thus positioning sost as an ideal new target for the treatment of bone loss. We have recently shown that over-expressing human Sost in transgenic mice results in osteopenia, while mice expressing a transgene that mimics the VB allele, are unaffected. Through a combination of cross-species sequence comparisons followed by in vitro and in vivo enhancer assays, we have identified a highly-conserved element, ECR5 that functions as an osteoblast/osteocyte enhancer in vitro and in vivo. Further, we have shown in vitro that ECR5 is PTH-responsive, and that PTH- mediated suppression of sost requires the ECR5 distal enhancer, independently of the proximal sost promoter. Since modulating expression of proteins that regulate bone formation is of great biomedical importance and because of the well-documented role of sost in regulating osteoblast activity and bone formation, the overarching goal of our research is to understand the hormonal regulation and signal transduction pathways involving negative regulators of bone formation or `bone- antagonists'. In particular, we are interested in elucidating the transcriptional mechanisms by which sost expression is modulated during osteogenesis, bone patterning, and bone metabolism. We hypothesize that this antagonist is under tight transcriptional control from several signaling pathways known to be critical during bone homeostasis, such as the PTH- and BMP- signaling, and is preferentially up-regulated or down-regulated as needed by members of the Myocyte Enhancer Factor 2 (Mef2) family to mediate its effector function via fine-tuning of its transcript levels.

Public Health Relevance

Over 25 million Americans suffer from osteoporosis. As we continue to live longer, the aging population is at greater risk of bone loss, and thus increasing the economic burden and the medical need for anabolic therapies capable of replacing lost bone mass. An important area of research is the identification and characterization of key molecules and pathways that promote bone formation, de novo. Recently, sost has been identified as the gene responsible for two severe hyperostoses characterized by increased bone mineral density: sclerosteosis and Van Buchem disease, thus positioning sost as an ideal new target for the treatment of bone loss. Since modulating the expression of proteins that regulate bone formation is of great biomedical importance and because of the well-documented role of sost in regulating osteoblast activity and bone formation, the overarching goal of our research is to understand the transcriptional regulation mechanisms that control sost expression during osteogenesis, bone patterning, and bone metabolism.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK075730-04
Application #
8288799
Study Section
Skeletal Biology Development and Disease Study Section (SBDD)
Program Officer
Malozowski, Saul N
Project Start
2009-07-17
Project End
2014-05-31
Budget Start
2012-06-01
Budget End
2013-05-31
Support Year
4
Fiscal Year
2012
Total Cost
$336,385
Indirect Cost
$123,213
Name
Lawrence Livermore National Laboratory
Department
Type
DUNS #
827171463
City
Livermore
State
CA
Country
United States
Zip Code
94550
Collette, Nicole M; Yee, Cristal S; Murugesh, Deepa et al. (2013) Sost and its paralog Sostdc1 coordinate digit number in a Gli3-dependent manner. Dev Biol 383:90-105
Loots, Gabriela G; Keller, Hansjoerg; Leupin, Olivier et al. (2012) TGF-? regulates sclerostin expression via the ECR5 enhancer. Bone 50:663-9
Genetos, Damian C; Yellowley, Clare E; Loots, Gabriela G (2011) Prostaglandin E2 signals through PTGER2 to regulate sclerostin expression. PLoS One 6:e17772
Taher, Leila; Collette, Nicole M; Murugesh, Deepa et al. (2011) Global gene expression analysis of murine limb development. PLoS One 6:e28358
Genetos, Damian C; Toupadakis, Chrisoula A; Raheja, Leah F et al. (2010) Hypoxia decreases sclerostin expression and increases Wnt signaling in osteoblasts. J Cell Biochem 110:457-67