Genomes and Genes
FUNCTION AND REGULATION OF OSTEONECTIN IN BONE
Principal Investigator: Anne M Delany
Abstract: DESCRIPTION (provided by applicant): 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.
Funding Period: 1998-08-01 - 2014-06-30
more information: NIH RePORT
- Osteonectin/SPARC polymorphisms in Caucasian men with idiopathic osteoporosisA M Delany
Center for Molecular Medicine, University of Connecticut Health Center, 263 Farmington Ave, Farmington, CT, 06030, USA
Osteoporos Int 19:969-78. 2008..We found haplotypes consisting of three single nucleotide polymorphisms (SNPs) in the 3' untranslated region (UTR) of the osteonectin gene are associated with bone density in Caucasian men with idiopathic osteoporosis...
- Accentuated osteoclastic response to parathyroid hormone undermines bone mass acquisition in osteonectin-null miceLuciene Machado do Reis
University of Sao Paulo, Sao Paulo, Brazil
Bone 43:264-73. 2008..bone catabolic effects remain poorly understood. Our results imply that osteonectin levels may play a role in modulating the balance of bone formation and resorption in response to PTH...
- miR-29 suppression of osteonectin in osteoblasts: regulation during differentiation and by canonical Wnt signalingKristina Kapinas
Center for Molecular Medicine, University of Connecticut Health Center, 263 Farmington Ave, Farmington, Connecticut 06030, USA
J Cell Biochem 108:216-24. 2009..Osteonectin and miR-29 are co-expressed in extra-skeletal tissues, and the post-transcriptional mechanisms regulating osteonectin in osteoblasts are likely to be active in other cell systems...
- miR-29 modulates Wnt signaling in human osteoblasts through a positive feedback loopKristina Kapinas
Center for Molecular Medicine, University of Connecticut Health Center, Farmington, Connecticut 06030, USA
J Biol Chem 285:25221-31. 2010..This novel regulatory circuit provides additional insight into how microRNAs interact with signaling molecules during osteoblast differentiation, allowing for fine-tuning of intricate cellular processes...
- Inactivation of SPARC enhances high-fat diet-induced obesity in miceJing Nie
Benaroya Research Institute at Virginia Mason, Seattle, Washington 98101, USA
Connect Tissue Res 52:99-108. 2011..In the absence of SPARC, mice show enhanced DIO. In adult animals, SPARC functions in the production and remodeling of adipose tissue, as well as in the regulation of preadipocyte differentiation...
- MicroRNA biogenesis and regulation of bone remodelingKristina Kapinas
Cell Biology Department, Room S7 318, University of Massachusetts Medical School, 55 Lake Avenue North, Worcester, MA 01655, USA
Arthritis Res Ther 13:220. 2011..An in-depth understanding of the roles of these regulatory RNAs in the skeleton will be critical for the development of new therapeutics aimed at treating bone loss and perhaps facilitating fracture repair...
- IGF-I 3' untranslated region: strain-specific polymorphisms and motifs regulating IGF-I in osteoblastsSpenser S Smith
Center for Molecular Medicine, University of Connecticut Health Center, 263 Farmington Avenue, Farmington, CT 06030, USA
Endocrinology 154:253-62. 2013..These microRNAs are increased in B6 and C3H cells during osteoblastic differentiation. Differential expression of the long Igf1 3' UTR isoform may be a possible mechanism for enhanced IGF-I regulation in B6 vs. C3H mice...
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- Signal Transduction Mechanism of Osteoclast DifferentiationNandini Ghosh-Choudhury; Fiscal Year: 2013..Our results will demonstrate how BMP-2 can orchestrate a complex transcriptional network in osteoblasts to tightly regulate osteoclast activation. ..
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- Pharmacology of Risperidone Effects on Bone Remodeling and Energy MetabolismKaren L Houseknecht; Fiscal Year: 2013....
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- Cellular Senescence and AgingJames L Kirkland; Fiscal Year: 2013..Our approach will provide timely, innovative, and clinically relevant interventional results based on addressing the fundamental question of the role of cellular senescence that has remained unanswered for many years. ..
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