Bone loss with aging results from imbalanced bone remodeling, with decreased osteoblast number, increased osteoclast number, and increased adipocyte number in the marrow. Mesenchymal stem cells (MSCs) give rise to both osteoblasts and adipocytes, and MSC lineage allocation is altered in aging. MSC lineage allocation is controlled by diverse intracellular signals, cell-cell interactions and the bone microenvironment. The most abundant non-collagen matrix protein in the bone microenvironment is the matricellular glycoprotein osteonectin (secreted protein acidic rich in cysteine, SPARC;BM-40). In the skeleton, osteonectin promotes osteoblast committment, suppresses adipogenesis, and regulates the balance between bone formation and resorption in response to PTH treatment. It is highly expressed early in osteoblastic differentiation, but its expression decreases as the cells acquire characteristics of mature osteoblasts. In contrast, osteonectin transcript levels change little during osteoblastic differentiation, indicating regulation at the level of translation. MicroRNAs (miRNAs) are small non-coding RNAs that mediate translational repression by interacting with the 3'untranslated region (UTR) of target mRNAs. We found that miR-29a and -29c act on the osteonectin 3'UTR and mediate translational repression in committed osteoblasts. We hypothesize that miR-29a and -29c regulate osteoblastic differentiation. Importantly, single nucleotide polymorphisms (SNPs) in the 3'UTR of osteonectin gene are associated with bone density in humans, and these SNPs modulate 3'UTR function. Since osteonectin is critical for normal bone remodeling and response to bone anabolic PTH therapy, the goal of our work is to understand post-transcriptional mechanisms regulating its expression in the skeleton. We will 1. determine how human osteonectin 3'UTR SNPs modulate protein levels during osteoblastic differentiation in vitro;2. determine the activity of human osteonectin 3'UTR haplotypes in vivo, using mice carrying knock-in mutations of the human UTR and 3. determine the role of miR-29 in osteoblast differentiation in vitro. These studies will fill a substantial void in the knowledge of key mechanisms regulating bone mass. In addition, the information we acquire could be applied to other diseases in which osteonectin is thought to play a role in pathology, such as obesity and cancer. This proposal contains basic and translational components, and we will obtain information relevant to both basic science and clinical studies.

Public Health Relevance

This project focuses on understanding the regulation of a bone matrix protein that is critical for the maintenance of bone mass. This protein is called osteonectin or SPARC, and polymorphisms in the gene coding for this protein are associated with bone density in humans. Information obtained from these studies could be used to identify novel targets for therapeutic intervention in the treatment of osteoporosis, and may be used to identify individuals at risk for developing osteoporosis.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR044877-15
Application #
8484792
Study Section
Skeletal Biology Development and Disease Study Section (SBDD)
Program Officer
Chen, Faye H
Project Start
1998-08-01
Project End
2014-06-30
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
15
Fiscal Year
2013
Total Cost
$312,848
Indirect Cost
$109,700
Name
University of Connecticut
Department
Other Basic Sciences
Type
Schools of Medicine
DUNS #
022254226
City
Farmington
State
CT
Country
United States
Zip Code
06030
Dole, Neha S; Delany, Anne M (2016) MicroRNA variants as genetic determinants of bone mass. Bone 84:57-68
Smith, Spenser S; Dole, Neha S; Franceschetti, Tiziana et al. (2016) MicroRNA-433 Dampens Glucocorticoid Receptor Signaling, Impacting Circadian Rhythm and Osteoblastic Gene Expression. J Biol Chem 291:21717-21728
Dole, Neha S; Kapinas, Kristina; Kessler, Catherine B et al. (2015) A single nucleotide polymorphism in osteonectin 3' untranslated region regulates bone volume and is targeted by miR-433. J Bone Miner Res 30:723-32
Franceschetti, Tiziana; Dole, Neha S; Kessler, Catherine B et al. (2014) Pathway analysis of microRNA expression profile during murine osteoclastogenesis. PLoS One 9:e107262
James, Eric N; Delany, Anne M; Nair, Lakshmi S (2014) Post-transcriptional regulation in osteoblasts using localized delivery of miR-29a inhibitor from nanofibers to enhance extracellular matrix deposition. Acta Biomater 10:3571-80
Smith, Spenser S; Kessler, Catherine B; Shenoy, Vikram et al. (2013) IGF-I 3' untranslated region: strain-specific polymorphisms and motifs regulating IGF-I in osteoblasts. Endocrinology 154:253-62
Franceschetti, Tiziana; Kessler, Catherine B; Lee, Sun-Kyeong et al. (2013) miR-29 promotes murine osteoclastogenesis by regulating osteoclast commitment and migration. J Biol Chem 288:33347-60
Kapinas, Kristina; Lowther, Katie M; Kessler, Catherine B et al. (2012) Bone matrix osteonectin limits prostate cancer cell growth and survival. Matrix Biol 31:299-307
Kapinas, Kristina; Delany, Anne M (2011) MicroRNA biogenesis and regulation of bone remodeling. Arthritis Res Ther 13:220
Nie, Jing; Bradshaw, Amy D; Delany, Anne M et al. (2011) Inactivation of SPARC enhances high-fat diet-induced obesity in mice. Connect Tissue Res 52:99-108

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