|
1
|
Wippert PM, Rector M, Kuhn G, Wuertz-Kozak K. Stress and Alterations in Bones: An Interdisciplinary Perspective. Front Endocrinol (Lausanne) 2017; 8:96. [PMID: 28507534 PMCID: PMC5410657 DOI: 10.3389/fendo.2017.00096] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/03/2017] [Accepted: 04/18/2017] [Indexed: 11/29/2022] Open
Abstract
Decades of research have demonstrated that physical stress (PS) stimulates bone remodeling and affects bone structure and function through complex mechanotransduction mechanisms. Recent research has laid ground to the hypothesis that mental stress (MS) also influences bone biology, eventually leading to osteoporosis and increased bone fracture risk. These effects are likely exerted by modulation of hypothalamic-pituitary-adrenal axis activity, resulting in an altered release of growth hormones, glucocorticoids and cytokines, as demonstrated in human and animal studies. Furthermore, molecular cross talk between mental and PS is thought to exist, with either synergistic or preventative effects on bone disease progression depending on the characteristics of the applied stressor. This mini review will explain the emerging concept of MS as an important player in bone adaptation and its potential cross talk with PS by summarizing the current state of knowledge, highlighting newly evolving notions (such as intergenerational transmission of stress and its epigenetic modifications affecting bone) and proposing new research directions.
Collapse
Affiliation(s)
- Pia-Maria Wippert
- Department of Health Sciences, Institute of Sociology of Health and Physical Activity, University of Potsdam, Potsdam, Germany
- Department of Health Sciences and Technology, Institute for Biomechanics, ETH Zurich, Zurich, Switzerland
- *Correspondence: Pia-Maria Wippert,
| | - Michael Rector
- Department of Health Sciences, Institute of Sociology of Health and Physical Activity, University of Potsdam, Potsdam, Germany
| | - Gisela Kuhn
- Department of Health Sciences and Technology, Institute for Biomechanics, ETH Zurich, Zurich, Switzerland
| | - Karin Wuertz-Kozak
- Department of Health Sciences, Institute of Sociology of Health and Physical Activity, University of Potsdam, Potsdam, Germany
- Department of Health Sciences and Technology, Institute for Biomechanics, ETH Zurich, Zurich, Switzerland
- Schön Klinik München Harlaching, Munich, Germany
- Spine Center, Academic Teaching Hospital and Spine Research Institute, Paracelsus Private Medical University Salzburg, Salzburg, Austria
- Competence Center for Applied Biotechnology and Molecular Medicine (CABMM), University of Zurich, Zurich, Switzerland
| |
Collapse
|
|
2
|
Brahmkhatri VP, Prasanna C, Atreya HS. Insulin-like growth factor system in cancer: novel targeted therapies. BIOMED RESEARCH INTERNATIONAL 2015; 2015:538019. [PMID: 25866791 PMCID: PMC4383470 DOI: 10.1155/2015/538019] [Citation(s) in RCA: 172] [Impact Index Per Article: 17.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/07/2014] [Revised: 10/13/2014] [Accepted: 10/20/2014] [Indexed: 12/15/2022]
Abstract
Insulin-like growth factors (IGFs) are essential for growth and survival that suppress apoptosis and promote cell cycle progression, angiogenesis, and metastatic activities in various cancers. The IGFs actions are mediated through the IGF-1 receptor that is involved in cell transformation induced by tumour. These effects depend on the bioavailability of IGFs, which is regulated by IGF binding proteins (IGFBPs). We describe here the role of the IGF system in cancer, proposing new strategies targeting this system. We have attempted to expand the general viewpoint on IGF-1R, its inhibitors, potential limitations of IGF-1R, antibodies and tyrosine kinase inhibitors, and IGFBP actions. This review discusses the emerging view that blocking IGF via IGFBP is a better option than blocking IGF receptors. This can lead to the development of novel cancer therapies.
Collapse
Affiliation(s)
| | - Chinmayi Prasanna
- NMR Research Centre, Indian Institute of Science, Bangalore 560012, India
| | - Hanudatta S. Atreya
- NMR Research Centre, Indian Institute of Science, Bangalore 560012, India
- Solid State and Structural Chemistry Unit, Indian Institute of Science, Bangalore 560012, India
| |
Collapse
|
|
3
|
Dobie R, MacRae VE, Huesa C, van't Hof R, Ahmed SF, Farquharson C. Direct stimulation of bone mass by increased GH signalling in the osteoblasts of Socs2-/- mice. J Endocrinol 2014; 223:93-106. [PMID: 25074853 PMCID: PMC4166176 DOI: 10.1530/joe-14-0292] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/29/2023]
Abstract
The suppressor of cytokine signalling (Socs2(-/-))-knockout mouse is characterised by an overgrowth phenotype due to enhanced GH signalling. The objective of this study was to define the Socs2(-/-) bone phenotype and determine whether GH promotes bone mass via IGF1-dependent mechanisms. Despite no elevation in systemic IGF1 levels, increased body weight in 4-week-old Socs2(-/-) mice following GH treatment was associated with increased cortical bone area (Ct.Ar) (P<0.01). Furthermore, detailed bone analysis of male and female juvenile and adult Socs2(-/-) mice revealed an altered cortical and trabecular phenotype consistent with the known anabolic effects of GH. Indeed, male Socs2(-/-) mice had increased Ct.Ar (P<0.05) and thickness associated with increased strength. Despite this, there was no elevation in hepatic Igf1 expression, suggesting that the anabolic bone phenotype was the result of increased local GH action. Mechanistic studies showed that in osteoblasts and bone of Socs2(-/-) mice, STAT5 phosphorylation was significantly increased in response to GH. Conversely, overexpression of SOCS2 decreased GH-induced STAT5 signalling. Although an increase in Igf1 expression was observed in Socs2(-/-) osteoblasts following GH, it was not evident in vivo. Igf1 expression levels were not elevated in response to GH in 4-week-old mice and no alterations in expression was observed in bone samples of 6-week-old Socs2(-/-) mice. These studies emphasise the critical role of SOCS2 in controlling the local GH anabolic bone effects. We provide compelling evidence implicating SOCS2 in the regulation of GH osteoblast signalling and ultimately bone accrual, which maybe via mechanisms that are independent of IGF1 production in vivo.
Collapse
Affiliation(s)
- R Dobie
- Division of Developmental BiologyThe Roslin Institute and R(D)SVS, The University of Edinburgh, Easter Bush, Midlothian, Edinburgh EH25 9RG, Scotland, UKInstitute of Ageing and Chronic DiseaseUniversity of Liverpool, Daulby Street, Liverpool L69 3GA, UKDevelopmental Endocrinology Research GroupSchool of Medicine, University of Glasgow, Yorkhill, Glasgow G3 8SJ, Scotland, UK
| | - V E MacRae
- Division of Developmental BiologyThe Roslin Institute and R(D)SVS, The University of Edinburgh, Easter Bush, Midlothian, Edinburgh EH25 9RG, Scotland, UKInstitute of Ageing and Chronic DiseaseUniversity of Liverpool, Daulby Street, Liverpool L69 3GA, UKDevelopmental Endocrinology Research GroupSchool of Medicine, University of Glasgow, Yorkhill, Glasgow G3 8SJ, Scotland, UK
| | - C Huesa
- Division of Developmental BiologyThe Roslin Institute and R(D)SVS, The University of Edinburgh, Easter Bush, Midlothian, Edinburgh EH25 9RG, Scotland, UKInstitute of Ageing and Chronic DiseaseUniversity of Liverpool, Daulby Street, Liverpool L69 3GA, UKDevelopmental Endocrinology Research GroupSchool of Medicine, University of Glasgow, Yorkhill, Glasgow G3 8SJ, Scotland, UK
| | - R van't Hof
- Division of Developmental BiologyThe Roslin Institute and R(D)SVS, The University of Edinburgh, Easter Bush, Midlothian, Edinburgh EH25 9RG, Scotland, UKInstitute of Ageing and Chronic DiseaseUniversity of Liverpool, Daulby Street, Liverpool L69 3GA, UKDevelopmental Endocrinology Research GroupSchool of Medicine, University of Glasgow, Yorkhill, Glasgow G3 8SJ, Scotland, UK
| | - S F Ahmed
- Division of Developmental BiologyThe Roslin Institute and R(D)SVS, The University of Edinburgh, Easter Bush, Midlothian, Edinburgh EH25 9RG, Scotland, UKInstitute of Ageing and Chronic DiseaseUniversity of Liverpool, Daulby Street, Liverpool L69 3GA, UKDevelopmental Endocrinology Research GroupSchool of Medicine, University of Glasgow, Yorkhill, Glasgow G3 8SJ, Scotland, UK
| | - C Farquharson
- Division of Developmental BiologyThe Roslin Institute and R(D)SVS, The University of Edinburgh, Easter Bush, Midlothian, Edinburgh EH25 9RG, Scotland, UKInstitute of Ageing and Chronic DiseaseUniversity of Liverpool, Daulby Street, Liverpool L69 3GA, UKDevelopmental Endocrinology Research GroupSchool of Medicine, University of Glasgow, Yorkhill, Glasgow G3 8SJ, Scotland, UK
| |
Collapse
|
|
4
|
Spyropoulou A, Basdra EK. Mechanotransduction in bone: Intervening in health and disease. World J Exp Med 2013; 3:74-86. [DOI: 10.5493/wjem.v3.i4.74] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/28/2013] [Revised: 09/06/2013] [Accepted: 11/03/2013] [Indexed: 02/06/2023] Open
Abstract
Mechanotransduction has been proven to be one of the most significant variables in bone remodeling and its alterations have been shown to result in a variety of bone diseases. Osteoporosis, Paget’s disease, orthopedic disorders, osteopetrosis as well as hyperparathyroidism and hyperthyroidism all comprise conditions which have been linked with deregulated bone remodeling. Although the significance of mechanotransduction for bone health and disease is unquestionable, the mechanisms behind this important process have not been fully understood. This review will discuss the molecules that have been found to be implicated in mechanotransduction, as well as the mechanisms underlying bone health and disease, emphasizing on what is already known as well as new molecules potentially taking part in conveying mechanical signals from the cell surface towards the nucleus under physiological or pathologic conditions. It will also focus on the model systems currently used in mechanotransduction studies, like osteoblast-like cells as well as three-dimensional constructs and their applications among others. It will also examine the role of mechanostimulatory techniques in preventing and treating bone degenerative diseases and consider their applications in osteoporosis, craniofacial development, skeletal deregulations, fracture treatment, neurologic injuries following stroke or spinal cord injury, dentistry, hearing problems and bone implant integration in the near future.
Collapse
|
|
5
|
Kubota T, Elalieh HZ, Saless N, Fong C, Wang Y, Babey M, Cheng Z, Bikle DD. Insulin-like growth factor-1 receptor in mature osteoblasts is required for periosteal bone formation induced by reloading. ACTA ASTRONAUTICA 2013; 92:73-78. [PMID: 23976802 PMCID: PMC3747570 DOI: 10.1016/j.actaastro.2012.08.007] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/02/2023]
Abstract
Skeletal loading and unloading has a pronounced impact on bone remodeling, a process also regulated by insulin-like growth factor 1 (IGF-1) signaling. Skeletal unloading leads to resistance to the anabolic effect of IGF-1, while reloading after unloading restores responsiveness to IGF-1. However, a direct study of the importance of IGF-1 signaling in the skeletal response to mechanical loading remains to be tested. In this study, we assessed the skeletal response of osteoblast-specific Igf-1 receptor deficient (Igf-1r-/- ) mice to unloading and reloading. The mice were hindlimb unloaded for 14 days and then reloaded for 16 days. Igf-1r-/- mice displayed smaller cortical bone and diminished periosteal and endosteal bone formation at baseline. Periosteal and endosteal bone formation decreased with unloading in Igf-1r+/+ mice. However, the recovery of periosteal bone formation with reloading was completely inhibited in Igf-1r-/- mice, although reloading-induced endosteal bone formation was not hampered. These changes in bone formation resulted in the abolishment of the expected increase in total cross-sectional area with reloading in Igf-1r-/- mice compared to the control mice. These results suggest that the Igf-1r in mature osteoblasts has a critical role in periosteal bone formation in the skeletal response to mechanical loading.
Collapse
Affiliation(s)
- Takuo Kubota
- Department of Medicine, University of California San Francisco and Endocrine Research Unit, San Francisco Veterans Affairs Medical Center, 4150 Clement St, 111N, San Francisco, CA 94121, USA
| | | | | | | | | | | | | | | |
Collapse
|
|
6
|
Wang Y, Bikle DD, Chang W. Autocrine and Paracrine Actions of IGF-I Signaling in Skeletal Development. Bone Res 2013; 1:249-59. [PMID: 26273506 DOI: 10.4248/br201303003] [Citation(s) in RCA: 49] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2013] [Accepted: 06/29/2013] [Indexed: 11/10/2022] Open
Abstract
Insulin-like growth factor-I (IGF-I) regulates cell growth, survival, and differentiation by acting on the IGF-I receptor, (IGF-IR)-a tyrosine kinase receptor, which elicits diverse intracellular signaling responses. All skeletal cells express IGF-I and IGF-IR. Recent studies using tissue/cell-specific gene knockout mouse models and cell culture techniques have clearly demonstrated that locally produced IGF-I is more critical than the systemic IGF-I in supporting embryonic and postnatal skeletal development and bone remodeling. Local IGF-I/IGF-IR signaling promotes the growth, survival and differentiation of chondrocytes and osteoblasts, directly and indirectly, by altering other autocrine/paracrine signaling pathways in cartilage and bone, and by enhancing interactions among these skeletal cells through hormonal and physical means. Moreover, local IGF-I/IGF-IR signaling is critical for the anabolic bone actions of growth hormone and parathyroid hormone. Herein, we review evidence supporting the actions of local IGF-I/IGF-IR in the above aspects of skeletal development and remodeling.
Collapse
Affiliation(s)
- Yongmei Wang
- Endocrine Unit, University of California, San Francisco, Veterans Affairs Medical Center , San Francisco, CA, USA
| | - Daniel D Bikle
- Endocrine Unit, University of California, San Francisco, Veterans Affairs Medical Center , San Francisco, CA, USA
| | - Wenhan Chang
- Endocrine Unit, University of California, San Francisco, Veterans Affairs Medical Center , San Francisco, CA, USA
| |
Collapse
|
|
7
|
Sadie-Van Gijsen H, Crowther NJ, Hough FS, Ferris WF. The interrelationship between bone and fat: from cellular see-saw to endocrine reciprocity. Cell Mol Life Sci 2013; 70:2331-49. [PMID: 23178849 PMCID: PMC11113730 DOI: 10.1007/s00018-012-1211-2] [Citation(s) in RCA: 74] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2012] [Revised: 10/05/2012] [Accepted: 11/07/2012] [Indexed: 01/03/2023]
Abstract
The number of mature osteoblasts and marrow adipocytes in bone is influenced by the differentiation of the common mesenchymal progenitor cell towards one phenotype and away from the other. Consequently, factors which promote adipogenesis not only lead to fatty marrow but also inhibit osteoblastogenesis, resulting in decreased osteoblast numbers, diminished bone formation and, potentially, inadequate bone mass and osteoporosis. In addition to osteoblast and bone adipocyte numbers being influenced by this skewing of progenitor cell differentiation towards one phenotype, mature osteoblasts and adipocytes secrete factors which may evoke changes in the cell fate and function of each other. This review examines the endogenous factors, such as PPAR-γ2, Wnt, IGF-1, GH, FGF-2, oestrogen, the GP130 signalling cytokines, vitamin D and glucocorticoids, which regulate the selection between osteoblastogenesis and adipogenesis and the interrelationship between fat and bone. The role of adipokines on bone, such as adiponectin and leptin, as well as adipose-derived oestrogen, is reviewed and the role of bone as an energy regulating endocrine organ is discussed.
Collapse
Affiliation(s)
- H. Sadie-Van Gijsen
- Division of Endocrinology, Department of Medicine, Faculty of Medicine and Health Sciences, University of Stellenbosch, Francie van Zijl Drive, Tygerberg, 7505 South Africa
| | - N. J. Crowther
- Department of Chemical Pathology, National Health Laboratory Services, University of Witwatersrand Medical School, 7 York Road, Parktown, 2193 South Africa
| | - F. S. Hough
- Division of Endocrinology, Department of Medicine, Faculty of Medicine and Health Sciences, University of Stellenbosch, Francie van Zijl Drive, Tygerberg, 7505 South Africa
| | - W. F. Ferris
- Division of Endocrinology, Department of Medicine, Faculty of Medicine and Health Sciences, University of Stellenbosch, Francie van Zijl Drive, Tygerberg, 7505 South Africa
| |
Collapse
|
|
8
|
Crane JL, Zhao L, Frye JS, Xian L, Qiu T, Cao X. IGF-1 Signaling is Essential for Differentiation of Mesenchymal Stem Cells for Peak Bone Mass. Bone Res 2013; 1:186-94. [PMID: 26273502 DOI: 10.4248/br201302007] [Citation(s) in RCA: 56] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2013] [Accepted: 04/23/2013] [Indexed: 01/27/2023] Open
Abstract
Survival of children with chronic medical illnesses is leading to an increase in secondary osteoporosis due to impaired peak bone mass (PBM). Insulin-like growth factor type 1 (IGF-1) levels correlate with the pattern of bone mass accrual and many chronic illnesses are associated with low IGF-1 levels. Reduced serum levels of IGF-1 minimally affect the integrity of the skeleton, whereas recent studies suggest that skeletal IGF-I regulates PBM. To determine the role of IGF-1 in postnatal bone mass accrual regardless of source, we established an inducible type 1 Igf receptor Cre/lox knockout mouse model, in which the type 1 Igf receptor was deleted inducibely in the mesenchymal stem cells (MSCs) from 3-7 weeks of age. The size of the mouse was not affected as knockout and wild type mice had similar body weights and nasoanal and femoral lengths. However, bone volume and trabecular bone thickness were decreased in the secondary spongiosa of female knockout mice relative to wild type controls, indicating that IGF-1 is critical for bone mass. IGF-1 signaling in MSCs in vitro has been implicated to be involved in both migration to the bone surface and differentiation into bone forming osteoblasts. To clarify the exact role of IGF-1 in bone, we found by immunohistochemical analysis that a similar number of Osterix-positive osteoprogenitors were on the bone perimeter, indicating migration of MSCs was not affected. Most importantly, 56% fewer osteocalcin-positive mature osteoblasts were present on the bone perimeter in the secondary spongiosa in knockout mice versus wild type littermates. These in vivo data demonstrate that the primary role of skeletal IGF-1 is for the terminal differentiation of osteoprogenitors, but refute the role of IGF-1 in MSC migration in vivo. Additionally, these findings confirm that impaired IGF-1 signaling in bone MSCs is sufficient to impair bone mass acquisition.
Collapse
Affiliation(s)
- Janet L Crane
- Department of Pediatrics, Johns Hopkins University School of Medicine , Baltimore, MD 21205, USA ; Department of Orthopaedic Surgery, Johns Hopkins University School of Medicine , Baltimore. MD 21205, USA
| | - Luo Zhao
- Department of Orthopedics, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences , Beijing. 100730, P.R. China
| | - Joseph S Frye
- University of Missouri School of Medicine , Columbia, MO, 65211, USA
| | - Lingling Xian
- Department of Orthopaedic Surgery, Johns Hopkins University School of Medicine , Baltimore. MD 21205, USA
| | - Tao Qiu
- Department of Orthopaedic Surgery, Johns Hopkins University School of Medicine , Baltimore. MD 21205, USA
| | - Xu Cao
- Department of Orthopaedic Surgery, Johns Hopkins University School of Medicine , Baltimore. MD 21205, USA
| |
Collapse
|
|
9
|
Doorn J, Roberts SJ, Hilderink J, Groen N, van Apeldoorn A, van Blitterswijk C, Schrooten J, de Boer J. Insulin-like growth factor-I enhances proliferation and differentiation of human mesenchymal stromal cells in vitro. Tissue Eng Part A 2013; 19:1817-28. [PMID: 23530894 DOI: 10.1089/ten.tea.2012.0522] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Abstract
Human mesenchymal stromal cells (hMSCs) offer great potential for bone tissue engineering applications, but their in vivo performance remains limited. Preconditioning of these cells with small molecules to improve their differentiation before implantation, or incorporation of growth factors are possible solutions. Insulin-like growth factor-1 (IGF-1) is one of the most abundant growth factors in bone, involved in growth, development, and metabolism, but its effects on hMSCs are still subject of debate. Here we examined the effects of IGF-1 on proliferation and differentiation of hMSCs in vitro and we found that serum abolished the effects of IGF-1. Only in the absence of serum, IGF-1 increased proliferation, alkaline phosphatase expression, and osteogenic gene expression of hMSCs. Furthermore, we examined synergistic effects of bone morphogenetic protein-2 (BMP-2) and IGF-1 and, although IGF-1 enhanced BMP-2-induced mineralization, IGF-1 only slightly affected in vivo bone formation.
Collapse
Affiliation(s)
- Joyce Doorn
- MIRA Institute for Biomedical Technology and Technical Medicine, University of Twente, Enschede, The Netherlands
| | | | | | | | | | | | | | | |
Collapse
|
|
10
|
Singhal V, Goh BC, Bouxsein ML, Faugere MC, DiGirolamo DJ. Osteoblast-restricted Disruption of the Growth Hormone Receptor in Mice Results in Sexually Dimorphic Skeletal Phenotypes. Bone Res 2013; 1:85-97. [PMID: 26273494 DOI: 10.4248/br201301006] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2013] [Accepted: 01/26/2013] [Indexed: 11/10/2022] Open
Abstract
Growth hormone (GH) exerts profound anabolic actions during postnatal skeletal development, in part, through stimulating the production of insulin-like growth factor-1 (IGF-1) in liver and skeletal tissues. To examine the requirement for the GH receptor (GHR) in osteoblast function in bone, we used Cre-LoxP methods to disrupt the GHR from osteoblasts, both in vitro and in vivo. Disruption of GHR from primary calvarial osteoblasts in vitro abolished GH-induced signaling, as assessed by JAK2/STAT5 phosphorylation, and abrogated GH-induced proliferative and anti-apoptotic actions. Osteoblasts lacking GHR exhibited reduced IGF-1-induced Erk and Akt phosphorylation and attenuated IGF-1-induced proliferation and anti-apoptotic action. In addition, differentiation was modestly impaired in osteoblasts lacking GHR, as demonstrated by reduced alkaline phosphatase staining and calcium deposition. In order to determine the requirement for the GHR in bone in vivo, we generated mice lacking the GHR specifically in osteoblasts (ΔGHR), which were born at the expected Mendelian frequency, had a normal life span and were of normal size. Three week-old, female ΔGHR mice had significantly reduced osteoblast numbers, consistent with the in vitro data. By six weeks of age however, female ΔGHR mice demonstrated a marked increase in osteoblasts, although mineralization was impaired; a phenotype similar to that observed previously in mice lacking IGF-1R specifically in osteoblasts. The most striking phenotype occurred in male mice however, where disruption of the GHR from osteoblasts resulted in a "feminization" of bone geometry in 16 week-old mice, as observed by μCT. These results demonstrate that the GHR is required for normal postnatal bone development in both sexes. GH appears to serve a primary function in modulating local IGF-1 action. However, the changes in bone geometry observed in male ΔGHR mice suggest that, in addition to facilitating IGF-1 action, GH may function to a greater extent than previously appreciated in establishing the sexual dimorphism of the skeleton.
Collapse
Affiliation(s)
- Vandana Singhal
- Department of Orthopaedic Surgery, Johns Hopkins University School of Medicine , Baltimore, MD, USA
| | - Brian C Goh
- Department of Orthopaedic Surgery, Johns Hopkins University School of Medicine , Baltimore, MD, USA
| | - Mary L Bouxsein
- Center for Advanced Orthopedic Studies, Beth Israel Deaconess Medical Center and Harvard Medical School , Boston, MA, USA
| | | | - Douglas J DiGirolamo
- Department of Orthopaedic Surgery, Johns Hopkins University School of Medicine , Baltimore, MD, USA
| |
Collapse
|
|
11
|
Li Z, Wu Z, Ren G, Zhao Y, Liu D. Expression patterns of insulin-like growth factor system members and their correlations with growth and carcass traits in Landrace and Lantang pigs during postnatal development. Mol Biol Rep 2012; 40:3569-76. [PMID: 23269622 DOI: 10.1007/s11033-012-2430-1] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2012] [Accepted: 12/18/2012] [Indexed: 01/24/2023]
Abstract
The IGF system plays important roles in growth. Nevertheless, few data have been reported so far on the expression of IGF system members and their relationship with growth in domestic animals, especially pigs. In this study, hepatic transcript level of IGF1, IGF2, IGF binding protein 2 (IGFBP2), IGFBP3 and IGF 1 receptor (IGF1R), plasma protein level of IGF1 and IGFBP3, and eight growth or carcass traits, including chest circumference, body length, body height (BH), body weight, carcass weight, loin muscle area (LMA), back fat thickness and average daily gain, were measured in fast-growing Landrace and slow-growing Lantang pigs at the age of 1, 27, 90, 150 and 180 days. The results showed that liver mRNA level of IGF1, IGF2 and IGF1R, and blood protein level of IGF1 have a similar developmental profile in both Landrace and Lantang pigs. Their levels were higher at the early age than that at other older ages. Hepatic transcript abundances of the two growth inhibitors, IGFBP2 and IGFBP3, were mostly higher in Lantang pigs than that in Landrace pigs, at 5 examined postnatal stages. The IGF system members' liver mRNA level and/or serum protein level have significant correlation with each other in different age of Landrace or Lantang pigs. Hepatic mRNA level or serum protein level of IGF system members also has significant correlation with investigated traits, especially with BH and LMA, in different age of Lantang or Landrace pigs. Our results revealed the change profiles of porcine IGF system members' liver transcript level and plasma protein level between different pig breeds and different postnatal developmental ages. Moreover, the correlation analysis results suggest that the IGF system members act coordinately to regulate the growth performance and carcass composition in pigs. The information obtained from the present study is important for elucidation of the regulatory mechanism of IGF system underlying growth, and for genetic improvement in pigs.
Collapse
Affiliation(s)
- Zicong Li
- Department of Animal Genetics, Breeding and Reproduction, College of Animal Science, South China Agricultural University, Guangzhou 510642, People's Republic of China
| | | | | | | | | |
Collapse
|
|
12
|
Strohbach CA, Scofield DE, Nindl BC, Centi AJ, Yanovich R, Evans RK, Moran DS. Female recruits sustaining stress fractures during military basic training demonstrate differential concentrations of circulating IGF-I system components: a preliminary study. Growth Horm IGF Res 2012; 22:151-157. [PMID: 22704365 DOI: 10.1016/j.ghir.2012.04.007] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/19/2011] [Revised: 04/24/2012] [Accepted: 04/25/2012] [Indexed: 11/30/2022]
Abstract
OBJECTIVE Stress fracture injuries sustained during military basic combat training (BT) are a significant problem and occur at a higher rate in female recruits than male recruits. Insulin-like growth factor-I (IGF-I) is an easily measured biomarker that is involved in bone formation and positively correlated with bone mineral density, especially in women. This study examined the response of the IGF-I system between female soldiers that sustained a stress fracture (SFX, n=13) during BT and female soldiers who did not (NSFX, n=49). DESIGN Female soldiers (n=62, 18.8 ± 0.6 yr) from 2 companies of a gender-integrated combat battalion in the Israeli Defense Forces participated in this study. Height, weight and blood draws were taken upon entry to BT (preBT) and after a four-month BT program (postBT). Stress fractures were diagnosed by bone scan. Serum was analyzed for total IGF-I, free IGF-I, IGF binding proteins (IGFBP)1-6, BAP, calcium, CTx, IL1β, IL6, PINP, PTH, TNFα, TRAP, and 25(OH)D. Statistical differences between SFX and NSFX groups and time points were assessed by RM ANOVA with Fisher post-hoc (p≤0.05). RESULTS The SFX group was significantly taller and had lower BMI than NSFX (p≤0.05). Serum concentrations of total IGF-I, bioavailable IGF-I, other bone biomarkers, and cytokines were not significantly different between SFX and NSFX preBT. Serum IGFBP-2 and IGFBP-5 were significantly higher in the SFX compared to the NSFX preBT (p≤0.05). In both groups, total IGF-I increased pre to postBT (p≤0.05). Additionally, a significant difference was observed in the bioavailable IGF-I response pre to postBT for both groups. The SFX group demonstrated a significant decrease in bioavailable IGF-I pre to postBT (preBT: 0.58 ± 0.58 ng/mL; postBT 0.39 ± 0.48; p≤0.05) whereas the NSFX group demonstrated a significant increase in bioavailable IGF-I pre to postBT (preBT: 0.53 ± 0.37 ng/mL; postBT: 0.63 ± 0.45; p≤0.05). CONCLUSIONS Our study demonstrated that serum IGF-I changes during basic training and that women sustaining stress fractures during BT significantly decreased bioavailable IGF-I, whereas their uninjured counter parts increased bioavailable IGF-I. These results suggest that stress fracture susceptibility may be related to differential IGF-I system concentrations and response to physical training.
Collapse
Affiliation(s)
- C A Strohbach
- Military Performance Division, U.S. Army Research Institute of Environmental Medicine, Natick, MA 01760, USA.
| | | | | | | | | | | | | |
Collapse
|
|
13
|
Abstract
Skeletal health is dependent on the balance between bone resorption and formation during bone remodeling. Multiple signaling pathways play essential roles in the maintenance of skeletal integrity by positively or negatively regulating bone cells. During the last years, significant advances have been made in our understanding of the essential signaling pathways that regulate bone cell commitment, differentiation and survival. New signaling anabolic pathways triggered by parathyroid hormone, local growth factors, Wnt signaling, and calcium sensing receptor have been identified. Novel signals induced by interactions between bone cells-matrix (integrins), osteoblasts/osteocytes (cadherins, connexins), and osteoblasts/osteoclast (ephrins, Wnt-RhoA, semaphorins) have been discovered. Recent studies revealed the key pathways (MAPK, PI3K/Akt) that critically control bone cells and skeletal mass. This review summarizes the most recent knowledge on the major signaling pathways that control bone cells, and their potential impact on the development of therapeutic strategies to improve human bone health.
Collapse
Affiliation(s)
- Pierre J Marie
- Laboratory of osteoblast biology and pathology, INSERM, UMR-606, University Paris Diderot, Sorbonne Paris Cité, Hopital Lariboisiere, 2 rue Ambroise Pare, 75475 Paris cedex 10, France.
| |
Collapse
|
|
14
|
Chen J, Yuan K, Mao X, Miano JM, Wu H, Chen Y. Serum response factor regulates bone formation via IGF-1 and Runx2 signals. J Bone Miner Res 2012; 27:1659-68. [PMID: 22434656 PMCID: PMC3977219 DOI: 10.1002/jbmr.1607] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
Serum response factor (SRF) plays vital roles in numerous cellular processes; however, the physiological function of SRF in skeletal tissue remains unknown. In several organ systems, SRF regulates the expression of insulin-like growth factor-1 (IGF-1), which is crucial for normal development of mineralized skeleton and bone remodeling throughout life. Here, we show that conditional deletion of SRF in osteoblasts by osteocalcin-Cre generated viable mice with normal body size and body weight. Compared with normal siblings, osteoblast-specific SRF-deficient adult mice exhibited a marked decrease in bone mineral density and bone formation rate. Deletion of SRF in primary mouse calvarial osteoblasts reduced cell differentiation and mineralization in vitro. This was accompanied by a decrease in IGF-1 expression and secretion. Addition of IGF-1 in the culture media enhanced osteoblast differentiation in control cells and partially restored the mineralization defect of SRF-deficient cells, supporting an important role of SRF in regulating IGF-1 and IGF-1-mediated osteoblast differentiation. IGF-1-induced Akt activation was inhibited in SRF-deficient calvarial cells and enhanced in the SRF overexpressed cells. In addition, SRF deficiency decreased the transcriptional activity of Runx2, the key transcription factor for osteogenesis. Overexpression of SRF induced Runx2 transactivity in control cells and restored Runx2 transactivity in the SRF-deficient cells. Taken together, we conclude that SRF is important for IGF-1-induced osteoblast differentiation and mineralization via regulating IGF-1 expression and Runx2 transactivity.
Collapse
Affiliation(s)
- Jianfeng Chen
- Department of Pathology, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Kaiyu Yuan
- Department of Pathology, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Xia Mao
- Department of Pathology, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Joseph M Miano
- Aab Cardiovascular Research Institute, School of Medicine and Dentistry, University of Rochester, Rochester, NY, USA
| | - Hui Wu
- Department of Pediatric Dentistry, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Yabing Chen
- Department of Pathology, University of Alabama at Birmingham, Birmingham, AL, USA
- Veterans Administration Medical Center Research, Birmingham, AL, USA
| |
Collapse
|
|
15
|
Kawai M, Rosen CJ. The insulin-like growth factor system in bone: basic and clinical implications. Endocrinol Metab Clin North Am 2012; 41:323-33, vi. [PMID: 22682633 PMCID: PMC3576021 DOI: 10.1016/j.ecl.2012.04.013] [Citation(s) in RCA: 75] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
The insulin-like growth factor (IGF) regulatory system is critical for skeletal growth and maintenance. Initially there was great hope that the recombinant IGFs might be used clinically for disorders ranging from short stature to fracture repair and osteoporosis. Although this potential was not realized, basic and translational studies have continued, providing significant insights into the role of this family of growth factors in skeletal homeostasis and the pathophysiology of several bone disorders. This article reviews the importance of the IGF regulatory system in skeletal growth and maintenance.
Collapse
Affiliation(s)
- Masanobu Kawai
- Department of Bone and Mineral Research, Osaka Medical Center and Research Institute for Maternal and Child Health, Izumi, Osaka, Japan 594-1101
| | - Clifford J. Rosen
- Center for Translational Research, Maine Medical Center Research Institute, Scarborough, ME 04074, USA
| |
Collapse
|
|
16
|
Abstract
The importance of the insulin-like growth factor (IGF)-I axis in the regulation of bone size and bone mineral density, two important determinants of bone strength, has been well established from clinical studies involving patients with growth hormone deficiency and IGF-I gene disruption. Data from transgenic animal studies involving disruption and overexpression of components of the IGF-I axis also provide support for a key role for IGF-I in bone metabolism. IGF-I actions in bone are subject to regulation by systemic hormones, local growth factors, as well as mechanical stress. In this review we describe findings from various genetic mouse models that pertain to the role of endocrine and local sources of IGF-I in the regulation of skeletal growth.
Collapse
Affiliation(s)
- Subburaman Mohan
- Musculoskeletal Disease Center, Research Service (151), Jerry L Pettis VA Medical Center, 11201 Benton Street, Loma Linda, CA, 92357, USA.
| | | |
Collapse
|
|
17
|
Kumar S, Ponnazhagan S. Mobilization of bone marrow mesenchymal stem cells in vivo augments bone healing in a mouse model of segmental bone defect. Bone 2012; 50:1012-8. [PMID: 22342795 PMCID: PMC3339043 DOI: 10.1016/j.bone.2012.01.027] [Citation(s) in RCA: 80] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/11/2011] [Revised: 01/27/2012] [Accepted: 01/31/2012] [Indexed: 01/15/2023]
Abstract
Although the number of mesenchymal stem cells (MSC) in the bone marrow is sufficient to maintain skeletal homeostasis, in osteopenic pathology, aggravated osteoclast activity or insufficient osteoblast numbers ensue, affecting normal bone remodeling. Most of the currently available therapies are anti-resorptive with limited osteogenic potential. Since mobilization of stem/progenitors from the BM is a prerequisite for their participation in tissue repair, amplification of endogenous stem cells may provide an alternative approach in these conditions. The present study determined the potential of MSC mobilization in vivo, using combinations of different growth factors with the CXCR4 antagonist, AMD3100, in a mouse model of segmental bone defect. Results indicated that among several factors tested IGF1 had maximum proliferative ability of MSC in vitro. Results of the in vivo studies indicated that the combination of IGF1 and AMD3100 provided significant augmentation of bone growth as determined by DXA, micro-CT and histomorphometry in mice bearing segmental fractures. Further, characterization of MSC isolated from mice treated with IGF1 and AMD3100 indicated Akt/PI3K, MEK1/2-Erk1/2 and smad2/3 as key signaling pathways mediating this effect. These data indicate the potential of in vivo stem cell mobilization as a novel alternative for bone healing.
Collapse
Affiliation(s)
| | - Selvarangan Ponnazhagan
- Corresponding author Selvarangan Ponnazhagan, Ph.D., Department of Pathology, LHRB 513, 701, 19 Street South, University of Alabama at Birmingham, Birmingham, AL 35294-0007, Phone: (205) 934-6731, Fax: (205) 975-9927,
| |
Collapse
|
|
18
|
Association between bone mineral density and type 2 diabetes mellitus: a meta-analysis of observational studies. Eur J Epidemiol 2012; 27:319-32. [PMID: 22451239 PMCID: PMC3374119 DOI: 10.1007/s10654-012-9674-x] [Citation(s) in RCA: 309] [Impact Index Per Article: 23.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2011] [Accepted: 03/01/2012] [Indexed: 12/02/2022]
Abstract
Type 2 diabetes mellitus (T2DM) influences bone metabolism, but the relation of T2DM with bone mineral density (BMD) remains inconsistent across studies. The objective of this study was to perform a meta-analysis and meta-regression of the literature to estimate the difference in BMD (g/cm2) between diabetic and non-diabetic populations, and to investigate potential underlying mechanisms. A literature search was performed in PubMed and Ovid extracting data from articles prior to May 2010. Eligible studies were those where the association between T2DM and BMD measured by dual energy X-ray absorptiometry was evaluated using a cross-sectional, cohort or case–control design, including both healthy controls and subjects with T2DM. The analysis was done on 15 observational studies (3,437 diabetics and 19,139 controls). Meta-analysis showed that BMD in diabetics was significantly higher, with pooled mean differences of 0.04 (95% CI: 0.02, 0.05) at the femoral neck, 0.06 (95% CI: 0.04, 0.08) at the hip and 0.06 (95% CI: 0.04, 0.07) at the spine. The differences for forearm BMD were not significantly different between diabetics and non-diabetics. Sex-stratified analyses showed similar results in both genders. Substantial heterogeneity was found to originate from differences in study design and possibly diabetes definition. Also, by applying meta-regression we could establish that younger age, male gender, higher body mass index and higher HbA1C were positively associated with higher BMD levels in diabetic individuals. We conclude that individuals with T2DM from both genders have higher BMD levels, but that multiple factors influence BMD in individuals with T2DM.
Collapse
|
|
19
|
Bivi N, Condon KW, Allen MR, Farlow N, Passeri G, Brun LR, Rhee Y, Bellido T, Plotkin LI. Cell autonomous requirement of connexin 43 for osteocyte survival: consequences for endocortical resorption and periosteal bone formation. J Bone Miner Res 2012; 27:374-89. [PMID: 22028311 PMCID: PMC3271138 DOI: 10.1002/jbmr.548] [Citation(s) in RCA: 186] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/30/2023]
Abstract
Connexin 43 (Cx43) mediates osteocyte communication with other cells and with the extracellular milieu and regulates osteoblastic cell signaling and gene expression. We now report that mice lacking Cx43 in osteoblasts/osteocytes or only in osteocytes (Cx43(ΔOt) mice) exhibit increased osteocyte apoptosis, endocortical resorption, and periosteal bone formation, resulting in higher marrow cavity and total tissue areas measured at the femoral mid-diaphysis. Blockade of resorption reversed the increased marrow cavity but not total tissue area, demonstrating that endocortical resorption and periosteal apposition are independently regulated. Anatomical mapping of apoptotic osteocytes, osteocytic protein expression, and resorption and formation suggests that Cx43 controls osteoclast and osteoblast activity by regulating osteoprotegerin and sclerostin levels, respectively, in osteocytes located in specific areas of the cortex. Whereas empty lacunae and living osteocytes lacking osteoprotegerin were distributed throughout cortical bone in Cx43(ΔOt) mice, apoptotic osteocytes were preferentially located in areas containing osteoclasts, suggesting that osteoclast recruitment requires active signaling from dying osteocytes. Furthermore, Cx43 deletion in cultured osteocytic cells resulted in increased apoptosis and decreased osteoprotegerin expression. Thus, Cx43 is essential in a cell-autonomous fashion in vivo and in vitro for osteocyte survival and for controlling the expression of osteocytic genes that affect osteoclast and osteoblast function.
Collapse
Affiliation(s)
- Nicoletta Bivi
- Dept. Anatomy & Cell Biology, Indiana University School of Medicine, U.S.A
| | - Keith W. Condon
- Dept. Anatomy & Cell Biology, Indiana University School of Medicine, U.S.A
| | - Matthew R. Allen
- Dept. Anatomy & Cell Biology, Indiana University School of Medicine, U.S.A
| | - Nathan Farlow
- Dept. Anatomy & Cell Biology, Indiana University School of Medicine, U.S.A
| | - Giovanni Passeri
- Dept. Anatomy & Cell Biology, Indiana University School of Medicine, U.S.A
| | - Lucas R. Brun
- Dept. Anatomy & Cell Biology, Indiana University School of Medicine, U.S.A
| | - Yumie Rhee
- Dept. Anatomy & Cell Biology, Indiana University School of Medicine, U.S.A
| | - Teresita Bellido
- Dept. Anatomy & Cell Biology, Indiana University School of Medicine, U.S.A
- Dept. Internal Medicine, Div. Endocrinology, Indiana University School of Medicine, U.S.A
| | - Lilian I. Plotkin
- Dept. Anatomy & Cell Biology, Indiana University School of Medicine, U.S.A
| |
Collapse
|
|
20
|
Zhang W, Shen X, Wan C, Zhao Q, Zhang L, Zhou Q, Deng L. Effects of insulin and insulin-like growth factor 1 on osteoblast proliferation and differentiation: differential signalling via Akt and ERK. Cell Biochem Funct 2012; 30:297-302. [PMID: 22249904 DOI: 10.1002/cbf.2801] [Citation(s) in RCA: 96] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2011] [Revised: 12/07/2011] [Accepted: 12/16/2011] [Indexed: 12/18/2022]
Abstract
Insulin and insulin-like growth factor 1 (IGF-1) are evolutionarily conserved hormonal signalling molecules, which influence a wide array of physiological functions including metabolism, growth and development. Using genetic mouse studies, both insulin and IGF-1 have been shown to be anabolic agents in osteoblasts and bone development primarily through the activation of Akt and ERK signalling pathways. In this study, we examined the temporal signalling actions of insulin and IGF-1 on primary calvarial osteoblast growth and differentiation. First, we observed that the IGF-1 receptor expression decreases whereas insulin receptor expression increases during osteoblast differentiation. Subsequently, we show that although both insulin and IGF-1 promote osteoblast differentiation and mineralization in vitro, IGF-1, but not insulin, can induce osteoblast proliferation. The IGF-1-induced osteoblast proliferation was mediated via both MAPK and Akt pathways because the IGF-1-mediated cell proliferation was blocked by U0126, an MEK/MAPK inhibitor, or LY294002, a PI3-kinase inhibitor. Osteocalcin, an osteoblast-specific protein whose expression corresponds with osteoblast differentiation, was increased in a dose- and time-dependent manner after insulin treatment, whereas it was decreased with IGF-1 treatment. Moreover, insulin treatment dramatically induced osteocalcin promoter activity, whereas IGF-1 treatment significantly inhibited it, indicating direct effect of insulin on osteocalcin synthesis.
Collapse
Affiliation(s)
- Wei Zhang
- Shanghai Key Laboratory of Combination of Traditional Chinese and Western Medicine in Prevention and Therapy of Osteoarthropathy, Shanghai Institute of Traumatology and Orthopedics, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | | | | | | | | | | | | |
Collapse
|
|
21
|
Iikubo M, Kojima I, Sakamoto M, Kobayashi A, Ikeda H, Sasano T. Morphological and histopathological changes in orofacial structures of experimentally developed acromegaly-like rats: an overview. Int J Endocrinol 2012; 2012:254367. [PMID: 22518118 PMCID: PMC3299391 DOI: 10.1155/2012/254367] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/09/2011] [Accepted: 11/14/2011] [Indexed: 11/18/2022] Open
Abstract
Tongue enlargement and mandibular prognathism are clinically recognized in almost all patients with acromegaly. An acromegaly-like rat model recently developed by exogenous administration of insulin-like growth factor I (IGF-I) was used to investigate morphological and histopathological changes in orofacial structures and to clarify whether these changes were reversible. Exogenous administration of IGF-I evoked specific enlargement of the tongue with identifiable histopathological changes (increased muscle bundle width, increased space between muscle bundles, and increased epithelial thickness), elongation of the mandibular alveolar bone and ascending ramus, and lateral expansion of the mandibular dental arch. Regarding histopathological changes in the mandibular condyle, the cartilaginous layer width, bone matrix ratio, and number of osteoblasts were all significantly greater in this rat model. After normalization of the circulating IGF-I level, tongue enlargement and histopathological changes in the tongue and mandibular condyle were reversible, whereas morphological skeletal changes in the mandible remained.
Collapse
Affiliation(s)
- Masahiro Iikubo
- Department of Oral Diagnosis, Tohoku University Graduate School of Dentistry, 4-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi 980-8575, Japan
- *Masahiro Iikubo:
| | - Ikuho Kojima
- Department of Oral Diagnosis, Tohoku University Graduate School of Dentistry, 4-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi 980-8575, Japan
| | - Maya Sakamoto
- Department of Oral Diagnosis, Tohoku University Graduate School of Dentistry, 4-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi 980-8575, Japan
| | - Akane Kobayashi
- Department of Oral Diagnosis, Tohoku University Graduate School of Dentistry, 4-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi 980-8575, Japan
| | - Hidetoshi Ikeda
- Research Institute for Pituitary Disease, Southern Tohoku General Hospital, 7-115, Yatsuyamada, Koriyama, Fukushima 963-8563, Japan
| | - Takashi Sasano
- Department of Oral Diagnosis, Tohoku University Graduate School of Dentistry, 4-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi 980-8575, Japan
| |
Collapse
|
|
22
|
Ma L, Oei L, Jiang L, Estrada K, Chen H, Wang Z, Yu Q, Zillikens MC, Gao X, Rivadeneira F. Association between bone mineral density and type 2 diabetes mellitus: a meta-analysis of observational studies. Eur J Epidemiol 2012; 27. [PMID: 22451239 PMCID: PMC3374119 DOI: 10.1007/s10654-012-9674-x&n935688=v942995] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
Abstract
Type 2 diabetes mellitus (T2DM) influences bone metabolism, but the relation of T2DM with bone mineral density (BMD) remains inconsistent across studies. The objective of this study was to perform a meta-analysis and meta-regression of the literature to estimate the difference in BMD (g/cm(2)) between diabetic and non-diabetic populations, and to investigate potential underlying mechanisms. A literature search was performed in PubMed and Ovid extracting data from articles prior to May 2010. Eligible studies were those where the association between T2DM and BMD measured by dual energy X-ray absorptiometry was evaluated using a cross-sectional, cohort or case-control design, including both healthy controls and subjects with T2DM. The analysis was done on 15 observational studies (3,437 diabetics and 19,139 controls). Meta-analysis showed that BMD in diabetics was significantly higher, with pooled mean differences of 0.04 (95% CI: 0.02, 0.05) at the femoral neck, 0.06 (95% CI: 0.04, 0.08) at the hip and 0.06 (95% CI: 0.04, 0.07) at the spine. The differences for forearm BMD were not significantly different between diabetics and non-diabetics. Sex-stratified analyses showed similar results in both genders. Substantial heterogeneity was found to originate from differences in study design and possibly diabetes definition. Also, by applying meta-regression we could establish that younger age, male gender, higher body mass index and higher HbA(1C) were positively associated with higher BMD levels in diabetic individuals. We conclude that individuals with T2DM from both genders have higher BMD levels, but that multiple factors influence BMD in individuals with T2DM.
Collapse
Affiliation(s)
- Lili Ma
- Department of Rheumatology, Fudan University, Shanghai, China
| | - Ling Oei
- Department of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands ,Department of Epidemiology, Erasmus MC, Rotterdam, The Netherlands
| | - Lindi Jiang
- Department of Rheumatology, Fudan University, Shanghai, China
| | - Karol Estrada
- Department of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands ,Department of Epidemiology, Erasmus MC, Rotterdam, The Netherlands
| | - Huiyong Chen
- Department of Rheumatology, Fudan University, Shanghai, China
| | - Zhen Wang
- Department of Rheumatology, Fudan University, Shanghai, China
| | - Qiang Yu
- Department of Rheumatology, Fudan University, Shanghai, China
| | - Maria Carola Zillikens
- Department of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands ,Department of Epidemiology, Erasmus MC, Rotterdam, The Netherlands
| | - Xin Gao
- Department of Endocrinology, Fudan University, Shanghai, China
| | - Fernando Rivadeneira
- Department of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands ,Department of Epidemiology, Erasmus MC, Rotterdam, The Netherlands ,Genetic Laboratory-Room Ee 579, Department of Internal Medicine, Erasmus MC, PO Box 2040, 3000 CA Rotterdam, The Netherlands
| |
Collapse
|
|
23
|
Ma L, Oei L, Jiang L, Estrada K, Chen H, Wang Z, Yu Q, Zillikens MC, Gao X, Rivadeneira F. Association between bone mineral density and type 2 diabetes mellitus: a meta-analysis of observational studies. Eur J Epidemiol 2012; 27. [PMID: 22451239 PMCID: PMC3374119 DOI: 10.1007/s10654-012-9674-x&n985841=v916733] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
Abstract
Type 2 diabetes mellitus (T2DM) influences bone metabolism, but the relation of T2DM with bone mineral density (BMD) remains inconsistent across studies. The objective of this study was to perform a meta-analysis and meta-regression of the literature to estimate the difference in BMD (g/cm(2)) between diabetic and non-diabetic populations, and to investigate potential underlying mechanisms. A literature search was performed in PubMed and Ovid extracting data from articles prior to May 2010. Eligible studies were those where the association between T2DM and BMD measured by dual energy X-ray absorptiometry was evaluated using a cross-sectional, cohort or case-control design, including both healthy controls and subjects with T2DM. The analysis was done on 15 observational studies (3,437 diabetics and 19,139 controls). Meta-analysis showed that BMD in diabetics was significantly higher, with pooled mean differences of 0.04 (95% CI: 0.02, 0.05) at the femoral neck, 0.06 (95% CI: 0.04, 0.08) at the hip and 0.06 (95% CI: 0.04, 0.07) at the spine. The differences for forearm BMD were not significantly different between diabetics and non-diabetics. Sex-stratified analyses showed similar results in both genders. Substantial heterogeneity was found to originate from differences in study design and possibly diabetes definition. Also, by applying meta-regression we could establish that younger age, male gender, higher body mass index and higher HbA(1C) were positively associated with higher BMD levels in diabetic individuals. We conclude that individuals with T2DM from both genders have higher BMD levels, but that multiple factors influence BMD in individuals with T2DM.
Collapse
Affiliation(s)
- Lili Ma
- Department of Rheumatology, Fudan University, Shanghai, China
| | - Ling Oei
- Department of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands ,Department of Epidemiology, Erasmus MC, Rotterdam, The Netherlands
| | - Lindi Jiang
- Department of Rheumatology, Fudan University, Shanghai, China
| | - Karol Estrada
- Department of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands ,Department of Epidemiology, Erasmus MC, Rotterdam, The Netherlands
| | - Huiyong Chen
- Department of Rheumatology, Fudan University, Shanghai, China
| | - Zhen Wang
- Department of Rheumatology, Fudan University, Shanghai, China
| | - Qiang Yu
- Department of Rheumatology, Fudan University, Shanghai, China
| | - Maria Carola Zillikens
- Department of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands ,Department of Epidemiology, Erasmus MC, Rotterdam, The Netherlands
| | - Xin Gao
- Department of Endocrinology, Fudan University, Shanghai, China
| | - Fernando Rivadeneira
- Department of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands ,Department of Epidemiology, Erasmus MC, Rotterdam, The Netherlands ,Genetic Laboratory-Room Ee 579, Department of Internal Medicine, Erasmus MC, PO Box 2040, 3000 CA Rotterdam, The Netherlands
| |
Collapse
|
|
24
|
Brennan-Speranza TC, Rizzoli R, Kream BE, Rosen C, Ammann P. Selective osteoblast overexpression of IGF-I in mice prevents low protein-induced deterioration of bone strength and material level properties. Bone 2011; 49:1073-9. [PMID: 21840432 DOI: 10.1016/j.bone.2011.07.039] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/09/2011] [Revised: 07/21/2011] [Accepted: 07/29/2011] [Indexed: 12/24/2022]
Abstract
Protein deficiency is frequently observed in elderly osteoporotic patients. Undernutrition leads to decreased levels of IGF-I, an important factor in regulating bone homeostasis throughout life. IGF-I is produced in the liver and locally in the skeleton. We hypothesized that increasing IGF-I expression in the osteoblasts, the bone forming cells, would protect the skeleton from the negative effects of a low-protein diet. To test our hypothesis, we employed a mouse model in which IGF-I was overexpressed exclusively in osteoblasts and fed either a 15% (normal) or a 2.5% (low) protein isocaloric diet to the transgenic (TG) mice and their wild-type (WT) littermates for 8 weeks. Blood was collected for biochemical determinations and weight was monitored weekly. Bones were excised for microstructural analysis (μCT), as well as biomechanical and material level properties. Histomorphometric analysis was performed for bone formation parameters. A low protein diet decreased body weight, circulating IGF-I and osteocalcin levels regardless of genotype. Overexpression of IGF-I in the osteoblasts was, however, able to protect the negative effects of low protein diet on microstructure including tibia cortical thickness and volumetric density, and on bone strength. Overexpression of IGF-I in osteoblasts in these mice protected the vertebrae from the substantial negative effects of low protein on the material level properties as measured my nanoindentation. TG mice also had larger overall geometric properties than WT mice regardless of diet. This study provides evidence that while a low protein diet leads to decreased circulating IGF-I, altered microstructure and decreased bone strength, these negative effects can be prevented with IGF-I overexpression exclusively in bone cells.
Collapse
Affiliation(s)
- Tara C Brennan-Speranza
- Service of Bone Diseases, Department of Rehabilitation and Geriatrics, Geneva University Hospitals and Faculty of Medicine, 1211 Geneva 14, Switzerland.
| | | | | | | | | |
Collapse
|
|
25
|
Simmons JH, Raines M, Ness KD, Hall R, Gebretsadik T, Mohan S, Spagnoli A. Metabolic control and bone health in adolescents with type 1 diabetes. INTERNATIONAL JOURNAL OF PEDIATRIC ENDOCRINOLOGY 2011; 2011:13. [PMID: 22029838 PMCID: PMC3215174 DOI: 10.1186/1687-9856-2011-13] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Download PDF] [Subscribe] [Scholar Register] [Received: 07/11/2011] [Accepted: 10/26/2011] [Indexed: 11/23/2022]
Abstract
Background Adults with type 1 diabetes (T1D) have decreased bone mineral density (BMD) and increased fracture risk, yet the etiologies remain elusive. Early detection of derangements in bone biomarkers during adolescence could lead to timely recognition. In adolescents with T1D, we evaluated the relationships between metabolic control, BMD, and bone anabolic and turnover markers. Methods Cross-sectional study of 57 adolescent subjects with T1D who had HbA1c consistently ≥ 9% (Poor Control, PC n = 27) or < 9% (Favorable Control, FC n = 30) for two years prior to enrollment. Subjects had T1DM for at least three years and were without diabetes complications, known celiac disease, or other chronic diseases. Results There were no differences between HbA1c groups in BMD, components of the IGF system, or 25-hydroxyvitamin D status. The prevalence of 25-hydroxyvitamin D abnormalities was similar to that seen in the general adolescent population. Few patients met the recommended dietary allowance (RDA) for vitamin D or calcium. Conclusions These data provide no evidence of association between degree of metabolic control and BMD in adolescents with T1D. Adolescents with T1D have a high prevalence of serum 25-hydroxyvitamin D abnormalities. Longitudinal studies are needed to evaluate the predictive value of vitamin D abnormalities on fracture risk.
Collapse
Affiliation(s)
- Jill H Simmons
- Department of Pediatrics, Division of Endocrinology and Diabetes, Vanderbilt Children's Hospital, Nashville, TN, USA.
| | | | | | | | | | | | | |
Collapse
|
|
26
|
Yoshikawa Y, Kode A, Xu L, Mosialou I, Silva BC, Ferron M, Clemens TL, Economides AN, Kousteni S. Genetic evidence points to an osteocalcin-independent influence of osteoblasts on energy metabolism. J Bone Miner Res 2011; 26:2012-25. [PMID: 21557308 PMCID: PMC3656486 DOI: 10.1002/jbmr.417] [Citation(s) in RCA: 109] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
The skeleton has been shown recently to regulate glucose metabolism through an osteoblast-specific hormone, osteocalcin, which favors β-cell proliferation, insulin secretion, insulin sensitivity, and energy expenditure. An implication of this finding is that a decrease in osteoblast numbers would compromise glucose metabolism in an osteocalcin-dependent manner. To test this hypothesis, osteoblasts were inducibly ablated by cross-breeding transgenic mice expressing a tamoxifen-regulated Cre under the control of the osteocalcin promoter with mice in which an inactive form of the diphtheria toxin A chain was introduced into a ubiquitously expressed locus. Ablation of osteoblasts in adult mice profoundly affected glucose metabolism. In a manner similar to what is seen in the case of osteocalcin deficiency, a partial ablation of this cell population resulted in hypoinsulinemia, hyperglycemia, glucose intolerance, and decreased insulin sensitivity. However, and unlike what is seen in osteocalcin-deficient mice, osteoblast ablation also decreased gonadal fat and increased energy expenditure and the expression of resistin, an adipokine proposed to mediate insulin resistance. While administration of osteocalcin reversed (fully) the glucose intolerance and reinstated normal blood glucose and insulin levels, it only partially restored insulin sensitivity and did not affect the improved gonadal fat weight and energy expenditure in osteoblast-depleted mice. These observations not only strengthen the notion that osteoblasts are necessary for glucose homeostasis and energy expenditure but also suggest that in addition to osteocalcin, other osteoblast-derived hormones may contribute to the emerging function of the skeleton as a regulator of energy metabolism.
Collapse
Affiliation(s)
- Yoshihiro Yoshikawa
- Department of Medicine, Division of Endocrinology, College of Physicians & Surgeons, Columbia University, New York, NY, USA
| | - Aruna Kode
- Department of Medicine, Division of Endocrinology, College of Physicians & Surgeons, Columbia University, New York, NY, USA
| | - Lili Xu
- Department of Medicine, Division of Endocrinology, College of Physicians & Surgeons, Columbia University, New York, NY, USA
| | - Ioanna Mosialou
- Department of Medicine, Division of Endocrinology, College of Physicians & Surgeons, Columbia University, New York, NY, USA
| | - Barbara C. Silva
- Department of Medicine, Division of Endocrinology, College of Physicians & Surgeons, Columbia University, New York, NY, USA
| | - Mathieu Ferron
- Department of Genetics and Development, College of Physicians & Surgeons, Columbia University, New York, NY, USA
| | - Thomas L. Clemens
- Center for Musculoskeletal Research, Department of Orthopedic Surgery, Johns Hopkins University, Baltimore, MD USA
| | - Aris N. Economides
- Bone & Cartilage Biology Group, Genome Engineering Technologies Group Regeneron Pharmaceuticals, Inc, Tarrytown, NY, USA
| | - Stavroula Kousteni
- Department of Medicine, Division of Endocrinology, College of Physicians & Surgeons, Columbia University, New York, NY, USA
| |
Collapse
|
|
27
|
|
|
28
|
Hall SL, Chen ST, Wergedal JE, Gridley DS, Mohan S, Lau KHW. Stem cell antigen-1 positive cell-based systemic human growth hormone gene transfer strategy increases endosteal bone resorption and bone loss in mice. J Gene Med 2011; 13:77-88. [PMID: 21322098 DOI: 10.1002/jgm.1542] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022] Open
Abstract
BACKGROUND The present study assesses the effect of the stem cell antigen-1 positive (Sca-1(+) ) cell-based human growth hormone (hGH) ex vivo gene transfer strategy on endosteal bone mass in the mouse. METHODS Sublethally irradiated recipient mice were transplanted with Sca-1(+) cells transduced with lentiviral vectors expressing hGH or β-galactosidase control genes. Bone parameters were assessed by micro-computed tomography and histomorphometry. RESULTS This hGH strategy drastically increased hGH mRNA levels in bone marrow cells and serum insulin-like growth factor-I (IGF-I) (by nearly 50%, p < 0.002) in hGH recipient mice. Femoral trabecular bone volume of the hGH mice was significantly reduced by 35% (p < 0.002). The hGH mice also had decreased trabecular number (by 26%; p < 0.0001), increased trabecular separation (by 38%; p < 0.0002) and reduced trabecular connectivity density (by 64%; p < 0.001), as well as significantly more osteoclasts (2.5-fold; p < 0.05) and greater osteoclastic surface per bone surface (2.6-fold; p < 0.01). CONCLUSIONS Targeted expression of hGH in cells of marrow cavity through the Sca-1(+) cell-based gene transfer strategy increased circulating IGF-I and decreased endosteal bone mass through an increase in resorption in recipient mice. These results indicate that high local levels of hGH or IGF-I in the bone marrow microenvironment enhanced resorption, which is consistent with previous findings in transgenic mice with targeted bone IGF-I expression showing that high local IGF-I expression increased bone remodeling, favoring a net bone loss. Thus, GH and/or IGF-I would not be an appropriate transgene for use in this Sca-1(+) cell-based gene transfer strategy to promote endosteal bone formation. Published 2011 John Wiley & Sons, Ltd.
Collapse
Affiliation(s)
- Susan L Hall
- Musculoskeletal Disease Center, Jerry L. Pettis Memorial VA Medical Center, Loma Linda, CA, USA.
| | | | | | | | | | | |
Collapse
|
|
29
|
Luo W, Friedman MS, Hankenson KD, Woolf PJ. Time series gene expression profiling and temporal regulatory pathway analysis of BMP6 induced osteoblast differentiation and mineralization. BMC SYSTEMS BIOLOGY 2011; 5:82. [PMID: 21605425 PMCID: PMC3126716 DOI: 10.1186/1752-0509-5-82] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/01/2011] [Accepted: 05/23/2011] [Indexed: 12/27/2022]
Abstract
Background BMP6 mediated osteoblast differentiation plays a key role in skeletal development and bone disease. Unfortunately, the signaling pathways regulated by BMP6 are largely uncharacterized due to both a lack of data and the complexity of the response. Results To better characterize the signaling pathways responsive to BMP6, we conducted a time series microarray study to track BMP6 induced osteoblast differentiation and mineralization. These temporal data were analyzed using a customized gene set analysis approach to identify temporally coherent sets of genes that act downstream of BMP6. Our analysis identified BMP6 regulation of previously reported pathways, such as the TGF-beta pathway. We also identified previously unknown connections between BMP6 and pathways such as Notch signaling and the MYB and BAF57 regulatory modules. In addition, we identify a super-network of pathways that are sequentially activated following BMP6 induction. Conclusion In this work, we carried out a microarray-based temporal regulatory pathway analysis of BMP6 induced osteoblast differentiation and mineralization using GAGE method. This novel temporal analysis is more informative and powerful than the classical static pathway analysis in that: (1) it captures the interconnections between signaling pathways or functional modules and demonstrates the even higher level organization of molecular biological systems; (2) it describes the temporal perturbation patterns of each pathway or module and their dynamic roles in osteoblast differentiation. The same set of experimental and computational strategies employed in our work could be useful for studying other complex biological processes.
Collapse
Affiliation(s)
- Weijun Luo
- Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI 48109, USA
| | | | | | | |
Collapse
|
|
30
|
Capilla E, Teles-García A, Acerete L, Navarro I, Gutiérrez J. Insulin and IGF-I effects on the proliferation of an osteoblast primary culture from sea bream (Sparus aurata). Gen Comp Endocrinol 2011; 172:107-14. [PMID: 21447336 DOI: 10.1016/j.ygcen.2011.03.020] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/31/2010] [Revised: 03/03/2011] [Accepted: 03/19/2011] [Indexed: 11/19/2022]
Abstract
Bone deformities in several fish species, like gilthead sea bream (Sparus aurata), are currently a major problem in aquaculture. To gain knowledge of fish skeletal development, a primary cell culture has been established from sea bream vertebra. The initial fibroblastic phenotype of the cells changed to a polygonal shape during the culture, and the addition of an osteogenic medium promoted the deposition of minerals in the extracellular matrix. Cell proliferation was analyzed using the MTT assay in control and mineralizing conditions at different culture days, up to day 20. The capacity of the cells to differentiate into osteoblasts was evaluated using Alizarin red stain. The cells showed slightly increased proliferation and differentiation in the presence of osteogenic medium. Furthermore, pluripotentiality of these cells was demonstrated by inducing them to differentiate into adipocytes, and the accumulation of lipids into the cells was detected with Oil Red O staining. Subsequently, the effects of insulin (1, 10, 100 and 1000 nM) and IGF-I (0.1, 1 and 10nM) on cell proliferation were evaluated with the MTT assay at day 3. Both peptides significantly stimulated the proliferation of the cells in a dose-dependent manner after either 24 or 48 h of incubation, with IGF-I apparently being more potent than insulin. In summary, a primary culture of sea bream osteoblasts has been characterized. This cellular system can be a good model to study the process of osteoblastogenesis in fish and its endocrine regulation, which may help to improve the quality of the product in aquaculture.
Collapse
Affiliation(s)
- Encarnación Capilla
- Department of Physiology and Immunology, Faculty of Biology, University of Barcelona, Av. Diagonal 645, Barcelona 08028, Spain.
| | | | | | | | | |
Collapse
|
|
31
|
Burr DB, Bellido T, White KE. Bone structure and function. Rheumatology (Oxford) 2011. [DOI: 10.1016/b978-0-323-06551-1.00009-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022] Open
|
|
32
|
Abstract
Insulin-like growth factor-1 (IGF-1) plays a central role in cellular growth, differentiation, survival, and cell cycle progression. It is expressed early during development and its effects are mediated through binding to a tyrosine kinase receptor, the insulin-like growth factor-1 receptor (IGF-1R). In the circulation, the IGFs bind to IGF-binding proteins (IGFBPs), which determine their bioavailability and regulate the interaction between the IGFs and IGF-1R. Studies in animal models and in humans have established critical roles for IGFs in skeletal growth and development. In this review we present new and old findings from mouse models of the IGF system and discuss their clinical relevance to normal and pathological skeletal physiology.
Collapse
Affiliation(s)
- Shoshana Yakar
- Division of Endocrinology, University of North Carolina, Chapel Hill, NC, USA.
| | | | | |
Collapse
|
|
33
|
Duan C, Ren H, Gao S. Insulin-like growth factors (IGFs), IGF receptors, and IGF-binding proteins: roles in skeletal muscle growth and differentiation. Gen Comp Endocrinol 2010; 167:344-51. [PMID: 20403355 DOI: 10.1016/j.ygcen.2010.04.009] [Citation(s) in RCA: 326] [Impact Index Per Article: 21.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/18/2009] [Revised: 04/07/2010] [Accepted: 04/14/2010] [Indexed: 12/22/2022]
Abstract
The insulin-like growth factor (IGF) signaling pathway consists of multiple IGF ligands, IGF receptors, and IGF-binding proteins (IGFBPs). Studies in a variety of animal and cellular systems suggest that the IGF signaling pathway plays a key role in regulating skeletal muscle growth, differentiation, and in maintaining homeostasis of the adult muscle tissues. Intriguingly, IGFs stimulate both myoblast proliferation and differentiation, which are two mutually exclusive biological events during myogenesis. Both of these actions are mediated through the same IGF-1 receptor. Recent studies have shed new insights into the molecular mechanisms underlying these paradoxical actions of IGFs in muscle cells. In this article, we provide a brief review of our current understanding of the IGF signaling system and discuss recent findings on how local oxygen availability and IGFBPs act to specify IGF actions in muscle cells.
Collapse
Affiliation(s)
- Cunming Duan
- Department of Molecular, Cellular and Developmental Biology, University of Michigan, Ann Arbor, MI 48109, USA.
| | | | | |
Collapse
|
|
34
|
Hong D, Chen HX, Ge R, Li JC. Genetically engineered mesenchymal stem cells: The ongoing research for bone tissue engineering. Anat Rec (Hoboken) 2010; 293:531-7. [PMID: 20027644 DOI: 10.1002/ar.21045] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022]
Abstract
Bone grafting is crucial in the surgical treatment of bone defects and nonunion fractures. Autogenous bone, allogenous bone, and biomaterial scaffold are three main sources of bone grafts. The biomaterial scaffold, both natural and synthetic, is widely accessible but weak in osteogenic potential. One approach to solve this problem is cell-based bone tissue engineering (BTE), established by growing living osteogenic cells on scaffold in vitro to build up its osteoinducitive capability. Mesenchymal stem cell (MSC) is suitable for use in cell-based BTE, but it remains a considerable challenge to induce MSCs to form solely bone and while preventing MSCs from differentiating into fats, muscles, and possibly neural elements in vivo. Recently, there is a drastic rise in use of genetically engineered MSCs, which can secrete growth factors or alter the transcription level, leading to osteoblast lineage commitment, bone formation, fracture repair, and spinal fusion. In this article, we reviewed the literatures regarding applications of genetically engineered MSCs in BTE. We addressed the currently applicable genes and candidate genes for MSCs modification, transduction efficiency and safety issues of the transfect vectors, and administration routes, and we briefly described in vivo tracking and potential clinical application of the genetically modified MSCs in BTE.
Collapse
Affiliation(s)
- Dun Hong
- Institute of Cell Biology, Medical College of Zhejiang University, Hangzhou, China
| | | | | | | |
Collapse
|
|
35
|
Cannata D, Vijayakumar A, Fierz Y, LeRoith D. The GH/IGF-1 axis in growth and development: new insights derived from animal models. Adv Pediatr 2010; 57:331-51. [PMID: 21056746 DOI: 10.1016/j.yapd.2010.09.003] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Affiliation(s)
- Dara Cannata
- Division of Endocrinology, Diabetes and Bone Diseases, The Samuel Bronfman Department of Medicine, Mount Sinai School of Medicine, One Gustave L. Levy Place, Atran 4th Floor-36, PO Box 1055, New York, NY 10029-6574, USA
| | | | | | | |
Collapse
|
|
36
|
Abstract
PURPOSE OF REVIEW Description of recent progress in our understanding of growth hormone (GH) effects on bone. RECENT FINDINGS Growth hormone deficiency is associated with low bone mass in children and adults, in addition to its well established impact on growth. Although GH and insulin-like growth factor I have direct skeletal actions, it is also possible that disordered parathyroid hormone secretion or effect may mediate some of the deleterious consequences of GH deficiency on bone. The benefits of GH replacement on bone mineral density have been demonstrated in many studies, but it remains unclear whether these are consistent across patient subgroups. The impact of GH replacement on fracture risk has not been definitively established. The positive effects of GH administration on growth are well established in childhood-onset growth hormone deficiency, as well as in several other pediatric conditions. Data on investigational uses of GH are also presented. SUMMARY GH may have a relevant role in bone physiology and several disease states in addition to growth hormone deficiency. Although the salutary effects of GH replacement on bone growth and bone density are well characterized, additional studies are required to examine the impact of GH replacement on fracture risk as well as potential benefits in osteoporosis.
Collapse
Affiliation(s)
- Nicholas A Tritos
- Neuroendocrine Unit, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.
| | | |
Collapse
|
|
37
|
Nanes MS, Kallen CB. Clinical assessment of fracture risk and novel therapeutic strategies to combat osteoporosis. Fertil Steril 2009; 92:403-12. [PMID: 19559412 DOI: 10.1016/j.fertnstert.2009.05.049] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2009] [Revised: 05/20/2009] [Accepted: 05/20/2009] [Indexed: 11/16/2022]
Abstract
OBJECTIVE To review the latest tools in the clinical assessment of fracture risk and to review new and emerging options for osteoporosis therapy. DESIGN Retrospective analysis of published studies regarding the diagnosis and treatment of osteoporosis. RESULT(S) Large-scale epidemiologic data were recently assembled by the World Health Organization to produce a Web-based clinical assessment tool, FRAX, which uses clinical and historical data to provide prompt assessment and quantitation of fracture risk. The FRAX models were developed from studying population-based cohorts in Europe, North America, Asia, and Australia. The FRAX algorithms indicate the 10-year probability of hip fracture and the 10-year probability of a major osteoporotic fracture (at the clinical spine, forearm, hip, or shoulder) on which to base treatment decisions. Recent progress in the study of bone metabolism including anabolic pathways that enhance bone maintenance, is anticipated to improve the ways in which skeletal health can be maintained and osteoporosis can be treated. CONCLUSION(S) Using FRAX, fracture risk in now easily assessed in the clinical setting. New and emerging treatment strategies for bone maintenance are reviewed. Improved assessment of fracture risk, combined with tailored therapies for at-risk patients, will increase the number of patients who receive appropriate bone-sparing therapies.
Collapse
Affiliation(s)
- Mark S Nanes
- Division of Endocrinology, Department of Medicine, Emory University School of Medicine, Atlanta, and VA Medical Center, Medical Service, Veterans Affairs Medical Center, Decatur, Georgia 30322, USA
| | | |
Collapse
|
|
38
|
Papachroni KK, Karatzas DN, Papavassiliou KA, Basdra EK, Papavassiliou AG. Mechanotransduction in osteoblast regulation and bone disease. Trends Mol Med 2009; 15:208-16. [PMID: 19362057 DOI: 10.1016/j.molmed.2009.03.001] [Citation(s) in RCA: 174] [Impact Index Per Article: 10.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2009] [Revised: 03/06/2009] [Accepted: 03/06/2009] [Indexed: 01/20/2023]
Abstract
Osteoblasts are key components of the bone multicellular unit and have a seminal role in bone remodeling, which is an essential function for the maintenance of the structural integrity and metabolic capacity of the skeleton. The coordinated function of skeletal cells is regulated by several hormones, growth factors and mechanical cues that act via interconnected signaling networks, resulting in the activation of specific transcription factors and, in turn, their target genes. Bone cells are responsive to mechanical stimuli and this is of pivotal importance in developing biomechanical strategies for the treatment of osteodegenerative diseases. Here, we review the molecular pathways and players activated by mechanical stimulation during osteoblastic growth, differentiation and activity in health, and consider the role of mechanostimulatory approaches in treating various bone pathophysiologies.
Collapse
Affiliation(s)
- Katerina K Papachroni
- Department of Biological Chemistry, University of Athens Medical School, 11527 Athens, Greece
| | | | | | | | | |
Collapse
|
|
39
|
Chaudhry AA, Castro-Magana M, Aloia JF, Yeh JK. Differential effects of growth hormone and alpha calcidol on trabecular and cortical bones in hypophysectomized rats. Pediatr Res 2009; 65:403-8. [PMID: 19092717 DOI: 10.1203/pdr.0b013e3181975f70] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/19/2023]
Abstract
Growth hormone (GH) deficiency in children causes severe growth retardation, vitamin D deficiency, and osteopenia. We investigated whether alfacalcidol (1OHD) alone or in combination with GH can improve bone formation. Forty hypophysectomized female rats (HX) at the age of 8 wk were divided into HX, HX + 1OHD (oral 0.25 microg/kg daily), HX+GH (0.666 mg/0.2 mL SC daily) and HX+GH + 1OHD groups for a 4-wk study. Results showed that GH increased body weight, bone area, bone mineral content (BMC), and bone mineral density (BMD), whereas 1OHD only increased BMC and BMD. In cortical bone, GH increased both periosteal and endocortical bone formation resulting in a significant increase in cortical size and area in percentage, whereas 1OHD suppressed endocortical erosion surface per bone surface (ES/BS) without a significant effect on bone formation rate per bone surface (BFR/BS). In trabecular bone, GH mitigated the bone loss by increasing BFR/BS, whereas the 1OHD effect was by suppression of trabecular bone turnover in the HX rats. The combination of GH and 1OHD had no additive effect on increasing trabecular bone mass. In conclusion, GH activates new bone formation and increases bone turnover whereas 1OHD suppresses bone turnover. The combination intervention does not seem to provide any additive benefit.
Collapse
Affiliation(s)
- Afshan A Chaudhry
- Department of Pediatric Endocrinology, Winthrop University Hospital, Mineola, New York 11501, USA.
| | | | | | | |
Collapse
|
|
40
|
Yao W, Zhong J, Yu J, Warner T, Bozic T, Ye P, D’Ercole AJ, Hock JM, Lee WH. IGF-I improved bone mineral density and body composition of weaver mutant mice. Growth Horm IGF Res 2008; 18:517-525. [PMID: 18550407 PMCID: PMC2633297 DOI: 10.1016/j.ghir.2008.04.006] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/10/2007] [Revised: 04/01/2008] [Accepted: 04/25/2008] [Indexed: 11/16/2022]
Abstract
Our recent report on a parallel decrease in the body weights and serum IGF-I levels of weaver mice suggests that IGF-I's endocrine function may be impaired in neurodegenerative diseases. To further understand the overall effects of IGF-I deficiency on the postnatal growth, we measured bone mineral density (BMD), bone mineral content (BMC), lean body mass (LBM) and fat mass in male and female weaver mice and wild-type littermates on D21 (prepuberty), D45 (puberty), and D60 (postpuberty) using dual-energy X-ray absorptiometry (DEXA). In both male and female weaver mice, we found that the levels of circulating IGF-I paralleled those of BMD, BMC, and LBM, but not the fat mass. Male weaver mice have normal fat mass at all three ages studied, whereas female weaver mice showed a trend to increase their fat mass as they mature. To determine whether circulating IGF-I is a determinant of body composition, we crossbred IGF-I transgenic mice with homozygous weaver mice, which resulted in a significant increase in circulating IGF-I levels in both male and female weaver mice and normalization of their BMD, BMC and body weights. In summary, our results demonstrated that normal circulating IGF-I levels are important in maintaining BMD, BMC, and body composition in neurodegenerative diseases, such as hereditary cerebellar ataxia.
Collapse
Affiliation(s)
- Weiguo Yao
- Department of Anatomy and Cell Biology, Indiana University School of Medicine, Indianapolis, IN 46202
| | - Jin Zhong
- Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN 46202
| | - Jun Yu
- Department of Anatomy and Cell Biology, Indiana University School of Medicine, Indianapolis, IN 46202
| | - Therry Warner
- Department of Anatomy and Cell Biology, Indiana University School of Medicine, Indianapolis, IN 46202
| | - Tomica Bozic
- Department of Anatomy and Cell Biology, Indiana University School of Medicine, Indianapolis, IN 46202
- Department of Pediatrics, Clinical Hospital, 88000 Mostar, Bosnia and Herzegovina
| | - Ping Ye
- Department of Pediatrics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7039
| | - A. Joseph D’Ercole
- Department of Pediatrics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7039
| | - Janet. M. Hock
- Department of Anatomy and Cell Biology, Indiana University School of Medicine, Indianapolis, IN 46202
| | - Wei-Hua Lee
- Department of Anatomy and Cell Biology, Indiana University School of Medicine, Indianapolis, IN 46202
- Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN 46202
| |
Collapse
|
|
41
|
Nakasaki M, Yoshioka K, Miyamoto Y, Sasaki T, Yoshikawa H, Itoh K. IGF-I secreted by osteoblasts acts as a potent chemotactic factor for osteoblasts. Bone 2008; 43:869-79. [PMID: 18718566 DOI: 10.1016/j.bone.2008.07.241] [Citation(s) in RCA: 64] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/11/2008] [Revised: 07/03/2008] [Accepted: 07/15/2008] [Indexed: 10/21/2022]
Abstract
Osteoblast recruitment to the site of future bone formation is essential for skeletal development, bone remodeling and fracture healing. A number of factors associated with bone tissue have been reported to induce directional migration of osteoblasts but the mechanism remains to be clarified. In this study, to explore a major chemotactic factor(s) for osteoblasts, we examined the serum-free medium conditioned by MC3T3-E1 osteoblast-like cells for its ability to induce osteoblast migration. Employing sequential chromatography and tandem mass spectrometry analysis, we purified and identified IGF-I as a potent chemotactic factor from the conditioned medium. IGF-I induced cell migration of both MC3T3-E1 cells and primary mouse osteoblasts, and checkerboard analysis revealed that IGF-I markedly induced directional migration (chemotaxis) of osteoblasts. Neutralization of mouse IGF-I with monoclonal antibodies resulted in delayed osteoblast monolayer wound healing and cellular polarization but addition of human IGF-I reversed these effects. IGF-I also promoted cell spreading on fibronectin in an integrin beta1-dependent manner. IGF-I induced Akt and Rac activation and localized accumulation of phosphatidylinositol 3,4,5-triphosphate (PtdIns (3,4,5)P3) at the membrane in osteoblasts. The phosphatidyl inositol 3 kinase (PI3K) inhibitor LY294002 inhibited IGF-I-induced cell migration and wound healing. Together, the results suggest that IGF-I secreted from osteoblasts in the bone tissue is a potent chemotactic factor that may play a major role in recruitment of osteoblasts during bone formation.
Collapse
Affiliation(s)
- Manando Nakasaki
- Department of Biology, Osaka Medical Center for Cancer and Cardiovascular Diseases, 1-3-2 Nakamichi, Higashinari-ku, Osaka 537-8511, Japan.
| | | | | | | | | | | |
Collapse
|
|
42
|
Bikle DD. Integrins, insulin like growth factors, and the skeletal response to load. Osteoporos Int 2008; 19:1237-46. [PMID: 18373051 PMCID: PMC9005159 DOI: 10.1007/s00198-008-0597-z] [Citation(s) in RCA: 36] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/05/2007] [Accepted: 02/11/2008] [Indexed: 01/17/2023]
Abstract
Bone loss during skeletal unloading, whether due to neurotrauma resulting in paralysis or prolonged immobilization due to a variety of medical illnesses, accelerates bone loss. In this review the evidence that skeletal unloading leads to bone loss, at least in part, due to disrupted insulin like growth factor (IGF) signaling, resulting in reduced osteoblast proliferation and differentiation, will be examined. The mechanism underlying this disruption in IGF signaling appears to involve integrins, the expression of which is reduced during skeletal unloading. Integrins play an important, albeit not well defined, role in facilitating signaling not only by IGF but also by other growth factors. However, the interaction between selected integrins such as alphaupsilonbeta3 and beta1 integrins and the IGF receptor are of especial importance with respect to the ability of bone to respond to mechanical load. Disruption of this interaction blocks IGF signaling and results in bone loss.
Collapse
Affiliation(s)
- D D Bikle
- Medicine and Dermatology, University of California San Francisco, San Francisco, CA, USA.
| |
Collapse
|
|
43
|
Tiago DM, Laizé V, Cancela ML. Alternatively spliced transcripts of Sparus aurata insulin-like growth factor 1 are differentially expressed in adult tissues and during early development. Gen Comp Endocrinol 2008; 157:107-15. [PMID: 18555066 DOI: 10.1016/j.ygcen.2008.04.006] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/09/2007] [Revised: 04/02/2008] [Accepted: 04/14/2008] [Indexed: 11/23/2022]
Abstract
Spliced variants of insulin-like growth factor 1 (IGF-1), a small peptide with a critical role in metabolism and growth, have been identified in various vertebrate species. However, despite recent functional data in mammalian systems suggesting specific roles (e.g. in muscle formation) for their pro-peptides and/or E domains, their function remains unclear. In this study, three alternatively spliced variants of Sparus aurata proIGF-1 (1a, 1b, and 1c) were identified and their expression analyzed. In adult fish, IGF-1 gene expression was observed in various soft tissues (highest levels in liver) and calcified tissues, with IGF-1c being always the most expressed isoform. In developing larvae, each isoform presented a specific pattern of expression, characterized by different onset and extent and consistent with a possible role of IGF-1a and 1b during early post-hatching events (e.g. bone or muscle formation), while IGF-1c would be rather involved in early larvae formation but probably acts in concerted action with other isoforms at later stages. We also propose that, in adults, IGF-1a and 1b isoforms may have a local action, while isoform 1c would assume a systemic action, as its mammalian counterpart. This hypothesis was further supported by in silico analysis of isoform distribution, revealing that only IGF-1c/Ea isoform has been conserved throughout evolution and that other fish isoforms (i.e. 1a and 1b) may be associated with mechanisms of osmoregulation. We finally propose that IGF-1 variants may exhibit different modes of action (systemic or local) and may be involved in different developmental and adaptive mechanisms.
Collapse
Affiliation(s)
- Daniel M Tiago
- Centre of Marine Sciences (CCMAR), University of Algarve, Campus de Gambelas, 8005-139 Faro, Portugal
| | | | | |
Collapse
|
|
44
|
Abstract
Monitoring gene expression in vitro and in vivo, is crucial when analyzing osteogenesis and developing effective bone gene therapy protocols. Until recently, molecular analytical tools were only able to detect protein expression either in vitro or in vivo. These systems include histology and immunohistochemistry, fluorescent imaging, PET (micro-PET), CT (micro-CT), and bioluminescent imaging. The last is the only system to date that can enable efficient quantitative monitoring of gene expression both in vitro and in vivo. Effective bioluminescent imaging in bone can be achieved by using transgenic mice harboring the luciferase reporter gene, downstream of an osteogenesis specific promoter. The aim of this chapter is to comprehensively describe the various protocols needed for the detection of bioluminescence in bone development and repair.
Collapse
Affiliation(s)
- Yoram Zilberman
- Skeletal Biotechnology Laboratory, Hebrew University-Hadassah Medical Center, Jerusalem, Israel
| | | | | | | | | |
Collapse
|
|
45
|
Affiliation(s)
- Ernesto Canalis
- Department of Research, Saint Francis Hospital and Medical Center, Hartford, CT 06105-1299, USA.
| | | | | |
Collapse
|
|
46
|
Abstract
The insulin-like growth factors (IGFs) play a central role in controlling somatic growth in mammals and exert anabolic effects on most tissues, including bone. IGF action is mediated by the IGF-I receptor and additionally is regulated by six high-affinity IGF binding proteins (IGFBP-1 through IGFBP-6), of which IGFBP-4 and IGFBP-5 are most abundant in bone. The focus of this brief review is on the role of IGFBP-5 in bone biology. IGFBP-5 has been implicated as a pro-osteogenic factor in several studies but conversely has been shown to act as an inhibitor of bone formation, primarily by interfering with IGF actions on osteoblasts. These potentially contradictory effects of IGFBP-5 in bone are further complicated by observations indicating that IGFBP-5 additionally may function in an IGF-independent way, and may have been accentuated by differences in both experimental design and methodology among published studies. Suggestions are made for a more systematic approach to help discern the true roles of IGFBP-5 in bone physiology.
Collapse
Affiliation(s)
- Aditi Mukherjee
- Department of Biochemistry and Molecular Biology, Oregon Health & Science University, 3181 SW Sam Jackson Park Road, Portland, OR 97239-3098, USA
| | | |
Collapse
|
|
47
|
Duren DL, Sherwood RJ, Choh AC, Czerwinski SA, Chumlea WC, Lee M, Sun SS, Demerath EW, Siervogel RM, Towne B. Quantitative genetics of cortical bone mass in healthy 10-year-old children from the Fels Longitudinal Study. Bone 2007; 40:464-70. [PMID: 17056310 PMCID: PMC1945206 DOI: 10.1016/j.bone.2006.09.015] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/22/2006] [Revised: 08/18/2006] [Accepted: 09/14/2006] [Indexed: 11/15/2022]
Abstract
The genetic influences on bone mass likely change throughout the life span, but most genetic studies of bone mass regulation have focused on adults. There is, however, a growing awareness of the importance of genes influencing the acquisition of bone mass during childhood on lifelong bone health. The present investigation examines genetic influences on childhood bone mass by estimating the residual heritabilities of different measures of second metacarpal bone mass in a sample of 600 10-year-old participants from 144 families in the Fels Longitudinal Study. Bivariate quantitative genetic analyses were conducted to estimate genetic correlations between cortical bone mass measures, and measures of bone growth and development. Using a maximum likelihood-based variance components method for pedigree data, we found a residual heritability estimate of 0.71 for second metacarpal cortical index. Residual heritability estimates for individual measures of cortical bone (e.g., lateral cortical thickness, medial cortical thickness) ranged from 0.47 to 0.58, at this pre-pubertal childhood age. Low genetic correlations were found between cortical bone measures and both bone length and skeletal age. However, after Bonferonni adjustment for multiple testing, rho(G) was not significantly different from 0 for any of these pairs of traits. Results of this investigation provide evidence of significant genetic control over bone mass largely independent of maturation while bones are actively growing and before rapid accrual of bone that typically occurs during puberty.
Collapse
Affiliation(s)
- Dana L Duren
- Lifespan Health Research Center, Department of Community Health, Wright State University Boonshoft School of Medicine, 3171 Research Boulevard, Dayton, OH 45420, USA.
| | | | | | | | | | | | | | | | | | | |
Collapse
|
|
48
|
Jiang J, Lichtler AC, Gronowicz GA, Adams DJ, Clark SH, Rosen CJ, Kream BE. Transgenic mice with osteoblast-targeted insulin-like growth factor-I show increased bone remodeling. Bone 2006; 39:494-504. [PMID: 16644298 DOI: 10.1016/j.bone.2006.02.068] [Citation(s) in RCA: 84] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/19/2005] [Revised: 02/09/2006] [Accepted: 02/22/2006] [Indexed: 11/17/2022]
Abstract
To determine the effects of locally-expressed insulin-like growth factor (IGF-I) on bone remodeling, a transgene was produced in which murine IGF-I cDNA was cloned downstream of a gene fragment comprising 3.6 kb of 5' upstream regulatory sequence and most of the first intron of the rat Col1a1 gene. The construct was expressed at the mRNA and protein level in transfected osteoblasts. Five lines of transgenic mice were generated by embryo microinjection. Transgene mRNA levels were highest in calvaria, long bone and tendon, and lower in skin. Serum IGF-I and body weight were increased in males and females only in the highest expressing line. Histomorphometry showed that transgenic calvaria were wider and had greater marrow area and bone area. Transgenic calvaria had increased osteoclast number per bone surface. Percent collagen synthesis and cell replication were increased in transgenic calvaria. Femur length, cortical width and cross-sectional area were increased in transgenic femurs of the highest expressing line, while femoral trabecular bone volume was little affected. Thus, broad overexpression of IGF-I in cells of the osteoblast lineage increased indices of bone formation and resorption.
Collapse
Affiliation(s)
- Jin Jiang
- Department of Oral Health and Diagnostic Sciences, University of Connecticut Health Center, Farmington, CT 06030, USA.
| | | | | | | | | | | | | |
Collapse
|
|
49
|
He J, Rosen CJ, Adams DJ, Kream BE. Postnatal growth and bone mass in mice with IGF-I haploinsufficiency. Bone 2006; 38:826-35. [PMID: 16427371 DOI: 10.1016/j.bone.2005.11.021] [Citation(s) in RCA: 69] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/25/2005] [Revised: 10/25/2005] [Accepted: 11/17/2005] [Indexed: 11/23/2022]
Abstract
We examined the influence of IGF-I haploinsufficiency on growth, bone mass and osteoblast differentiation in Igf1 heterozygous knockout (HET) mice. Cohorts of male and female wild type (WT) and HET mice in the outbred CD-1 background were analyzed at 1, 2, 4, 8, 12, 15 and 18 months of age for body weight, serum IGF-I and bone morphometry. Compared to WT mice, HET mice had 20-30% lower serum IGF-I levels in both genders and in all age groups. Female HET mice showed significant reductions in body weight (10-20%), femur length (4-6%) and femoral bone mineral density (BMD) (7-12%) before 15 months of age. Male HET mice showed significant differences in all parameters at 2 months and thereafter. At 8 and 12 months, WT mice also showed a significant gender effect: despite their lower body weight, female mice had higher femoral BMD and femur length compared to males. Microcomputed tomography showed a significant reduction in cortical bone area (7-20%) and periosteal circumference (5-13%) with no consistent pattern of change in trabecular bone measurements in 2- and 8-month old HET mice in both genders. HET primary osteoblast cultures showed a 40% reduction in IGF-I protein expression and a 50% decrease in IGF-I mRNA expression. Cell growth and proliferation were decreased in HET cultures. Thus, IGF-I haploinsufficiency in outbred male and female mice resulted in reduced body weight, femur length and areal BMD at most ages. Serum IGF-I levels showed a high level of positive correlation with body weight and skeletal morphometry. These studies show that IGF-I is a determinant of bone size and mass in postnatal life. We speculate that impaired osteoblast proliferation may contribute to the skeletal phenotype of mice with IGF-I haploinsufficiency.
Collapse
Affiliation(s)
- Jianing He
- Department of Medicine, The University of Connecticut Health Center, Farmington, 06030-1850, USA
| | | | | | | |
Collapse
|
|
50
|
Niu T, Rosen CJ. The insulin-like growth factor-I gene and osteoporosis: a critical appraisal. Gene 2005; 361:38-56. [PMID: 16183214 DOI: 10.1016/j.gene.2005.07.016] [Citation(s) in RCA: 107] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2005] [Revised: 06/16/2005] [Accepted: 07/08/2005] [Indexed: 12/17/2022]
Abstract
Osteoporosis, a disorder of skeletal fragility, is common in the elderly, and its prevalence is increasing as more individuals with low bone mineral density (BMD), the strongest predictor of fracture risk, are detected. Previous basic and clinical studies imply there is a significant role for insulin-like growth factor-I (IGF-I) in determining BMD. Recently, polymorphisms upstream of the P1 promoter region of the human IGF-I gene have been found to be associated with serum levels of IGF-I, BMD and fracture risk in various ethnic groups. Multiple quantitative trait loci (QTLs) have been identified that underlie serum IGF-I in a mouse intercross between two inbred strains. The most promising QTL on mouse chromosome 6 has provided clues for unraveling the molecular mechanisms that regulate osteoblast differentiation. Genomic engineering resulting in IGF-I deficient mice, and mice with targeted over-expression of IGF-I reinforce the essential role of IGF-I in bone development at both the embryonic and postnatal stages. Thus, it is apparent that significant new insights into the role of the IGF-I gene in bone remodeling occur through several distinct mechanisms: (1) the skeletal IGF regulatory system; (2) the systemic growth hormone/IGF-I axis; (3) parathyroid hormone signaling; (4) sex steroids; and (5) the OPG/RANKL/RANK cytokine system. Molecular dissection of the IGF regulatory system and its signaling pathway in bone may reveal novel therapeutic targets for the treatment of osteoporosis.
Collapse
Affiliation(s)
- Tianhua Niu
- Division of Preventive Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02215, USA.
| | | |
Collapse
|