FUNCTION AND REGULATION OF OSTEONECTIN IN BONE

Summary

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

Top Publications

  1. pmc Osteonectin/SPARC polymorphisms in Caucasian men with idiopathic osteoporosis
    A M Delany
    Center for Molecular Medicine, University of Connecticut Health Center, 263 Farmington Ave, Farmington, CT, 06030, USA
    Osteoporos Int 19:969-78. 2008
  2. pmc Accentuated osteoclastic response to parathyroid hormone undermines bone mass acquisition in osteonectin-null mice
    Luciene Machado do Reis
    University of Sao Paulo, Sao Paulo, Brazil
    Bone 43:264-73. 2008
  3. pmc miR-29 suppression of osteonectin in osteoblasts: regulation during differentiation and by canonical Wnt signaling
    Kristina Kapinas
    Center for Molecular Medicine, University of Connecticut Health Center, 263 Farmington Ave, Farmington, Connecticut 06030, USA
    J Cell Biochem 108:216-24. 2009
  4. pmc miR-29 modulates Wnt signaling in human osteoblasts through a positive feedback loop
    Kristina Kapinas
    Center for Molecular Medicine, University of Connecticut Health Center, Farmington, Connecticut 06030, USA
    J Biol Chem 285:25221-31. 2010
  5. ncbi Inactivation of SPARC enhances high-fat diet-induced obesity in mice
    Jing Nie
    Benaroya Research Institute at Virginia Mason, Seattle, Washington 98101, USA
    Connect Tissue Res 52:99-108. 2011
  6. pmc MicroRNA biogenesis and regulation of bone remodeling
    Kristina 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
  7. pmc IGF-I 3' untranslated region: strain-specific polymorphisms and motifs regulating IGF-I in osteoblasts
    Spenser S Smith
    Center for Molecular Medicine, University of Connecticut Health Center, 263 Farmington Avenue, Farmington, CT 06030, USA
    Endocrinology 154:253-62. 2013

Research Grants

  1. HORMONAL CONTROL OF CALCIUM METABOLISM
    John T Potts; Fiscal Year: 2013
  2. Impact of Amyloid on the Aging Brain
    Reisa A Sperling; Fiscal Year: 2013
  3. Osteoporosis treatment response assessed by micromechanical modeling of MRI data.
    Felix W Wehrli; Fiscal Year: 2013
  4. Glucocorticoids, Bone Strength and Angiogenesis
    ROBERT STEWART WEINSTEIN; Fiscal Year: 2013
  5. Signal Transduction Mechanism of Osteoclast Differentiation
    Nandini Ghosh-Choudhury; Fiscal Year: 2013
  6. Biomechanical Stimulation &Skeletal Health in Adolescents with Anorexia Nervosa
    Amy D DiVasta; Fiscal Year: 2013
  7. G PROTEIN SIGNALING IN OSTEOBLASTS
    ROBERT NISSENSON; Fiscal Year: 2013
  8. Pharmacology of Risperidone Effects on Bone Remodeling and Energy Metabolism
    Karen L Houseknecht; Fiscal Year: 2013
  9. Signaling in Inflammation, Stress, and Tumorigenesis
    GEORGE ROBERT STARK; Fiscal Year: 2013
  10. Regulation of osteoblast number by PTH
    Robert L Jilka; Fiscal Year: 2013

Detail Information

Publications8

  1. pmc Osteonectin/SPARC polymorphisms in Caucasian men with idiopathic osteoporosis
    A 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...
  2. pmc Accentuated osteoclastic response to parathyroid hormone undermines bone mass acquisition in osteonectin-null mice
    Luciene 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...
  3. pmc miR-29 suppression of osteonectin in osteoblasts: regulation during differentiation and by canonical Wnt signaling
    Kristina 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...
  4. pmc miR-29 modulates Wnt signaling in human osteoblasts through a positive feedback loop
    Kristina 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...
  5. ncbi Inactivation of SPARC enhances high-fat diet-induced obesity in mice
    Jing 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...
  6. pmc MicroRNA biogenesis and regulation of bone remodeling
    Kristina 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...
  7. pmc IGF-I 3' untranslated region: strain-specific polymorphisms and motifs regulating IGF-I in osteoblasts
    Spenser 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...

Research Grants31

  1. HORMONAL CONTROL OF CALCIUM METABOLISM
    John T Potts; Fiscal Year: 2013
    ....
  2. Impact of Amyloid on the Aging Brain
    Reisa A Sperling; Fiscal Year: 2013
    ..This PPG brings together an exceptional multidisciplinary team of clinical, statistical, cognitive neuroscience, imaging, and laboratory investigators dedicated to exploring the impact of amyloid on the aging brain. ..
  3. Osteoporosis treatment response assessed by micromechanical modeling of MRI data.
    Felix W Wehrli; Fiscal Year: 2013
    ..The successful completion of the project will provide new insight into the potential for image-based computational biomechanics for monitoring prophylactic intervention. ..
  4. Glucocorticoids, Bone Strength and Angiogenesis
    ROBERT STEWART WEINSTEIN; Fiscal Year: 2013
    ..The proposed studies aimed at the mechanisms of the loss of bone strength in GIO should provide new insights that are sorely needed and immediately vital to veterans health care. ..
  5. Signal Transduction Mechanism of Osteoclast Differentiation
    Nandini 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. ..
  6. Biomechanical Stimulation &Skeletal Health in Adolescents with Anorexia Nervosa
    Amy D DiVasta; Fiscal Year: 2013
    ..Given the health care burden associated with the current epidemic of osteoporosis in the elderly, establishing effective measures to prevent bone loss during childhood and adolescence is paramount. ..
  7. G PROTEIN SIGNALING IN OSTEOBLASTS
    ROBERT NISSENSON; Fiscal Year: 2013
    ..abstract_text> ..
  8. Pharmacology of Risperidone Effects on Bone Remodeling and Energy Metabolism
    Karen L Houseknecht; Fiscal Year: 2013
    ....
  9. Signaling in Inflammation, Stress, and Tumorigenesis
    GEORGE ROBERT STARK; Fiscal Year: 2013
    ..abstract_text> ..
  10. Regulation of osteoblast number by PTH
    Robert L Jilka; Fiscal Year: 2013
    ....
  11. Mitochondrial Dysfunction in Neurodegeneration of Aging
    Gary E Gibson; Fiscal Year: 2013
    ..Successful completion of the goals of these projects can be expected to provide new insights into neurodegenerative processes and contribute to novel approaches to ameliorating age-related neurodegenerations. ..
  12. MOLECULAR AND CELLULAR MECHANISMS OF OSTEOPOROSIS
    Stavros C Manolagas; Fiscal Year: 2013
    ....
  13. DETECTION AND MODELS OF TOXICANT EXPOSURE
    Robert H Tukey; Fiscal Year: 2013
    ..Our combined efforts are anticipated to provide new insights into the molecular mechanisms that lead to environmental illness, and improve our understanding of the consequences of exposure to Superfund site contaminants. ..
  14. Cellular Senescence and Aging
    James 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. ..
  15. Effect of Adrenal and Gonadal Hormones on Bone Marrow and Appendicular BMD
    Catherine M Gordon; Fiscal Year: 2013
    ..Knowledge gained from this study may also have application to other diseases across the age spectrum that are associated with bone loss and involve alterations in bone marrow composition. ..
  16. Cox-2 Regulation of Bone Responses to PTH: Role of Osteoclasts
    Carol C Pilbeam; Fiscal Year: 2013
    ..The possibility that manipulation of endogenous PGs might increase the anabolic effects of PTH could have clinical applications. ..