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Olansen J, Aaron RK. Similar Pathophysiological Mechanisms Between Osteoarthritis and Vascular Disease. FRONT BIOSCI-LANDMRK 2024; 29:320. [PMID: 39344315 DOI: 10.31083/j.fbl2909320] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2024] [Revised: 06/17/2024] [Accepted: 06/25/2024] [Indexed: 10/01/2024]
Abstract
Osteoarthritis (OA) is a prevalent, chronic joint disorder affecting millions of people worldwide, characterized by articular cartilage degradation, subchondral bone remodeling, synovial cytokine secretion, and osteophyte formation. OA primarily affects the hips, knees, hands, and spine. Patients with OA exhibit a higher prevalence of cardiovascular comorbidities and potentially important associations between OA and cardiovascular diseases have prompted investigations into potentially similar pathophysiological associations. This review explores the coexistence of atherosclerotic peripheral vascular disease (ASPVD) in OA patients, including evidence from a contemporary study suggesting associations between OA and arterial wall thickness and blood flow changes which are characteristic of early atherosclerosis, and which stimulate reactive pathology in endothelial cells. Observations from this study demonstrate elevated arterial flow volume and increased intima-media thickness in arteries ipsilateral to OA knees, suggesting a potential link between OA and arterial wall disease. We further explore the intricate relationship between the vascular system and skeletal health, highlighting bidirectional interactions among endothelial cells, inflammatory cells, and various bone cells. Mechanical endothelial cell dysfunction is discussed, emphasizing the impact of vessel wall material changes and endothelial cell responses to alterations in fluid shear stress. Inflammatory changes in OA and ASPVD are also explored, showcasing shared pathophysiological processes involving immune cell infiltration and pro-inflammatory cytokines. Additionally, the role of hypofibrinolysis in OA and ASPVD is discussed, highlighting similarities in elevations of the hypercoagulative and hypofibrinolytic factor, plasminogen activator inhibitor (PAI-1). The review suggests a provocative relationship among low-grade chronic inflammation, endothelial dysfunction, and hypofibrinolytic states in OA and ASPVD, warranting further investigation. In conclusion, this review provides an exploration of the possible associations between OA and ASPVD. While the ongoing study's findings and other reports are observational, they suggest shared pathophysiological processes and emphasize the need for further research to elucidate additional potentially correlative linkages between these conditions. Understanding common molecular pathways may pave a way for targeted interventions that address both OA and ASPVD.
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Affiliation(s)
- Jon Olansen
- Department of Orthopaedics, Warren Alpert Medical School, Brown University, RI 02905, USA
| | - Roy K Aaron
- Department of Orthopaedics, Warren Alpert Medical School, Brown University, RI 02905, USA
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Abstract
The skeleton is highly vascularized due to the various roles blood vessels play in the homeostasis of bone and marrow. For example, blood vessels provide nutrients, remove metabolic by-products, deliver systemic hormones, and circulate precursor cells to bone and marrow. In addition to these roles, bone blood vessels participate in a variety of other functions. This article provides an overview of the afferent, exchange and efferent vessels in bone and marrow and presents the morphological layout of these blood vessels regarding blood flow dynamics. In addition, this article discusses how bone blood vessels participate in bone development, maintenance, and repair. Further, mechanical loading-induced bone adaptation is presented regarding interstitial fluid flow and pressure, as regulated by the vascular system. The role of the sympathetic nervous system is discussed in relation to blood vessels and bone. Finally, vascular participation in bone accrual with intermittent parathyroid hormone administration, a medication prescribed to combat age-related bone loss, is described and age- and disease-related impairments in blood vessels are discussed in relation to bone and marrow dysfunction. © 2020 American Physiological Society. Compr Physiol 10:1009-1046, 2020.
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Affiliation(s)
- Rhonda D Prisby
- Bone Vascular and Microcirculation Laboratory, Department of Kinesiology, University of Texas at Arlington, Arlington, Texas, USA
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Maffei P, Dassie F, Wennberg A, Parolin M, Vettor R. The Endothelium in Acromegaly. Front Endocrinol (Lausanne) 2019; 10:437. [PMID: 31396153 PMCID: PMC6667653 DOI: 10.3389/fendo.2019.00437] [Citation(s) in RCA: 32] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/13/2019] [Accepted: 06/18/2019] [Indexed: 12/12/2022] Open
Abstract
Growth hormone (GH) and insulin like growth factor-1 (IGF-1) excess induce well-known deleterious effects on the cardiovascular system, especially after long-term exposition. Acromegaly, a condition of chronic GH and IGF-1 hypersecretion, is frequently associated to cardiovascular complications, although recent studies have shown a reduction in the prevalence of these comorbidities in well-controlled patients and a mortality risk similar to normal aging population. Many factors could contribute to the increased cardiovascular risk of acromegaly patients. Among these factors, the endothelium plays a key role in the pathogenesis of atherosclerotic plaques and could be considered an early marker of atherosclerosis and cardiovascular dysfunction. In this review we examined the relationship between GH/IGF-1 excess and the endothelium, from basic studies to clinical evidence. Many studies involving various arterial districts (microvascular arteries of retina, kidney and brain, and major vessels as carotid and aorta) showed that GH/IGF-1 excess promotes endothelial dysfunction via several different mechanisms. Increased endothelial proliferation, dysfunction of endothelial progenitor cells, increased oxidative stress, and compromised oxidative defenses are the main factors that are associated with endothelial dysfunction. In the general population, these alterations are associated with the development of atherosclerosis with an increased incidence of coronary artery disease and cerebrovascular complications. However, in acromegaly this is still a debated issue, despite the presence of many pro-atherogenic factors and comorbidities, such as hypertension, diabetes, sleep apnoea, and metabolic syndrome. Preclinical markers of atherosclerosis as arterial intima media thickness, pulse wave velocity and flow mediated dilation seem to be impaired in acromegaly and partly mediated by the endothelium dysfunction. In conclusion, the pathophysiology of endothelial dysfunction in the condition of GH and IGF-1 excess remains a crucial area of investigation to fully dissect the association of acromegaly with cardiovascular disease complications.
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Affiliation(s)
- Pietro Maffei
- Clinica Medica 3, Department of Medicine (DIMED), Padua University Hospital, Padua, Italy
- *Correspondence: Pietro Maffei
| | - Francesca Dassie
- Clinica Medica 3, Department of Medicine (DIMED), Padua University Hospital, Padua, Italy
| | - Alexandra Wennberg
- Clinica Neurologica, Department of Neurosciences (DNS), Padua University Hospital, Padua, Italy
| | - Matteo Parolin
- Clinica Medica 3, Department of Medicine (DIMED), Padua University Hospital, Padua, Italy
| | - Roberto Vettor
- Clinica Medica 3, Department of Medicine (DIMED), Padua University Hospital, Padua, Italy
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Prisby RD. Mechanical, hormonal and metabolic influences on blood vessels, blood flow and bone. J Endocrinol 2017; 235:R77-R100. [PMID: 28814440 PMCID: PMC5611884 DOI: 10.1530/joe-16-0666] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/06/2017] [Accepted: 08/16/2017] [Indexed: 12/25/2022]
Abstract
Bone tissue is highly vascularized due to the various roles bone blood vessels play in bone and bone marrow function. For example, the vascular system is critical for bone development, maintenance and repair and provides O2, nutrients, waste elimination, systemic hormones and precursor cells for bone remodeling. Further, bone blood vessels serve as egress and ingress routes for blood and immune cells to and from the bone marrow. It is becoming increasingly clear that the vascular and skeletal systems are intimately linked in metabolic regulation and physiological and pathological processes. This review examines how agents such as mechanical loading, parathyroid hormone, estrogen, vitamin D and calcitonin, all considered anabolic for bone, have tremendous impacts on the bone vasculature. In fact, these agents influence bone blood vessels prior to influencing bone. Further, data reveal strong associations between vasodilator capacity of bone blood vessels and trabecular bone volume, and poor associations between estrogen status and uterine mass and trabecular bone volume. Additionally, this review highlights the importance of the bone microcirculation, particularly the vascular endothelium and NO-mediated signaling, in the regulation of bone blood flow, bone interstitial fluid flow and pressure and the paracrine signaling of bone cells. Finally, the vascular endothelium as a mediator of bone health and disease is considered.
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Affiliation(s)
- Rhonda D Prisby
- Department of KinesiologyUniversity of Texas at Arlington, Arlington, Texas, USA
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6
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Westley RL, May FEB. A twenty-first century cancer epidemic caused by obesity: the involvement of insulin, diabetes, and insulin-like growth factors. Int J Endocrinol 2013; 2013:632461. [PMID: 23983688 PMCID: PMC3747439 DOI: 10.1155/2013/632461] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/06/2012] [Accepted: 03/25/2013] [Indexed: 02/08/2023] Open
Abstract
Obesity has reached epidemic proportions in the developed world. The progression from obesity to diabetes mellitus type 2, via metabolic syndrome, is recognised, and the significant associated increase in the risk of major human cancers acknowledged. We review the molecular basis of the involvement of morbidly high concentrations of endogenous or therapeutic insulin and of insulin-like growth factors in the progression from obesity to diabetes and finally to cancer. Epidemiological and biochemical studies establish the role of insulin and hyperinsulinaemia in cancer risk and progression. Insulin-like growth factors, IGF-1 and IGF-2, secreted by visceral or mammary adipose tissue have significant paracrine and endocrine effects. These effects can be exacerbated by increased steroid hormone production. Structural studies elucidate how each of the three ligands, insulin, IGF-1, and IGF-2, interacts differently with isoforms A and B of the insulin receptor and with type I IGF receptor and explain how these protagonists contribute to diabetes-associated cancer. The above should inform appropriate treatment of cancers that arise in obese individuals and in those with diabetes mellitus type 2. Novel drugs that target the insulin and insulin-like growth factor signal transduction pathways are in clinical trial and should be effective if appropriate biomarker-informed patient stratification is implemented.
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Affiliation(s)
- Rosalyne L. Westley
- Northern Institute for Cancer Research, Faculty of Medical Sciences, University of Newcastle upon Tyne, Framlington Place, Newcastle upon Tyne NE2 4HH, UK
| | - Felicity E. B. May
- Northern Institute for Cancer Research, Faculty of Medical Sciences, University of Newcastle upon Tyne, Framlington Place, Newcastle upon Tyne NE2 4HH, UK
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Korres N, Tsiridis E, Pavlou G, Mitsoudis A, Perrea DN, Zoumbos AB. Biomechanical characteristics of bone in streptozotocin-induced diabetic rats: An in-vivo randomized controlled experimental study. World J Orthop 2013; 4:124-129. [PMID: 23878780 PMCID: PMC3717245 DOI: 10.5312/wjo.v4.i3.124] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/16/2012] [Revised: 01/04/2013] [Accepted: 05/10/2013] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the in vivo effects of type I diabetes on the mechanical strength of tibial bone in a rodent model.
METHODS: The biomechanical effect of diabetes on the structural integrity of the tibia in streptozotocin induced diabetic Wistar rats was analysed. Induction of diabetes was achieved by an intra-peritoneal injection and confirmed by measuring serial blood glucose levels (> 150 mg/dL). After 8 wk the tibiae were harvested and compared to a control group. Biomechanical analysis of harvested tibiae was performed using a three-point bending technique on a servo hydraulic MTS 858 MiniBionix frame. Maximum force applied to failure (N), stiffness (N × mm) and energy absorbed (N/mm) were recorded and plotted on load displacement curves. A displacement control loading mode of 1 mm/min was selected to simulate quasi-static loading conditions. Measurements from load-displacement curves were directly compared between groups.
RESULTS: Fourteen streptozotocin induced diabetic Wistar rats were compared against nineteen non-diabetic controls. An average increase of 155.2 g in body weight was observed in the control group compared with only 5 g in the diabetic group during the experimental study period. Levels of blood glucose increased to 440.25 mg/dL in the diabetic group compared to 116.62 mg/dL in the control group.The biomechanical results demonstrate a highly significant reduction in the maximum load to failure from 69.5 N to 58 N in diabetic group compared to control (P = 0.011). Energy absorption to fracture was reduced from 28.2 N in the control group to 23.5 N in the diabetic group (P = 0.082). No significant differences were observed between the groups for bending stiffness.
CONCLUSION: Streptozotocin-induced diabetes in rodents reduces the maximum force and energy absorption to failure of bone, suggesting a predisposition for fracture risk.
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Park AG, Paglia DN, Al-Zube L, Hreha J, Vaidya S, Breitbart E, Benevenia J, O'Connor JP, Lin SS. Local insulin therapy affects fracture healing in a rat model. J Orthop Res 2013; 31:776-82. [PMID: 23238765 DOI: 10.1002/jor.22287] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/16/2011] [Accepted: 11/08/2012] [Indexed: 02/04/2023]
Abstract
A significant number of lower extremity fractures result in mal-union necessitating effective treatments to restore ambulation. Prior research in diabetic animal fracture models demonstrated improved healing following local insulin application to the fracture site and indicated that local insulin therapy can aid bone regeneration, at least within an insulin-dependent diabetic animal model. This study tested whether local insulin therapy could accelerate femur fracture repair in normal, non-diabetic rats. High (20 units) and low (10 units) doses of insulin were delivered in a calcium sulfate carrier which provided sustained release of the exogenous insulin for 7 days after fracture. Histomorphometry, radiographic scoring, and torsional mechanical testing were used to measure fracture healing. The fracture calluses from rats treated with high-dose insulin had significantly more cartilage than untreated rats after 7 and 14 days of healing. After 4 weeks of healing, femurs from rats treated with low-dose insulin had significantly higher radiographic scores and mechanical strength (p < 0.05), compared to the no treatment control groups. The results of this study suggest that locally delivered insulin is a potential therapeutic agent for treating bone fractures. Further studies are necessary, such as large animal proof of concepts, prior to the clinical use of insulin for bone fracture treatment.
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Affiliation(s)
- Andrew G Park
- Department of Orthopaedics, University of Medicine, Dentistry of New Jersey-New Jersey Medical School, 185 South Orange Avenue, 90 Bergen Street, Suite 7300, Newark, NJ 07103, USA
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Paglia DN, Wey A, Breitbart EA, Faiwiszewski J, Mehta SK, Al-Zube L, Vaidya S, Cottrell JA, Graves D, Benevenia J, O’Connor JP, Lin SS. Effects of local insulin delivery on subperiosteal angiogenesis and mineralized tissue formation during fracture healing. J Orthop Res 2013; 31:783-91. [PMID: 23238777 PMCID: PMC6446235 DOI: 10.1002/jor.22288] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/31/2012] [Accepted: 11/08/2012] [Indexed: 02/04/2023]
Abstract
Local insulin delivery has been shown to improve osseous healing in diabetic animals. The purpose of this study was to quantify the effects of local intramedullary delivery of saline or Ultralente insulin (UL) on various fracture healing parameters using an in vivo non-diabetic BB Wistar rat model. Quantitation of local insulin levels showed a rapid release of insulin from the fractured femora, demonstrating complete release at 2 days. RT-PCR analysis revealed that the expression of early osteogenic markers (Col1α2, osteopontin) was significantly enhanced with UL treatment when compared with saline controls (p < 0.05). Significant differences in VEGF + cells and vascularity were evident between the treatment and control groups at day 7 (p < 0.05). At day 21, histomorphometric analysis demonstrated a significant increase in percent mineralized tissue in the UL-treated animals compared with controls (p < 0.05), particularly within the subperiosteal region of the fracture callus. Mechanical testing at 4 weeks showed significantly greater mechanical strength for UL-treated animals (p < 0.05), but healing in control animals caught up at 6 weeks post-fracture. These results suggest that the primary osteogenic effect of UL during the early stages of fracture healing (1-3 weeks) is through an increase in osteogenic gene expression, subperiosteal angiogenesis, and mineralized tissue formation.
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Affiliation(s)
- David N. Paglia
- Department of Orthopaedics, University of Medicine and Dentistry of New Jersey—New Jersey Medical School, 90 Bergen Street, Suite 7300, Newark, New Jersey 07103
| | - Aaron Wey
- Department of Orthopaedics, University of Medicine and Dentistry of New Jersey—New Jersey Medical School, 90 Bergen Street, Suite 7300, Newark, New Jersey 07103
| | - Eric A. Breitbart
- Department of Orthopaedics, University of Medicine and Dentistry of New Jersey—New Jersey Medical School, 90 Bergen Street, Suite 7300, Newark, New Jersey 07103
| | - Jonathan Faiwiszewski
- Department of Orthopaedics, University of Medicine and Dentistry of New Jersey—New Jersey Medical School, 90 Bergen Street, Suite 7300, Newark, New Jersey 07103
| | - Siddhant K. Mehta
- Department of Orthopaedics, University of Medicine and Dentistry of New Jersey—New Jersey Medical School, 90 Bergen Street, Suite 7300, Newark, New Jersey 07103
| | - Loay Al-Zube
- Department of Biochemistry and Molecular Biology, University of Medicine and Dentistry of New Jersey—New Jersey Medical School, Newark, New Jersey,Department of Biomedical Engineering, The Hashemite University, Zarqa 13115, Jordan
| | - Swaroopa Vaidya
- Department of Orthopaedics, University of Medicine and Dentistry of New Jersey—New Jersey Medical School, 90 Bergen Street, Suite 7300, Newark, New Jersey 07103,Department of Biochemistry and Molecular Biology, University of Medicine and Dentistry of New Jersey—New Jersey Medical School, Newark, New Jersey
| | - Jessica A. Cottrell
- Department of Biochemistry and Molecular Biology, University of Medicine and Dentistry of New Jersey—New Jersey Medical School, Newark, New Jersey
| | - Dana Graves
- Department of Periodontics, University of Pennsylvania, 240 South 40 Street, Philadelphia, PA, 19104
| | - Joseph Benevenia
- Department of Orthopaedics, University of Medicine and Dentistry of New Jersey—New Jersey Medical School, 90 Bergen Street, Suite 7300, Newark, New Jersey 07103
| | - J. Patrick O’Connor
- Department of Biochemistry and Molecular Biology, University of Medicine and Dentistry of New Jersey—New Jersey Medical School, Newark, New Jersey
| | - Sheldon S. Lin
- Department of Orthopaedics, University of Medicine and Dentistry of New Jersey—New Jersey Medical School, 90 Bergen Street, Suite 7300, Newark, New Jersey 07103
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Prisby RD, Dominguez JM, Muller-Delp J, Allen MR, Delp MD. Aging and estrogen status: a possible endothelium-dependent vascular coupling mechanism in bone remodeling. PLoS One 2012. [PMID: 23185266 PMCID: PMC3502426 DOI: 10.1371/journal.pone.0048564] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/14/2023] Open
Abstract
Bone loss with aging and menopause may be linked to vascular endothelial dysfunction. The purpose of the study was to determine whether putative modifications in endothelium-dependent vasodilation of the principal nutrient artery (PNA) of the femur are associated with changes in trabecular bone volume (BV/TV) with altered estrogen status in young (6 mon) and old (24 mon) female Fischer-344 rats. Animals were divided into 6 groups: 1) young intact, 2) old intact, 3) young ovariectomized (OVX), 4) old OVX, 5) young OVX plus estrogen replacement (OVX+E2), and 6) old OVX+E2. PNA endothelium-dependent vasodilation was assessed in vitro using acetylcholine. Trabecular bone volume of the distal femoral metaphysis was determined by microCT. In young rats, vasodilation was diminished by OVX and restored with estrogen replacement (intact, 82±7; OVX, 61±9; OVX+E2, 90±4%), which corresponded with similar modifications in BV/TV (intact, 28.7±1.6; OVX, 16.3±0.9; OVX+E2, 25.7±1.4%). In old animals, vasodilation was unaffected by OVX but enhanced with estrogen replacement (intact, 55±8; OVX, 59±7; OVX+E2, 92±4%). Likewise, modifications in BV/TV followed the same pattern (intact, 33.1±1.6; OVX, 34.4±3.7; OVX+E2, 42.4±2.1%). Furthermore, in old animals with low endogenous estrogen (i.e., intact and old OVX), vasodilation was correlated with BV/TV (R2 = 0.630; P<0.001). These data demonstrate parallel effects of estrogen on vascular endothelial function and BV/TV, and provide for a possible coupling mechanism linking endothelium-dependent vasodilation to bone remodeling.
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Affiliation(s)
- Rhonda D. Prisby
- Department of Kinesiology and Applied Physiology, University of Delaware, Newark, Delaware, United States of America
| | - James M. Dominguez
- Department of Applied Physiology and Kinesiology and the Center for Exercise Science, University of Florida, Gainesville, Florida, United States of America
| | - Judy Muller-Delp
- Department of Physiology and Functional Genomics, University of Florida, Gainesville, Florida, United States of America
| | - Matthew R. Allen
- Department of Anatomy and Cell Biology, Indiana University School of Medicine, Indianapolis, Indiana, United States of America
| | - Michael D. Delp
- Department of Applied Physiology and Kinesiology and the Center for Exercise Science, University of Florida, Gainesville, Florida, United States of America
- * E-mail:
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Nakajima KI, Kanno Y, Nakamura M, Gao XD, Kawamura A, Itoh F, Ishisaki A. Bovine milk lactoferrin induces synthesis of the angiogenic factors VEGF and FGF2 in osteoblasts via the p44/p42 MAP kinase pathway. Biometals 2011; 24:847-56. [DOI: 10.1007/s10534-011-9439-0] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2010] [Accepted: 03/04/2011] [Indexed: 11/29/2022]
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Abstract
Blood vessels have a fundamental role both in skeletal homeostasis and in bone repair. Angiogenesis is also important for a successful bone engineering. Therefore, scaffolds should be tested for their ability to favour endothelial cell adhesion, proliferation and functions. The type of endothelial cell to use for in vitro assays should be carefully considered, because the properties of these cells may depend on their source. Morphological and functional relationships between endothelial cells and osteoblasts are evaluated with co-cultures, but this model should still be standardized, particularly for distinguishing the two cell types. Platelet-rich plasma and recombinant growth factors may be useful for stimulating angiogenesis.
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13
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Abstract
Because the microenvironment that supports hematopoietic stem cell (HSC) proliferation and differentiation is not fully understood, we adapted a heterotopic bone formation model as a new approach for studying the HSC microenvironment in vivo. Endogenous HSCs homed to tissue-engineered ossicles and individually sorted HSCs from ossicles were able to reconstitute lethally irradiated mice. To further explore this model as a system to study the stem cell niche, ossicles were established with or without anabolic parathyroid hormone (PTH) treatment during the 4-week course of bone development. Histology and micro-computed tomography showed higher bone area-to-total area ratios, thicker cortical bone and trabecular bone, significantly higher bone mineral density and bone volume fraction in PTH-treated groups than in controls. By an in vivo competitive long-term reconstitution assay, HSC frequency in the ossicle marrow was 3 times greater in PTH groups than in controls. When whole bone marrow cells were directly injected into the ossicles after lethal irradiation, the PTH-treated groups showed an enhanced reconstitution rate compared with controls. These findings suggest the residence of HSCs in heterotopic bone marrow and support the future use of this ossicle model in elucidating the composition and regulation of the HSC niche.
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Faure C, Linossier MT, Malaval L, Lafage-Proust MH, Peyroche S, Vico L, Guignandon A. Mechanical signals modulated vascular endothelial growth factor-A (VEGF-A) alternative splicing in osteoblastic cells through actin polymerisation. Bone 2008; 42:1092-101. [PMID: 18374641 DOI: 10.1016/j.bone.2008.02.011] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/13/2007] [Revised: 02/05/2008] [Accepted: 02/09/2008] [Indexed: 01/10/2023]
Abstract
Since VEGF-A is involved in mechanically induced bone gain and because vegf exists under 6 isoforms exerting various biological effects, we studied vegf isoform expression and VEGF protein production in osteoblastic cells (rat Ros17/2.8 and human osteoblasts) submitted to 4 mechanical regimens. Mechanical regimens (1% stretch deformation) were designed with a fixed number of cycles (450) delivered at various frequencies (0.05 to 5 Hz). We found a negative correlation (R(2)=0.76, p<0.0001) between production of soluble VEGF and mechanical stretch frequency and a positive correlation (R(2)=0.99, p<0.0001) between production of matrix-bound VEGF and mechanical stretch frequency. mRNA expressions of soluble VEGF isoforms (121, 165) were specifically expressed under low frequency while matrix-bound VEGF isoforms (206, 189, 165, 145) were specifically expressed under high frequency in human osteoblasts. As f-actin stress fiber formation was significantly increased selectively in high frequency conditions, we disrupted actin fibers in Ros17/2.8 and found that immobilisation of VEGF was abolished. Conversely, Jasplakinolide treatment which increases stress fiber formation was able to mimic high frequency stretch-induced immobilisation of VEGF. Thus, we speculate that the stretch-induced increase in cell tension is responsible for matrix-bound vegf isoform production. Mechanically induced selection of soluble or matrix-bound VEGF production may modify osteoblast and endothelial cell crosstalk crucial during osteogenesis and fracture healing.
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15
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Ma HZ, Zeng BF, Li XL. Upregulation of VEGF in subchondral bone of necrotic femoral heads in rabbits with use of extracorporeal shock waves. Calcif Tissue Int 2007; 81:124-31. [PMID: 17629736 DOI: 10.1007/s00223-007-9046-9] [Citation(s) in RCA: 73] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/20/2007] [Accepted: 05/20/2007] [Indexed: 01/05/2023]
Abstract
Extracorporeal shock wave treatment appears to be effective in patients with avascular necrosis of the femoral head. However, the pathway of biological events whereby this is accomplished has not been fully elucidated. The purpose of this study was to investigate the effect of extracorporeal shock waves on vascular endothelial growth factor (VEGF) expression in necrotic femoral heads of rabbits. VEGF expression was assessed by immunohistochemistry, quantitative real-time PCR, and Western blot analysis. The degree of angiogenesis was also assessed, as determined by the microvessel density (MVD), the assessment of which was based on CD31-expressing vessels. Bilateral avascular necrosis of femoral heads was induced with methylprednisolone and lipopolysaccharide in 30 New Zealand rabbits. The left limb (the study side) received shock wave therapy to the femoral head. The right limb (the control side) received no shock wave therapy. Biopsies of the femoral heads were performed at 1, 2, 4, 8, and 12 weeks. Western blot analysis and real-time PCR showed that shock wave therapy significantly increased VEGF protein and mRNA expression, respectively, in the subchondral bone of the treated necrotic femoral heads. Compared with the contralateral control without shock wave treatment, the VEGF mRNA expression levels increased to a peak at 2 weeks after the shock wave treatment and remained high for 8 weeks, then declined at 12 weeks, whereas the VEGF protein expression levels increased to a peak at 4 weeks after the shock wave treatment and remained high for 12 weeks. The immunostaining of VEGF was weak in the control group, and the immunoreactivity level in the shock-wave-treated group increased at 4 weeks and persisted for 12 weeks. The most intensive VEGF immunoreactivity was observed in the proliferative zone above the necrotic zone. At 4, 8, and 12 weeks after the shock wave treatment, MVD in subchondral bone from treated femoral heads was significantly higher than that in subchondral bone from untreated femoral heads. These data clearly show that extracorporeal shock waves can significantly upregulate the expression of VEGF. The upregulation of VEGF may play a role in inducing the ingrowth of neovascularization and in improving the blood supply to the femoral head.
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Affiliation(s)
- Huan-Zhi Ma
- Department of Orthopedic Surgery, Shanghai Sixth People's Hospital, Shanghai Jiaotong University, Shanghai, 200233, China.
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Samani AA, Yakar S, LeRoith D, Brodt P. The role of the IGF system in cancer growth and metastasis: overview and recent insights. Endocr Rev 2007; 28:20-47. [PMID: 16931767 DOI: 10.1210/er.2006-0001] [Citation(s) in RCA: 730] [Impact Index Per Article: 40.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
IGF-I receptor (IGF-IR) signaling and functions are mediated through the activities of a complex molecular network of positive (e.g., type I IGF) and negative (e.g., the type II IGF receptor, IGF-IIR) effectors. Under normal physiological conditions, the balance between the expression and activities of these molecules is tightly controlled. Changes in this delicate balance (e.g., overexpression of one effector) may trigger a cascade of molecular events that can ultimately lead to malignancy. In recent years, evidence has been mounting that the IGF axis may be involved in human cancer progression and can be targeted for therapeutic intervention. Here we review old and more recent evidence on the role the IGF system in malignancy and highlight experimental and clinical studies that provide novel insights into the complex mechanisms that contribute to its oncogenic potential. Controversies arising from conflicting evidence on the relevance of IGF-IR and its ligands to human cancer are discussed. Our review highlights the importance of viewing the IGF axis as a complex multifactorial system and shows that changes in the expression levels of any one component of the axis, in a given malignancy, should be interpreted with caution and viewed in a wider context that takes into account the expression levels, state of activation, accessibility, and functionality of other interacting components. Because IGF targeting for anticancer therapy is rapidly becoming a clinical reality, an understanding of this complexity is timely because it is likely to have an impact on the design, mode of action, and clinical outcomes of newly developed drugs.
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Affiliation(s)
- Amir Abbas Samani
- Department of Medicine, McGill University Health Center, Royal Victoria Hospital, Room H6.25687, Pine Avenue West, Montreal, Québec, Canada H3A 1A1
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Guvakova MA. Insulin-like growth factors control cell migration in health and disease. Int J Biochem Cell Biol 2007; 39:890-909. [PMID: 17113337 DOI: 10.1016/j.biocel.2006.10.013] [Citation(s) in RCA: 54] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2006] [Revised: 10/13/2006] [Accepted: 10/19/2006] [Indexed: 12/30/2022]
Abstract
Insulin-like growth factors I and II (IGF-I and IGF-II) have an ancient origin and play essential roles in fundamental biological processes. Although IGFs are principally known for their roles in regulating cell growth and survival, their ability to influence cell motility is just as significant. In the past 20 years, research has provided indisputable evidence for the regulatory role of IGFs in the migration of various cell types. Cell migration is crucial for reproduction, development, and tissue regeneration; IGFs play an important role in coordinating these processes. Moreover, studies continue to uncover the IGFs' role in stimulating cancer cell migration, invasion and metastasis. This review surveys current knowledge on the cell migration-modulating properties of IGFs and the biochemical pathways by which these peptides regulate cell movement in both physiological and pathological conditions.
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Affiliation(s)
- Marina A Guvakova
- Division of Endocrine and Oncologic Surgery, Department of Surgery, School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
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18
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Kim IS, Song JK, Zhang YL, Lee TH, Cho TH, Song YM, Kim DK, Kim SJ, Hwang SJ. Biphasic electric current stimulates proliferation and induces VEGF production in osteoblasts. BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH 2006; 1763:907-16. [PMID: 16930744 DOI: 10.1016/j.bbamcr.2006.06.007] [Citation(s) in RCA: 73] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/28/2005] [Revised: 06/07/2006] [Accepted: 06/07/2006] [Indexed: 10/24/2022]
Abstract
This study investigated biphasic electric current (BEC) functions as a new type of electrical stimulation to induce rat calvarial osteoblasts to proliferate, differentiate and synthesize cytokines. The culture system was designed so that biphasic current flowed between upper and lower gold plates. BEC helps to minimize the net charge accumulation during cell exposure to the electrical stimulation. Osteoblasts were exposed to electrical stimulation of 1.5 microA/cm2 at 3000 Hz, and the effect of BEC was assessed in the interrupted mode (6 h daily) and in the continuous mode (24 h daily), depending on the interval of stimulation. Whereas proliferation increased by 31% after stimulation in the continuous mode for 2 days, it was unaffected in the interrupted mode. The transcriptional expression of osteogenesis-related genes such as alkaline phosphatase (ALP), osteopontin, and type I collagen was unchanged 4 days after stimulation in both modes, while cbfa1 was decreased under the same conditions. There was no detectable change in mRNA expression of growth factors (BMP-2, -4, IGF-2 and TGF-beta1) that promote osteoblast differentiation. However, real-time RT-PCR and ELISA demonstrated that vascular endothelial growth factor (VEGF) was markedly up-regulated by BEC. Induction of VEGF by BEC was not hypoxia driven. In conclusion, the present in vitro study demonstrates that BEC increases cell proliferation and induces the production of VEGF. The BEC was more effective with continuous stimulation than with interrupted stimulation. To confirm whether BEC can enhance osteogenesis, further in vivo studies are needed.
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Affiliation(s)
- In Sook Kim
- Department of Oral & Maxillofacial Surgery, College of Dentistry, Seoul National University, Brain Korea 21 2nd Program, Korea
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Fiedler J, Brill C, Blum WF, Brenner RE. IGF-I and IGF-II stimulate directed cell migration of bone-marrow-derived human mesenchymal progenitor cells. Biochem Biophys Res Commun 2006; 345:1177-83. [PMID: 16716263 DOI: 10.1016/j.bbrc.2006.05.034] [Citation(s) in RCA: 95] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2006] [Accepted: 05/07/2006] [Indexed: 01/14/2023]
Abstract
Insulin-like growth factors (IGFs) are known to be key regulators of bone growth, remodeling, and repair. Since all these processes depend on the recruitment of cells with the potential to be committed to the osteoblastic lineage, we studied possible effects of IGF-I and -II on migration of human mesenchymal progenitor cells (MPC) using a modified Boyden chamber assay. The results were compared to those of primary osteoblasts and in vitro-osteogenic-differentiated MPC. IGF-I and -II stimulated cell migration of all these cell populations in a dose-dependent manner from 1 to 100ng/mL. The maximal chemotactic index (CI) was 4-5 for MPC and primary osteoblasts and about 3 for in vitro-differentiated MPC. Checkerboard analysis revealed that IGFs stimulated true directed cell migration (chemotaxis) and not simply chemokinesis. Addition of an antibody against the type I IGF receptor (alphaIR3) completely abolished (MPC) or markedly reduced (primary osteoblasts) the chemotactic effects of each of the IGFs. IGFBP-3 itself had no direct effect, while IGFBP-5 stimulated MPC migration at concentrations of 80 and 160ng/mL. Parallel application of IGFBP-3 had borderline inhibitory effects while the addition of 40ng/mL of IGFBP-5 enhanced the chemotactic effect of IGF-I on MPC. In conclusion, our results show that IGF-I and -II are chemotactic factors for MPC and indicate that IGFBP-5 both modulates the IGF-I effect and directly stimulates migration of human mesenchymal progenitor cells.
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Affiliation(s)
- Jörg Fiedler
- Orthopaedic Department, Division for Biochemistry of Joint and Connective Tissue Diseases, University of Ulm, Ulm, Germany
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20
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Brandi ML, Collin-Osdoby P. Vascular biology and the skeleton. J Bone Miner Res 2006; 21:183-92. [PMID: 16418774 DOI: 10.1359/jbmr.050917] [Citation(s) in RCA: 229] [Impact Index Per Article: 12.1] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/07/2004] [Revised: 06/08/2005] [Accepted: 10/03/2005] [Indexed: 12/20/2022]
Affiliation(s)
- Maria Luisa Brandi
- Department of Internal Medicine, University of Florence, Florence, Italy
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21
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Yao Z, Lafage-Proust MH, Plouët J, Bloomfield S, Alexandre C, Vico L. Increase of both angiogenesis and bone mass in response to exercise depends on VEGF. J Bone Miner Res 2004; 19:1471-80. [PMID: 15312247 DOI: 10.1359/jbmr.040517] [Citation(s) in RCA: 84] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/17/2004] [Revised: 03/25/2004] [Accepted: 05/05/2004] [Indexed: 01/28/2023]
Abstract
UNLABELLED Physiological angiogenesis during bone remodeling is undefined. Treadmill-running rats displayed bone marrow angiogenesis concomitant with bone formation increase and resorption decrease and upregulation of VEGF and its R1 receptor mRNA in proximal tibia. VEGF blockade over 5 weeks of training fully prevented the exercise-induced bone mass gain. INTRODUCTION We investigated the role of vascular endothelial growth factor (VEGF) and angiogenesis in the osteogenic response to exercise. MATERIALS AND METHODS Nine-week-old male Wistar rats were treadmill-trained at 60% Vo(2max) for various periods. Bone and vascular histomorphometry was performed after 2- and 5-week experiments. On-line RT PCR for VEGF and its receptors R1 and R2 was done after a 10-day experiment. In the 5-week experiment, running rats received either a VEGF inhibitory antibody or a placebo. RESULTS After 2 weeks, tibial BMD did not change; however, vessel number in the proximal metaphysis increased by 20% in running versus sedentary rats. In running rats, vessel number correlated positively (r = 0.88) with bone formation rate and negatively (r = -0.85) with active resorption surfaces. After 10 days of training, upregulation of VEGF and VEGF receptor R1 mRNA was detected in periosteum and metaphyseal bone. VEGF blockade in 5-week trained rats fully prevented the exercise-induced increase in metaphyseal BMD (9%) and cancellous bone volume (BV/TV; 25%), as well as the increased vessel number (25%). In 5-week placebo-treated running rats, bone formation rate returned to initial values, whereas osteoclastic surfaces continued to decline compared with both sedentary and anti-VEGF-treated running rats. CONCLUSION VEGF signaling-mediated bone angiogenesis is tightly related to exercise-induced bone cellular uncoupling and is indispensable for bone gain induced by exercise.
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Affiliation(s)
- Zhenqiang Yao
- Faculté de Médecine, Laboratoire de Biologie du Tissu Osseux, Saint-Etienne Cedex 02 42023, France
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22
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Tokuda H, Hatakeyama D, Akamatsu S, Tanabe K, Yoshida M, Shibata T, Kozawa O. Involvement of MAP kinases in TGF-beta-stimulated vascular endothelial growth factor synthesis in osteoblasts. Arch Biochem Biophys 2003; 415:117-25. [PMID: 12801520 DOI: 10.1016/s0003-9861(03)00225-x] [Citation(s) in RCA: 35] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
Transforming growth factor-beta (TGF-beta) reportedly induces vascular endothelial growth factor (VEGF) synthesis in osteoblast-like MC3T3-E1 cells. We have recently shown that TGF-beta activates p44/p42 mitogen-activated protein (MAP) kinase and p38 MAP kinase in these cells. In the present study, we investigated the exact mechanism of TGF-beta behind the synthesis of VEGF in MC3T3-E1 cells. PD98059 and U-0126, specific inhibitors of MEK, suppressed the VEGF synthesis induced by TGF-beta. U-0126 inhibited the TGF-beta-induced p44/p42 MAP kinase phosphorylation. SB203580 and PD169316, inhibitors of p38 MAP kinase, reduced the TGF-beta-stimulated VEGF synthesis. SB202474, a negative control for p38 MAP kinase inhibitor, did not affect the VEGF synthesis. A combination with PD98059 and SB203580 almost completely suppressed the TGF-beta-induced VEGF synthesis. Retinoic acid, which alone failed to affect VEGF synthesis, markedly enhanced the VEGF synthesis stimulated by TGF-beta. Retinoic acid enhanced the TGF-beta-increased levels of VEGF mRNA. The amplifications by retinoic acid of TGF-beta-increased VEGF synthesis and levels of VEGF mRNA were reduced by PD98059 or SB203580. The combination of PD98059 and SB203580 almost completely suppressed the enhancement by retinoic acid of VEGF synthesis induced by TGF-beta. Taken together, our results strongly suggest that both p44/p42 MAP kinase and p38 MAP kinase take part in TGF-beta-stimulated VEGF synthesis in osteoblasts, and that retinoic acid upregulates the VEGF synthesis.
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Affiliation(s)
- Haruhiko Tokuda
- Department of Internal Medicine, Chubu National Hospital, National Institute for Longevity Sciences, Obu, Aichi 474-8511, Japan
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Tokimasa C, Kawata T, Fujita T, Kaku M, Kohno S, Tsutsui K, Tenjou K, Ohtani J, Motokawa M, Tanne K. Effects of insulin-like growth factor-I on the expression of osteoclasts and osteoblasts in the nasopremaxillary suture under different masticatory loading conditions in growing mice. Arch Oral Biol 2003; 48:31-8. [PMID: 12615139 DOI: 10.1016/s0003-9969(02)00161-9] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/27/2022]
Abstract
It is well accepted that mechanical loading inhibits bone resorption and increases in vivo bone formation. It is also known that cyclic mechanical loading, in particular, can enhance bone formation significantly. These findings suggest a significant role for mechanical stimuli in bone remodelling mediated by various local growth factors including insulin-like growth factor-I (IGF-I). Earlier studies showed that the nasal bone length and premaxillary bone width were significantly greater in mice fed a solid diet rather than a granulated diet, and that these dimensions increased significantly in a solid-diet group treated with IGF-I. The present study sought to examine the effect of IGF-I on the expression of osteoclasts and osteoblasts in the nasopremaxillary suture subjected to different masticatory loadings. For the solid-diet groups, the numbers of tartrate-resistant acid phosphatase (TRAP)-positive osteoclastic cells and osteoblasts were significantly greater in the group injected with IGF-I than in the animals injected with physiological saline. In the groups fed a granulated diet, no significant differences in the numbers of TRAP-positive osteoclastic cells and osteoblasts were found over the entire experimental period between mice injected with either IGF-I or physiological saline. It is shown that IGF-I significantly induces the expression of osteoclasts and osteoblasts and the subsequent bone remodelling, and that the effect may be additive as compared to that of mechanical masticatory loading, which seems to be more important in bone remodelling in terms of the numbers of osteoclasts and osteoblasts.
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Affiliation(s)
- C Tokimasa
- Department of Orthodontics and Craniofacial Developmental Biology, Graduate School of Biomedical Sciences, Faculty of Dentistry, Hiroshima University, 1-2-3 Kasumi, Minamiku, 734-8553, Hiroshima, Japan.
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Beam HA, Parsons JR, Lin SS. The effects of blood glucose control upon fracture healing in the BB Wistar rat with diabetes mellitus. J Orthop Res 2002; 20:1210-6. [PMID: 12472231 DOI: 10.1016/s0736-0266(02)00066-9] [Citation(s) in RCA: 146] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
Several clinical series, analyzing fracture healing in patients with diabetes mellitus (DM). demonstrated significant incidence of delayed union, non-union, and pseudarthrosis. In this study, analysis was performed to evaluate the effects of blood glucose (BG) control on fracture healing in the DM BB Wistar rat, a rat strain that represents a close homology to Type I DM in man. Our study showed decreased cell proliferation at the fracture site as well as decreased mechanical stiffness and bony content in the poorly controlled DM rats. To determine the effect of BG control, DM rats were treated with insulin sufficient to maintain physiologic BG levels throughout the course of the study. Values of cellular proliferation, biomechanical properties and callus bone content in tightly controlled DM animals were not significantly different from values of non-DM control values. This study suggests that insulin treatment with resultant improved BG control will ameliorate the impaired early and late parameters of DM fracture healing.
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Affiliation(s)
- Heather A Beam
- Department of Orthopaedics, University of Medicine and Dentistry of New Jersey, New, Jersey Medical School, MSB G-574, 185 South Orange Avenue, Newark, NJ 07103, USA
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Kawata T, Tokimasa C, Fujita T, Kaku M, Tsutsui K, Kohno S, Matsuki A, Tenjo K, Ohtani J, Motokawa M, Kobayakawa T, Shigekawa M, Tanne K. Effect of insulin-like growth factor-I (IGF-I) on femoral bone modeling in growing mice. Exp Anim 2002; 51:521-4. [PMID: 12451716 DOI: 10.1538/expanim.51.521] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/31/2022] Open
Abstract
The time-dependent effects of daily dosing of IGF-I (1.21 mg/g) on the linear growth of the femur were investigated in mice. The femoral length and volume and the number of osteoclasts were significantly greater after IGF-I injection as compared to the non-injected control, suggesting that the IGF-I imbalance might cause a quick turnover cycle of the bone resulting in the altered femoral modeling.
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Affiliation(s)
- Toshitsugu Kawata
- Department of Orthodontics and Craniofacial Developmental Biology, Graduate School of Biomedical Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8553, Japan
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26
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Samani AA, Fallavollita L, Jaalouk DE, Galipeau J, Brodt P. Inhibition of carcinoma cell growth and metastasis by a vesicular stomatitis virus G-pseudotyped retrovector expressing type I insulin-like growth factor receptor antisense. Hum Gene Ther 2001; 12:1969-77. [PMID: 11686938 DOI: 10.1089/104303401753204544] [Citation(s) in RCA: 20] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Abstract
A replication-defective, vesicular stomatitis virus G-pseudotyped, Moloney murine leukemia virus retroviral vector (vLTR-IGF-IR(AS)) was generated in which a type I insulin-like growth factor receptor (IGF-IR) antisense fragment is expressed in a bicistronic mRNA with an enhanced green fluorescent protein (EGFP) reporter under the control of a potent long terminal repeat (LTR). The suitability of these retroparticles for gene therapy was tested with highly metastatic, carcinoma H-59 cells, which depend on IGF-IR expression for tumorigenicity and metastasis. Transduction with these, but not with control retroviral particles expressing EGFP only, resulted in a 70% reduction in IGF-IR levels and the loss of IGF-IR-regulated functions. Moreover, the ability of vLTR-IGF-IR(AS) retroparticle-transduced tumor cells to form experimental hepatic metastases was significantly reduced relative to controls. The results identify retrovector-mediated delivery of IGF-IR antisense as a potential strategy for cancer gene therapy.
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Affiliation(s)
- A A Samani
- Department of Medicine, McGill University Health Center-Royal Victoria Hospital, Montreal, Quebec, Canada
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Ikeo S, Yamauchi K, Shigematsu S, Nakajima K, Aizawa T, Hashizume K. Differential effects of growth hormone and insulin-like growth factor I on human endothelial cell migration. Am J Physiol Cell Physiol 2001; 280:C1255-61. [PMID: 11287339 DOI: 10.1152/ajpcell.2001.280.5.c1255] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Effects of growth hormone (GH), insulin-like growth factor I (IGF-I), and endothelin-1 (ET-1) on endothelial cell migration and the underlying molecular mechanisms were explored using a human umbilical cord endothelial cell line, ECV304 cells, in vitro. Treatment of the cells with IGF-I or ET-1, but not GH, stimulated the cell migration. Interestingly, however, ET-1-induced, but not IGF-I-induced, migration of the cells was inhibited by GH. Both ET-1 and IGF-I caused activation of mitogen-activated protein kinase (MAPK) in the cells, and GH eliminated the MAPK activation produced by ET-1 but not that produced by IGF-I. On the other hand, migration of the cells was stimulated by protein kinase C (PKC) agonist, phorbol 12-myristate 13-acetate. ET-1 promoted PKC activity, and a PKC inhibitor, GF-109203X, blocked ET-1-induced cell migration. Although GH inhibited ET-1-induced cell migration and MAPK activity, it did not block ET-1-induced PKC activation. Thus ET-1 stimulation of endothelial cell migration appears to be mediated by PKC/MAPK pathway, and GH may inhibit the MAPK activation by ET-1 at the downstream of PKC.
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Affiliation(s)
- S Ikeo
- Department of Aging Medicine and Geriatrics, Shinshu University School of Medicine, Matsumoto, 390-8621 Japan
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28
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Samani AA, Brodt P. The Receptor for the Type I Insulin-like Growth Factor and its Ligands Regulate Multiple Cellular Functions That Impact on Metastasis. Surg Oncol Clin N Am 2001. [DOI: 10.1016/s1055-3207(18)30066-8] [Citation(s) in RCA: 43] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
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Shymkiw RC, Bray RC, Boyd SK, Kantzas A, Zernicke RF. Physiological and mechanical adaptation of periarticular cancellous bone after joint ligament injury. J Appl Physiol (1985) 2001; 90:1083-7. [PMID: 11181623 DOI: 10.1152/jappl.2001.90.3.1083] [Citation(s) in RCA: 19] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
The relation between blood flow and bone mineral density (BMD) of periarticular bone was examined in an in vivo model of joint instability. Eighty mature New Zealand White rabbits were randomly assigned to experimental [anterior cruciate ligament transection (ACLX)], sham-operated control, or age-matched normal control groups. Experimental rabbits underwent unilateral transection of the right anterior cruciate ligament, and the nonoperated left [contralateral (Cntra)] limb was a within-animal control. BMD and blood flow to the periarticular bone in the femoral condyles were assessed in each group at 2, 4, 6, 14, and 48 wk postsurgery, using quantitative computed tomography scanning and entrapment of colored microspheres. BMD was significantly lower (5%) in the ACLX compared with Cntra limbs. Periarticular bone blood flow in the ACLX limbs was significantly greater than in the Cntra limb (29%) in the early stages (6 wk) after injury. Up to 48 wk post-ACLX, a significant correlation was found between increased blood flow and decreased BMD in the periarticular bone of the femoral condyles in the ACLX limbs. This correlation suggested that heightened blood flow may be linked to mechanisms of bone adaptation in joints after ligament injury.
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Affiliation(s)
- R C Shymkiw
- McCaig Centre for Joint Injury and Arthritis Research, Department of Mechanical Engineering, University of Calgary, Alberta, Canada
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30
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Tokimasa C, Kawata T, Fujita T, Kaku M, Kawasoko S, Kohno S, Tanne K. Effects of insulin-like growth factor-I on nasopremaxillary growth under different masticatory loadings in growing mice. Arch Oral Biol 2000; 45:871-8. [PMID: 10973560 DOI: 10.1016/s0003-9969(00)00057-1] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/18/2022]
Abstract
It is well accepted that reduced masticatory function induced by a diet with soft physical consistency causes alterations in the craniofacial morphology in growing animals. It is assumed that these alterations are associated with reduced proliferative activity of osteoblasts on the bone surface, indicating a significant role for mechanical stimuli mediated by various local growth factors including insulin-like growth factor-I (IGF-I). Here, the effects of IGF-I on the linear growth of nasal and premaxillary bones subjected to different masticatory loadings were examined. The length of the nasal bone and the width of the premaxilla were measured. These dimensions were significantly greater in mice fed a solid diet than in mice fed a granulated diet. In animals treated with IGF-I, the nasal bone length and premaxillary width increased significantly in a subgroup receiving a solid diet, but these changes were not found in a similar group fed a granulated diet. No statistically significant differences in these dimensions were found between solid-diet mice injected with saline and granulated-diet group injected with IGF-I. It is concluded that IGF-I induces nasal and premaxillary growth, and that its effect is enhanced or accelerated by increased mechanical masticatory loading.
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Affiliation(s)
- C Tokimasa
- Department of Orthodontics, Hiroshima University Faculty of Dentistry, Minamiku, Hiroshima 734-8553, Japan.
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31
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Colleran PN, Wilkerson MK, Bloomfield SA, Suva LJ, Turner RT, Delp MD. Alterations in skeletal perfusion with simulated microgravity: a possible mechanism for bone remodeling. J Appl Physiol (1985) 2000; 89:1046-54. [PMID: 10956349 DOI: 10.1152/jappl.2000.89.3.1046] [Citation(s) in RCA: 142] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
Bone loss occurs as a consequence of exposure to microgravity. Using the hindlimb-unloaded rat to model spaceflight, this study had as its purpose to determine whether skeletal unloading and cephalic fluid shifts alter bone blood flow. We hypothesized that perfusion would be diminished in the hindlimb bones and increased in skeletal structures of the forelimbs and head. Using radiolabeled microspheres, we measured skeletal perfusion during control standing and after 10 min, 7 days, and 28 days of hindlimb unloading (HU). Femoral and tibial perfusion were reduced with 10 min of HU, and blood flow to the femoral shaft and marrow were further diminished with 28 days of HU. Correspondingly, the mass of femora (-11%, P < 0. 05) and tibiae (-6%, P < 0.1) was lowered with 28 days of HU. In contrast, blood flow to the skull, mandible, clavicle, and humerus was increased with 10 min HU but returned to control levels with 7 days HU. Mandibular (+10%, P < 0.05), clavicular (+18%, P < 0.05), and humeral (+8%, P < 0.1) mass was increased with chronic HU. The data demonstrate that simulated microgravity alters bone perfusion and that such alterations correspond to unloading-induced changes in bone mass. These results support the hypothesis that alterations in bone blood flow provide a stimulus for bone remodeling during periods of microgravity.
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Affiliation(s)
- P N Colleran
- Department of Health and Kinesiology, and Cardiovascular Research Institute, Texas A&M University, College Station, Texas 77843, USA
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Cemborain A, Castilla-Cortázar I, García M, Muguerza B, Delgado G, Díaz-Sánchez M, Picardi A. Effects of IGF-I treatment on osteopenia in rats with advanced liver cirrhosis. J Physiol Biochem 2000; 56:91-99. [PMID: 11014614 DOI: 10.1007/bf03179904] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
IGF-I is an anabolic hormone which has been reported to increase bone formation in several conditions of undernutrition. Advanced liver cirrhosis is associated with osteopenia and also with low serum levels of IGF-I. Previous results showed that low doses of IGF-I increase osteoblastic activity and decrease bone reabsorption in early liver cirrhosis. The aim of this study was to evaluate whether IGF-I-treatment also induces beneficial effect on osteopenia associated with advanced cirrhosis. Rats with ascitic cirrhosis were divided into two groups: group CI (n=10) which received saline and group CI+IGF (n=10) which were treated with IGF-I (2 microg/100 g bw x day, sc, during 21 days). Healthy controls which received saline were studied in parallel (CO n=10). On the 22nd day, the animals were sacrificed, and bone parameters were analyzed in femur. Posterior-anterior diameter was similar in all groups. No significant differences were observed in bone content of calcium, total proteins, collagen and hydroxyapatite in cirrhotic rats as compared with controls. However, CI rats showed significant reductions in total bone density (-13.5%, p<0.001) assessed by densitometry and radiological study. In CI+IGF rat bone density (assessed by densitometry) improved significantly as compared with CI animals. In summary, osteopenia characterized by loss of bone mass and preserved bone composition was found in rats with advanced cirrhosis induced by CCl4 and phenobarbital in drinking water. This bone disorder is partially restored by treatment with low doses of IGF-I during only three weeks. Thus, IGF-I could be considered as a possible therapy for osteopenia associated with advanced liver cirrhosis.
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Affiliation(s)
- A Cemborain
- Department of Physiology, School of Medicine, University of Navarra, Pamplona, Spain
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Deckers MM, Karperien M, van der Bent C, Yamashita T, Papapoulos SE, Löwik CW. Expression of vascular endothelial growth factors and their receptors during osteoblast differentiation. Endocrinology 2000; 141:1667-74. [PMID: 10803575 DOI: 10.1210/endo.141.5.7458] [Citation(s) in RCA: 345] [Impact Index Per Article: 13.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
Endochondral bone formation is regulated by systemically and locally acting growth factors. A role for vascular endothelial growth factor (VEGF) in this process has recently been proposed, because inactivation of VEGF inhibits endochondral bone formation via inhibition of angiogenesis. Despite the known effect of VEGF as specific endothelial growth factor, its effects on osteoblast differentiation have not been studied. We, therefore, examined the expression of VEGF-A, -B, -C, and -D and their receptors in a model of osteoblast differentiation using the mouse preosteoblast-like cell line KS483. Early in differentiation, KS483 cells express low levels VEGF-A, -B, and -D messenger RNA, whereas during mineralization, KS483 cells express high levels. In addition, expression of the VEGF receptors, VEGFR1, VEGFR2, and VEGF165R/neuropilin, coincided with expression of their ligands, being maximally expressed during mineralization. VEGF-A production during osteoblast differentiation was stimulated by insulin-like growth factor I that enhances osteoblast differentiation and was inhibited by PTH-related peptide that inhibits osteoblast differentiation. Furthermore, continuous treatment of KS483 cells with recombinant human VEGF-A stimulated nodule formation. Although treatment of KS483 cells with soluble FLT1, an agent that blocks binding of VEGF-A and -B to VEGFR1, did not inhibit nodule formation, this observation does not exclude involvement of VEGFR2 in the regulation of osteoblast differentiation. As it is known that VEGF-A, -C, and -D can act through activation of VEGFR2, other isoforms might compensate for VEGF-A loss. The expression pattern of VEGFs and their receptors shown here suggests that VEGFs play an important role in the regulation of bone remodeling by attracting endothelial cells and osteoclasts and by stimulating osteoblast differentiation.
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Affiliation(s)
- M M Deckers
- Department of Endocrinology and Metabolic Diseases, Leiden University Medical Center, The Netherlands.
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Abstract
By necessity, this article focuses on only a handful of molecules with demonstrated ability to affect growth of myeloma cells. The heterogeneity in growth-factor responsiveness has made formulation of a uniform hypothesis a daunting challenge. One trait that appears to be consistent among all myeloma patients is the uncoupling of the normally highly integrated relationship between terminal differentiation and loss of growth potential. Thus, the common feature in myeloma may not be the precise cytokines or cell-to-cell interactions that drive tumor-cell growth, but rather the underlying genetic traits that afford the tumor cell the ability to proliferate despite its relatively advanced stage of differentiation. The success of current strategies used to treat myeloma patients has thus far been somewhat limited, and in general, has only modestly prolonged survival. It is clear that successful treatment of this disease will require the development of new therapeutic agents aimed at the biochemical events that sustain the aberrant growth of the tumor cells. The knowledge of cell signaling, gene transcription, and cell growth and differentiation has expanded rapidly, and this information has provided a greater understanding of the cell biology of a variety of malignancies. Application of this information to the study of multiple myeloma, however, has thus far been relatively limited, primarily because the heterogeneity of the disease and the lack of appropriate model systems. Review of the literature, particularly over the last 5 years, reveals a significant number of exciting new findings in this field and the development of new model systems that are certain to yield greater insight into this devastating disease.
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Affiliation(s)
- D F Jelinek
- Department of Immunology, Mayo Clinic, Rochester, Minnesota, USA
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Abstract
Abstract
The chemotactic and growth-stimulatory effect of insulin-like growth factor 1 (IGF-1) was investigated in the experimental mouse 5T2 multiple myeloma (MM) model. Chemotaxis was analyzed by classical checkerboard analysis. Bone marrow fibroblasts–conditioned medium exhibited a chemotactic effect on 5T2 MM cells that could be neutralized by adding a blocking antibody to IGF-1. On the other hand, exogenously added IGF-1 also had a chemotactic effect on the 5T2 MM cells. Moreover, in vitro analysis demonstrated that transmigrated 5T2 MM cells have a higher expression of IGF-1 receptor, both in bone marrow–conditioned medium and in IGF-1–induced chemotaxis, in comparison to cells before migration. When analyzed in vivo, 18 hours after injection of the heterogeneous 5T2 MM population, 5T2 MM cells present in the bone marrow show a higher expression of the IGF-1 receptor than their counterparts before injection. When the proliferative effect of IGF-1 was analyzed, no stimulation was observed, which is in contrast to the influence of bone marrow–conditioned medium and interleukin-6. Our results suggest a causal relationship between the presence of IGF-1 in the bone marrow and the chemotaxis of MM cells to and their subsequent presence in the bone marrow.
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Abstract
The chemotactic and growth-stimulatory effect of insulin-like growth factor 1 (IGF-1) was investigated in the experimental mouse 5T2 multiple myeloma (MM) model. Chemotaxis was analyzed by classical checkerboard analysis. Bone marrow fibroblasts–conditioned medium exhibited a chemotactic effect on 5T2 MM cells that could be neutralized by adding a blocking antibody to IGF-1. On the other hand, exogenously added IGF-1 also had a chemotactic effect on the 5T2 MM cells. Moreover, in vitro analysis demonstrated that transmigrated 5T2 MM cells have a higher expression of IGF-1 receptor, both in bone marrow–conditioned medium and in IGF-1–induced chemotaxis, in comparison to cells before migration. When analyzed in vivo, 18 hours after injection of the heterogeneous 5T2 MM population, 5T2 MM cells present in the bone marrow show a higher expression of the IGF-1 receptor than their counterparts before injection. When the proliferative effect of IGF-1 was analyzed, no stimulation was observed, which is in contrast to the influence of bone marrow–conditioned medium and interleukin-6. Our results suggest a causal relationship between the presence of IGF-1 in the bone marrow and the chemotaxis of MM cells to and their subsequent presence in the bone marrow.
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Cemborain A, Castilla-Cortázar I, García M, Quiroga J, Muguerza B, Picardi A, Santidrián S, Prieto J. Osteopenia in rats with liver cirrhosis: beneficial effects of IGF-I treatment. J Hepatol 1998; 28:122-131. [PMID: 9537849 DOI: 10.1016/s0168-8278(98)80211-0] [Citation(s) in RCA: 71] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
BACKGROUND/AIMS Liver cirrhosis is associated with osteopenia and also with low levels of IGF-I. This hormone has been reported to stimulate bone formation in states of undernutrition and low bone turnover. Our aims were to evaluate whether osteopenia develops in male Wistar rats with CCl4-induced cirrhosis and whether IGF-I is effective in the restoration of bone mass in these animals. METHODS Cirrhotic rats were distributed into two groups: group CI (n = 12) which received placebo and group CI + IGF (n = 12) which was treated with human recombinant IGF-I (2 microg/100 g bw/day, s.c., 21 days). Twelve normal animals which received placebo constituted the control group. On the 22nd day, the animals were sacrificed, and bone parameters were analyzed in femur and/or tibia. RESULTS Posterior-anterior and latero-medial diameters were similar in all groups. Also, no significant differences were observed in bone contents of calcium, total proteins, collagen and hydroxyapatite in CI rats as compared with controls. However, CI rats showed significant reductions in bone weight (-13.5%, p < 0.001), total bone density (-9.28%, p < 0.001), and increased perimedullar bone resorption and urinary levels of deoxypyridinoline (a marker of bone resorption). In CI + IGF rats these parameters improved significantly as compared with CI animals. CONCLUSIONS Osteopenia characterized by loss of bone mass and preserved bone composition is found in rats with CCl4-induced cirrhosis. This bone disorder is partially corrected by treatment with low doses of IGF-I. Since osteoporosis seems to be the predominant form of osteopenia in patients with cirrhosis, IGF-I should be considered as a possible therapy for this disorder.
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Affiliation(s)
- A Cemborain
- Department of Human Physiology, School of Medicine, University of Navarra, Pamplona, Spain
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McCarthy ID, Andhoga M, Batten JJ, Mathie RT. Endothelium-dependent vasodilatation produced by the L-arginine/nitric oxide pathway in normal and ischemic bone. ACTA ORTHOPAEDICA SCANDINAVICA 1997; 68:361-8. [PMID: 9310041 DOI: 10.3109/17453679708996178] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
We used an experimental model of the perfused isolated rabbit tibia to investigate the vasodilatation produced by nitric oxide in the circulation of bone. Tibiae were perfused at a constant flow rate while the perfusion pressure was monitored continuously. Perfusion pressure was raised by the addition of noradrenaline to the perfusate, and dose responses were measured for bolus doses of acetylcholine and sodium nitroprusside. N omega-nitro-L-arginine methyl ester (L-NAME), an inhibitor of nitric oxide synthesis, was then added to the perfusate at a concentration of 10(-4) M, and the dose responses to acetylcholine and sodium nitroprusside were repeated. Measurements were performed on groups of bones after 0, 6, 12, and 24 hours of normothermic ischemia (n 5, 4, 6, and 9, respectively). Both acetylcholine and sodium nitroprusside produced significant vasodilatation after 0 and 6 hours' ischemia, but no significant response was observed after 12 or 24 hours of ischemia. The vasodilatation produced by acetylcholine was significantly attenuated when L-NAME was added to the perfusate, but the vasodilatation produced by sodium nitroprusside remained unchanged. These findings confirm endothelial production of NO by stimulation of muscarinic receptors on the endothelial cells in bone and indicate that vasodilatation via the L-arginine/NO pathway remains viable for 6 hours after normothermic ischemia.
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Affiliation(s)
- I D McCarthy
- Department of Surgery, Royal Postgraduate Medical School, London, UK.
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Abstract
The ability of bone to alter its morphology in response to local physical stimuli is predicated upon the appropriate recruitment of bone cell populations. In turn, the ability to initiate cellular recruitment is influenced by numerous local and systemic factors. In this paper, we discuss data from three ongoing projects from our laboratory that examine how physiological processes influence adaptation and growth in the skeleton. In the first study, we recorded in vivo strains to quantify the locomotion-induced distribution of two parameters closely related to bone fluid flow strain rate and strain gradients. We found that the magnitude of these parameters (and thus the implied fluid flow) varies substantially within a given cross-section, and that while strain rate magnitude increases uniformly with elevated speed, strain gradients increase focally as gait speed is increased. Secondly, we examined the influence of vascular alterations on bone adaptation by assessing bone blood flow and bone mechanical properties in an in vivo model of trauma-induced joint laxity. A strong negative correlation (r2 = 0.8) was found between increased blood flow (76%) in the primary and secondary spongiosa and decreased stiffness (-34%) following 14 weeks of joint laxity. These data suggest that blood flow and/or vascular adaptation may interact closely with bone adaptation initiated by trauma. Thirdly, we examined the effect of a systemic influence upon skeletal health. After 4 weeks old rats were fed high fat-sucrose diets for 2 yr, their bone mechanical properties were significantly reduced. These changes were primarily due to interference with normal calcium absorption. In the aggregate, these studies emphasize the complexity of bone's normal physical environment, and also illustrate the potential interactions of local and systemic factors upon the process by which bone adapts to physical stimuli.
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Affiliation(s)
- S Judex
- Department of Surgery, McCaig Centre for Joint Injury and Arthritis Research, University of Calgary, AB, Canada
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Benvenuti S, Masi L, Falchetti A, Mancini L, Formigli L, Zecchi S, Amorosi A, Tonelli F, Brandi ML. HPE cells: a clonal endothelial cell line established from human parathyroid tissue (human parathyroid cell line). ENDOTHELIUM : JOURNAL OF ENDOTHELIAL CELL RESEARCH 1997; 5:37-49. [PMID: 9142320 DOI: 10.3109/10623329709044157] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
We report the culture and cloning of human endothelial cells derived from parathyroid tissue surgically removed from a patient affected by Multiple Endocrine Neoplasia Type 1 syndrome. These cells, known as HPE, have been isolated and maintained in culture by serial passages for more than 15 months. The clonal cell line grows in a medium containing serum substitutes which favour endothelial cell growth. HPE cells replicate with a mean doubling time of 120 h, showing typical functional and morphological features of endothelial cells, such as uptake of acetylated low density lipoprotein and positive reaction for Factor VIII-Related Antigen. Basic fibroblast growth factor, vascular endothelial growth factor, insulin-like growth factor type I and ascorbic acid stimulate cell proliferation, whereas transforming growth factor beta and heparin act as inhibitory factors. Prostaglandin E2, secretin and epinephrine increased cAMP production, while human parathyroid hormone, histamine and glucagon were inert. Cells were found to express pro-collagen alpha 1 (type I) mRNA. In HPE cells Restriction Fragments Length Polymorphism and PCR analysis did not show allelic loss at chromosome 11q12-13, known to be a typical feature of MEN 1 parathyroid tumors. These cells are the first example of an established normal human clonal cell line with an endothelial phenotype.
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Affiliation(s)
- S Benvenuti
- Department of Clinical Physiopathology, University of Florence, Italy
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Leventhal PS, Feldman EL. Insulin-like Growth Factors as Regulators of Cell Motility Signaling Mechanisms. Trends Endocrinol Metab 1997; 8:1-6. [PMID: 18406779 DOI: 10.1016/s1043-2760(96)00202-0] [Citation(s) in RCA: 38] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/25/2022]
Abstract
Accumulating evidence indicates that the insulin-like growth factors (IGFs) function not only as mitogenic factors, but also as promoters of cell motility. In this article we review the current knowledge concerning the biochemical mechanisms whereby the IGFs activate cell motility. A key aspect of IGF-stimulated cell motility is the ability of IGFs to promote actin polymerization at the leading edge of the cell. This effect of the IGFs is mediated by activation and autophosphorylation of the type I IGF receptor, followed by docking of insulin receptor substrate-1 (IRS-1), stimulation of phosphatidylinositol (PI) 3-kinase, and possibly activation of the small GTPase Rac. IGF-stimulated cell motility also requires the formation of new adhesions, a process associated with tyrosine phosphorylation of paxillin and focal adhesion kinase. Determining the biochemical mechanisms by which IGFs regulate cell motility should allow for a better understanding of bone remodeling, neurite outgrowth, tumor metastasis, placental formation, and skin and blood vessel repair. (c) 1997, Elsevier Science Inc. (Trends Endocrinol Metab 1997;8:1-6).
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Affiliation(s)
- P S Leventhal
- Department of Anatomy and Cell Biology, SUNY Health Science Center, Syracuse, NY 13210, USA All work was performed in Dr. Feldman's laboratory
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Fiorelli G, Formigli L, Zecchi Orlandini S, Gori F, Falchetti A, Morelli A, Tanini A, Benvenuti S, Brandi ML. Characterization and function of the receptor for IGF-I in human preosteoclastic cells. Bone 1996; 18:269-76. [PMID: 8703583 DOI: 10.1016/8756-3282(95)00485-8] [Citation(s) in RCA: 37] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
Abstract
Using a coculture system, we have recently demonstrated that insulin-like growth factor I (IGF-I) is a mediator of preosteoclastic cell migration toward bone-derived endothelial cells. To better characterize the mechanisms of IGF-I action on preosteoclastic cells we evaluated the expression of type I IGFs receptor in the human leukemic cell line, FLG 29.1, which differentiates toward the osteoclastic phenotype following phorbol ester (TPA) treatment. Scatchard analysis of 125I-labeled IGF-I to FLG 29.1 cells revealed the presence of a single high affinity binding site in both untreated and TPA-treated cells with a similar Kd value (0.3 +/- 0.2 nmol/L and 0.4 +/- 0.1 nmol/L, respectively). In untreated cells, IGF-I binding capacity (1.43 +/- 0.41 fmol/10(6) cells) was significantly (p < 0.05) lower than in TPA-treated cells (2.62 +/- 0.87 fmol/10(6) cells). Competition analyses and crosslinking studies revealed the presence of type I IGF receptor both in untreated and TPA-treated cells. Northern analysis demonstrated that mRNA for IGF-I receptor was expressed by both untreated and TPA-treated FLG 29.1 cells. In addition, FLG 29.1 cells released in the conditioned medium IGFBP-2 and IGFBP-4, whose expression was increased by TPA treatment as demonstrated by ligand and immunoblot analyses. The previous observations of chemotactic action of IGF-I on FLG 29.1 cells was confirmed by ultrastructural observations. Indeed, these cells revealed a marked migratory activity in response to nanomolar concentrations of IGF-I. In addition, the IGF-I receptor alpha IR-3 antiserum inhibited the IGF-I-induced FLG 29.1 cell's migratory activity. These findings clearly show that type IIGF receptor is expressed by osteoclast precursors and that IGF-I induces migration of these through the binding to type I IGF receptors. Binding proteins expressed by osteoclast precursors may play an autocrine role in modulating the IGF-I bioeffects.
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Affiliation(s)
- G Fiorelli
- Department of Clinical Physiopathology, University of Florence, School of Medicine, Italy
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LeRoith D. Insulin-like growth factor receptors and binding proteins. BAILLIERE'S CLINICAL ENDOCRINOLOGY AND METABOLISM 1996; 10:49-73. [PMID: 8734451 DOI: 10.1016/s0950-351x(96)80298-9] [Citation(s) in RCA: 43] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
Abstract
The insulin-like growth factor receptors are integral membrane proteins and demonstrate separate, but important effects on the regulation of cellular processes. The IGF-I receptor signals multiple cascades via its inherent tyrosine kinase activity. The IGF-II/M-6-P receptor on the other hand is primarily involved in targeting of enzymes to various subcellular compartments. In contrast, the insulin-like binding proteins are secreted by the cells and accumulate in the extracellular matrix or on the external surface of the cell. They are also involved in regulating cellular processes more indirectly. They modulate the interactions of the IGFs with their receptors, and in addition, may have some IGF-independent effects probably by direct interaction with integrin and other cell membrane receptor proteins. The recent studies, as outlined in this review, strongly suggest an important, if not essential role for the IGF system in normal physiology and disease states. The challenge now is to define the mechanisms involved in these effects. More studies are required to fully understand the post-receptor mechanism involved in IGF-I receptor signal transduction and the mechanisms whereby the IGFBPs exert their interesting effects. Understanding these mechanisms will enable investigators to create new therapeutic modalities for diseases that are affected by the IGF system.
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Affiliation(s)
- D LeRoith
- Diabetes Branch, NIDDK, National Institutes of Health, Bethesda, MD 20892-1770, USA
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