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Caetano CCS, Azamor T, Meyer NM, Onwubueke C, Calabrese CM, Calabrese LH, Visperas A, Piuzzi NS, Husni ME, Foo SS, Chen W. Mechanistic insights into bone remodelling dysregulation by human viral pathogens. Nat Microbiol 2024; 9:322-335. [PMID: 38316931 PMCID: PMC11045166 DOI: 10.1038/s41564-023-01586-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2022] [Accepted: 12/12/2023] [Indexed: 02/07/2024]
Abstract
Bone-related diseases (osteopathologies) associated with human virus infections have increased around the globe. Recent findings have highlighted the intricate interplay between viral infection, the host immune system and the bone remodelling process. Viral infections can disrupt bone homeostasis, contributing to conditions such as arthritis and soft tissue calcifications. Osteopathologies can occur after arbovirus infections such as chikungunya virus, dengue virus and Zika virus, as well as respiratory viruses, such as severe acute respiratory syndrome coronavirus 2 and enteroviruses such as Coxsackievirus B. Here we explore how human viruses dysregulate bone homeostasis, detailing viral factors, molecular mechanisms, host immune response changes and bone remodelling that ultimately result in osteopathologies. We highlight model systems and technologies to advance mechanistic understanding of viral-mediated bone alterations. Finally, we propose potential prophylactic and therapeutic strategies, introduce 'osteovirology' as a research field highlighting the underestimated roles of viruses in bone-related diseases, and discuss research avenues for further investigation.
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Affiliation(s)
- Camila C S Caetano
- Infection Biology Program, Global Center for Pathogen Research and Human Health, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA
| | - Tamiris Azamor
- Infection Biology Program, Global Center for Pathogen Research and Human Health, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA
| | - Nikki M Meyer
- Infection Biology Program, Global Center for Pathogen Research and Human Health, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA
| | - Chineme Onwubueke
- Infection Biology Program, Global Center for Pathogen Research and Human Health, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA
- Cleveland Clinic Lerner College of Medicine, Case Western Reserve University, Cleveland, OH, USA
| | - Cassandra M Calabrese
- Department of Rheumatic and Immunologic Diseases, Cleveland Clinic, Cleveland, OH, USA
| | - Leonard H Calabrese
- Department of Rheumatic and Immunologic Diseases, Cleveland Clinic, Cleveland, OH, USA
| | - Anabelle Visperas
- Department of Orthopedic Surgery, Cleveland Clinic, Cleveland, OH, USA
| | - Nicolas S Piuzzi
- Department of Orthopedic Surgery, Cleveland Clinic, Cleveland, OH, USA
| | - M Elaine Husni
- Department of Rheumatic and Immunologic Diseases, Cleveland Clinic, Cleveland, OH, USA
| | - Suan-Sin Foo
- Infection Biology Program, Global Center for Pathogen Research and Human Health, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA.
- Cleveland Clinic Lerner College of Medicine, Case Western Reserve University, Cleveland, OH, USA.
| | - Weiqiang Chen
- Infection Biology Program, Global Center for Pathogen Research and Human Health, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA.
- Cleveland Clinic Lerner College of Medicine, Case Western Reserve University, Cleveland, OH, USA.
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Przerwa F, Uzar I, Bogacz A, Kotrych K, Sulikowski T, Wolek M, Kamiński A, Ziętek P, Czerny B. Osteoprotegerin Gene as a Biomarker in the Development of Osteoporosis in Postmenopausal Women. Biomedicines 2023; 11:3218. [PMID: 38137439 PMCID: PMC10740651 DOI: 10.3390/biomedicines11123218] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2023] [Revised: 11/27/2023] [Accepted: 12/01/2023] [Indexed: 12/24/2023] Open
Abstract
Osteoporosis is a multifactorial and polygenic disease caused by an imbalance between osteoclastogenesis and osteoblastogenesis, leading to a decrease in bone mineral density and the occurrence of disorders in the microarchitecture and metabolism of bone tissue. In postmenopausal women, there is a significant decrease in the production of estrogens, which play a key role in maintaining proper bone mineral density. Estrogens have an inhibitory effect on the development and activity of osteoclasts by reducing the synthesis of pro-resorption cytokines and stimulating the expression of osteoprotegerin (OPG). Osteoprotegerin is a cytokine that prevents bone loss by inhibiting the process of osteoclastogenesis, reducing bone resorption. The aim of our study was to determine the influence of the rs3102735 (-163A>G), rs3134070 (-245T>G), rs207361 (-950T>C), rs7844539 (6890A>C), and rs2073618 (1181G>C) polymorphisms of the OPG gene on the risk of osteoporosis and osteopenia in postmenopausal Polish women. The study included 802 unrelated women (osteoporosis: n = 317, osteopenia: n = 110, controls: n = 375) at postmenopausal age (54.7 ± 8.6 years). Genetic analysis was performed using real-time PCR. BMD values as well as clinical and bone parameters with the tested polymorphisms were analyzed among the study population. Analysis of the PPARG rs1801282 variants did not show any association with the risk of osteoporosis and osteopenia. However, for the OPG rs207361 polymorphism, we observed a statistically significant association with the risk of osteoporosis, suggesting that the OPG rs207361 variant may be one of the genetic markers associated with the pathogenesis of osteoporosis.
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Affiliation(s)
- Filip Przerwa
- Department of Pharmacology and Pharmacoeconomics, Pomeranian Medical University in Szczecin, 71-230 Szczecin, Poland; (F.P.); (I.U.); (B.C.)
| | - Izabela Uzar
- Department of Pharmacology and Pharmacoeconomics, Pomeranian Medical University in Szczecin, 71-230 Szczecin, Poland; (F.P.); (I.U.); (B.C.)
| | - Anna Bogacz
- Department of Personalized Medicine and Cell Therapy, Regional Blood Center, Marcelińska 44, 60-354 Poznan, Poland
| | - Katarzyna Kotrych
- Department of General and Dental Radiology, Pomeranian Medical University in Szczecin, al. Powstańców Wielkopolskch 72, 70-111 Szczecin, Poland;
| | - Tadeusz Sulikowski
- General, Mini-Invasive and Gastroenterogical Surgery Clinic, Pomeranian Medical University in Szczecin, 71-252 Szczecin, Poland;
| | - Marlena Wolek
- Department of Stem Cells and Regenerative Medicine, Institute of Natural Fibres and Medicinal Plants, Kolejowa 2, 62-064 Plewiska, Poland;
| | - Adam Kamiński
- Department of Orthopaedics and Traumatology, Independent Public Clinical Hospital No. 1, Pomeranian Medical University in Szczecin, Unii Lubelskiej 1, 71-252 Szczecin, Poland;
| | - Paweł Ziętek
- Department of Orthopaedics, Traumatology and Orthopaedic Oncology, Pomeranian Medical University, Unii Lubelskiej 1, 71-252 Szczecin, Poland;
| | - Bogusław Czerny
- Department of Pharmacology and Pharmacoeconomics, Pomeranian Medical University in Szczecin, 71-230 Szczecin, Poland; (F.P.); (I.U.); (B.C.)
- Department of Stem Cells and Regenerative Medicine, Institute of Natural Fibres and Medicinal Plants, Kolejowa 2, 62-064 Plewiska, Poland;
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Chen M, Fu W, Xu H, Liu CJ. Pathogenic mechanisms of glucocorticoid-induced osteoporosis. Cytokine Growth Factor Rev 2023; 70:54-66. [PMID: 36906448 PMCID: PMC10518688 DOI: 10.1016/j.cytogfr.2023.03.002] [Citation(s) in RCA: 51] [Impact Index Per Article: 25.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2022] [Revised: 02/21/2023] [Accepted: 03/01/2023] [Indexed: 03/08/2023]
Abstract
Glucocorticoid (GC) is one of the most prescribed medicines to treat various inflammatory and autoimmune diseases. However, high doses and long-term use of GCs lead to multiple adverse effects, particularly glucocorticoid-induced osteoporosis (GIO). Excessive GCs exert detrimental effects on bone cells, including osteoblasts, osteoclasts, and osteocytes, leading to impaired bone formation and resorption. The actions of exogenous GCs are considered to be strongly cell-type and dose dependent. GC excess inhibits the proliferation and differentiation of osteoblasts and enhances the apoptosis of osteoblasts and osteocytes, eventually contributing to reduced bone formation. Effects of GC excess on osteoclasts mainly include enhanced osteoclastogenesis, increased lifespan and number of mature osteoclasts, and diminished osteoclast apoptosis, which result in increased bone resorption. Furthermore, GCs have an impact on the secretion of bone cells, subsequently disturbing the process of osteoblastogenesis and osteoclastogenesis. This review provides timely update and summary of recent discoveries in the field of GIO, with a particular focus on the effects of exogenous GCs on bone cells and the crosstalk among them under GC excess.
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Affiliation(s)
- Meng Chen
- Department of Orthopaedic Surgery, New York University Grossman School of Medicine, New York, NY, USA; School of Life Sciences, Northwestern Polytechnical University, Xi'an, China
| | - Wenyu Fu
- Department of Orthopaedic Surgery, New York University Grossman School of Medicine, New York, NY, USA
| | - Huiyun Xu
- School of Life Sciences, Northwestern Polytechnical University, Xi'an, China.
| | - Chuan-Ju Liu
- Department of Orthopaedic Surgery, New York University Grossman School of Medicine, New York, NY, USA; Department of Cell Biology, New York University Grossman School of Medicine, New York, NY, USA.
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Brent MB. Pharmaceutical treatment of bone loss: From animal models and drug development to future treatment strategies. Pharmacol Ther 2023; 244:108383. [PMID: 36933702 DOI: 10.1016/j.pharmthera.2023.108383] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2022] [Revised: 02/18/2023] [Accepted: 03/09/2023] [Indexed: 03/17/2023]
Abstract
Animal models are fundamental to advance our knowledge of the underlying pathophysiology of bone loss and to study pharmaceutical countermeasures against it. The animal model of post-menopausal osteoporosis from ovariectomy is the most widely used preclinical approach to study skeletal deterioration. However, several other animal models exist, each with unique characteristics such as bone loss from disuse, lactation, glucocorticoid excess, or exposure to hypobaric hypoxia. The present review aimed to provide a comprehensive overview of these animal models to emphasize the importance and significance of investigating bone loss and pharmaceutical countermeasures from perspectives other than post-menopausal osteoporosis only. Hence, the pathophysiology and underlying cellular mechanisms involved in the various types of bone loss are different, and this might influence which prevention and treatment strategies are the most effective. In addition, the review sought to map the current landscape of pharmaceutical countermeasures against osteoporosis with an emphasis on how drug development has changed from being driven by clinical observations and enhancement or repurposing of existing drugs to today's use of targeted anti-bodies that are the result of advanced insights into the underlying molecular mechanisms of bone formation and resorption. Moreover, new treatment combinations or repurposing opportunities of already approved drugs with a focus on dabigatran, parathyroid hormone and abaloparatide, growth hormone, inhibitors of the activin signaling pathway, acetazolamide, zoledronate, and romosozumab are discussed. Despite the considerable progress in drug development, there is still a clear need to improve treatment strategies and develop new pharmaceuticals against various types of osteoporosis. The review also highlights that new treatment indications should be explored using multiple animal models of bone loss in order to ensure a broad representation of different types of skeletal deterioration instead of mainly focusing on primary osteoporosis from post-menopausal estrogen deficiency.
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Affiliation(s)
- Mikkel Bo Brent
- Department of Biomedicine, Aarhus University, Denmark, Wilhelm Meyers Allé 3, 8000 Aarhus C, Denmark.
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Tocotrienol as a Protecting Agent against Glucocorticoid-Induced Osteoporosis: A Mini Review of Potential Mechanisms. MOLECULES (BASEL, SWITZERLAND) 2022; 27:molecules27185862. [PMID: 36144598 PMCID: PMC9506150 DOI: 10.3390/molecules27185862] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/31/2022] [Revised: 09/03/2022] [Accepted: 09/08/2022] [Indexed: 11/18/2022]
Abstract
Glucocorticoid-induced osteogenic dysfunction is the main pathologyical mechanism underlying the development of glucocorticoid-induced osteoporosis. Glucocorticoids promote adipogenic differentiation and osteoblast apoptosis through various pathways. Various ongoing studies are exploring the potential of natural products in preventing glucocorticoid-induced osteoporosis. Preclinical studies have consistently shown the bone protective effects of tocotrienol through its antioxidant and anabolic effects. This review aims to summarise the potential mechanisms of tocotrienol in preventing glucocorticoid-induced osteoporosis based on existing in vivo and in vitro evidence. The current literature showed that tocotrienol prevents oxidative damage on osteoblasts exposed to high levels of glucocorticoids. Tocotrienol reduces lipid peroxidation and increases oxidative stress enzyme activities. The reduction in oxidative stress protects the osteoblasts and preserves the bone microstructure and biomechanical strength of glucocorticoid-treated animals. In other animal models, tocotrienol has been shown to activate the Wnt/β-catenin pathway and lower the RANKL/OPG ratio, which are the targets of glucocorticoids. In conclusion, tocotrienol enhances osteogenic differentiation and bone formation in glucocorticoid-treated osteoblasts while improving structural integrity in glucocorticoid-treated rats. This is achieved by preventing oxidative stress and osteoblast apoptosis. However, these preclinical results should be validated in a randomised controlled trial.
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Henning P, Conaway HH, Lerner UH. Stimulation of osteoclast formation and bone resorption by glucocorticoids: Synergistic interactions with the calcium regulating hormones parathyroid hormone and 1,25(OH) 2-vitamin D3. VITAMINS AND HORMONES 2022; 120:231-270. [PMID: 35953112 DOI: 10.1016/bs.vh.2022.04.005] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/15/2023]
Abstract
Osteoporosis is a significant health problem, with skeletal fractures increasing morbidity and mortality. Excess glucocorticoids (GC) represents the leading cause of secondary osteoporosis. The first phase of glucocorticoid-induced osteoporosis is increased bone resorption. In this Chapter, in vitro studies of the direct glucocorticoid receptor (GR) mediated cellular effects of GC on osteoclasts to affect bone resorption and indirect effects on osteoblast lineage cells to increase the RANKL/OPG ratio and stimulate osteoclastogenesis and bone resorption are reviewed in detail, together with detailed descriptions of in vivo effects of GC in different portions of the skeleton in research animals and humans. Brief sections are devoted to contrasting functions of GC in osteonecrosis, vitamin D formation, in vitro and in vivo bone resorptive actions dependent on vitamin D receptor and vitamin D toxicity, as well as the molecular basis of GR action. Included are also more detailed assessments of the interactions of GC with the major calcium regulating hormones, 1,25(OH)2-vitamin D3 and parathyroid hormone, describing the in vitro increases in RANKL/OPG ratios, osteoclastogenesis and synergistic bone resorption that occurs when GC is combined with either 1,25(OH)2-vitamin D3 or parathyroid hormone. Additionally, a molecular basic for the synergistic interaction of GC with 1,25(OH)2-vitamin D3 is provided along with a suggested molecular basic for the interaction between GC and parathyroid hormone.
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Affiliation(s)
- Petra Henning
- Department of Internal Medicine and Clinical Nutrition, Institute of Medicine, Sahlgrenska Osteoporosis Centre and Centre for Bone and Arthritis Research at the Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - H Herschel Conaway
- Department of Physiology and Cell Biology, University of Arkansas for Medical Sciences, Little Rock, Arkansas, United States
| | - Ulf H Lerner
- Department of Internal Medicine and Clinical Nutrition, Institute of Medicine, Sahlgrenska Osteoporosis Centre and Centre for Bone and Arthritis Research at the Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
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McCarty MF, Lewis Lujan L, Iloki Assanga S. Targeting Sirt1, AMPK, Nrf2, CK2, and Soluble Guanylate Cyclase with Nutraceuticals: A Practical Strategy for Preserving Bone Mass. Int J Mol Sci 2022; 23:4776. [PMID: 35563167 PMCID: PMC9104509 DOI: 10.3390/ijms23094776] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2022] [Revised: 04/19/2022] [Accepted: 04/25/2022] [Indexed: 12/15/2022] Open
Abstract
There is a vast pre-clinical literature suggesting that certain nutraceuticals have the potential to aid the preservation of bone mass in the context of estrogen withdrawal, glucocorticoid treatment, chronic inflammation, or aging. In an effort to bring some logical clarity to these findings, the signaling pathways regulating osteoblast, osteocyte, and osteoclast induction, activity, and survival are briefly reviewed in the present study. The focus is placed on the following factors: the mechanisms that induce and activate the RUNX2 transcription factor, a key driver of osteoblast differentiation and function; the promotion of autophagy and prevention of apoptosis in osteoblasts/osteoclasts; and the induction and activation of NFATc1, which promotes the expression of many proteins required for osteoclast-mediated osteolysis. This analysis suggests that the activation of sirtuin 1 (Sirt1), AMP-activated protein kinase (AMPK), the Nrf2 transcription factor, and soluble guanylate cyclase (sGC) can be expected to aid the maintenance of bone mass, whereas the inhibition of the serine kinase CK2 should also be protective in this regard. Fortuitously, nutraceuticals are available to address each of these targets. Sirt1 activation can be promoted with ferulic acid, N1-methylnicotinamide, melatonin, nicotinamide riboside, glucosamine, and thymoquinone. Berberine, such as the drug metformin, is a clinically useful activator of AMPK. Many agents, including lipoic acid, melatonin, thymoquinone, astaxanthin, and crucifera-derived sulforaphane, can promote Nrf2 activity. Pharmacological doses of biotin can directly stimulate sGC. Additionally, certain flavonols, notably quercetin, can inhibit CK2 in high nanomolar concentrations that may be clinically relevant. Many, though not all, of these agents have shown favorable effects on bone density and structure in rodent models of bone loss. Complex nutraceutical regimens providing a selection of these nutraceuticals in clinically meaningful doses may have an important potential for preserving bone health. Concurrent supplementation with taurine, N-acetylcysteine, vitamins D and K2, and minerals, including magnesium, zinc, and manganese, plus a diet naturally high in potassium, may also be helpful in this regard.
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Affiliation(s)
| | - Lidianys Lewis Lujan
- Department of Research and Postgraduate in Food Science, Sonoran University, Hermosillo 83200, Mexico;
| | - Simon Iloki Assanga
- Department of Biological Chemical Sciences, Sonoran University, Hermosillo 83200, Mexico;
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Park SS, Uzelac A, Kotsopoulos J. Delineating the role of osteoprotegerin as a marker of breast cancer risk among women with a BRCA1 mutation. Hered Cancer Clin Pract 2022; 20:14. [PMID: 35418083 PMCID: PMC9008947 DOI: 10.1186/s13053-022-00223-3] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2021] [Accepted: 03/30/2022] [Indexed: 11/26/2022] Open
Abstract
Women with a pathogenic germline mutation in the BRCA1 gene face a very high lifetime risk of developing breast cancer, estimated at 72% by age 80. Prophylactic bilateral mastectomy is the only effective way to lower their risk; however, most women with a mutation opt for intensive screening with annual MRI and mammography. Given that the BRCA1 gene was identified over 20 years ago, there is a need to identify a novel non-surgical approach to hereditary breast cancer prevention. Here, we provide a review of the emerging preclinical and epidemiologic evidence implicating the dysregulation of progesterone-mediated receptor activator of nuclear factor κB (RANK) signaling in the pathogenesis of BRCA1-associated breast cancer. Experimental studies have demonstrated that RANK inhibition suppresses Brca1-mammary tumorigenesis, suggesting a potential target for prevention. Data from studies conducted among women with a BRCA1 mutation further support this pathway in BRCA1-associated breast cancer development. Progesterone-containing (but not estrogen-alone) hormone replacement therapy is associated with an increased risk of breast cancer in women with a BRCA1 mutation. Furthermore, BRCA1 mutation carriers have significantly lower levels of circulating osteoprotegerin (OPG), the decoy receptor for RANK-ligand (RANKL) and thus endogenous inhibitor of RANK signaling. OPG levels may be associated with the risk of disease, suggesting a role of this protein as a potential biomarker of breast cancer risk. This may improve upon current risk prediction models, stratifying women at the highest risk of developing the disease, and further identify those who may be targets for anti-RANKL chemoprevention. Collectively, the evidence supports therapeutic inhibition of the RANK pathway for the primary prevention of BRCA1-associated breast cancer, which may generate unique prevention strategies (without prophylactic surgery) and enhance quality of life.
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Affiliation(s)
- Sarah Sohyun Park
- Department of Nutritional Sciences, University of Toronto, Toronto, Ontario, Canada
- Women's College Research Institute, Women's College Hospital, Toronto, Ontario, Canada
| | - Aleksandra Uzelac
- Women's College Research Institute, Women's College Hospital, Toronto, Ontario, Canada
- Department of Pharmacology and Toxicology, University of Toronto, Toronto, Canada
| | - Joanne Kotsopoulos
- Women's College Research Institute, Women's College Hospital, Toronto, Ontario, Canada.
- Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario, Canada.
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Ng JS, Chin KY. Potential mechanisms linking psychological stress to bone health. Int J Med Sci 2021; 18:604-614. [PMID: 33437195 PMCID: PMC7797546 DOI: 10.7150/ijms.50680] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/14/2020] [Accepted: 11/30/2020] [Indexed: 02/06/2023] Open
Abstract
Chronic psychological stress affects many body systems, including the skeleton, through various mechanisms. This review aims to provide an overview of the factors mediating the relationship between psychological stress and bone health. These factors can be divided into physiological and behavioural changes induced by psychological stress. The physiological factors involve endocrinological changes, such as increased glucocorticoids, prolactin, leptin and parathyroid hormone levels and reduced gonadal hormones. Low-grade inflammation and hyperactivation of the sympathetic nervous system during psychological stress are also physiological changes detrimental to bone health. The behavioural changes during mental stress, such as altered dietary pattern, cigarette smoking, alcoholism and physical inactivity, also threaten the skeletal system. Psychological stress may be partly responsible for epigenetic regulation of skeletal development. It may also mediate the relationship between socioeconomic status and bone health. However, more direct evidence is required to prove these hypotheses. In conclusion, chronic psychological stress should be recognised as a risk factor of osteoporosis and stress-coping methods should be incorporated as part of the comprehensive osteoporosis-preventing strategy.
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Affiliation(s)
- Jia-Sheng Ng
- Department of Pharmacology, Faculty of Medicine, Universiti Kebangsaan Malaysia, Cheras 56000, Malaysia
| | - Kok-Yong Chin
- Department of Pharmacology, Faculty of Medicine, Universiti Kebangsaan Malaysia, Cheras 56000, Malaysia
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Conaway HH, Henning P, Lie A, Tuckermann J, Lerner UH. Glucocorticoids employ the monomeric glucocorticoid receptor to potentiate vitamin D 3 and parathyroid hormone-induced osteoclastogenesis. FASEB J 2019; 33:14394-14409. [PMID: 31675485 PMCID: PMC6894088 DOI: 10.1096/fj.201802729rrr] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Glucocorticoid (GC) therapy decreases bone mass and increases the risk of fractures. We investigated interactions between the GC dexamethasone (DEX) and the bone resorptive agents 1,25(OH)2-vitamin D3 (D3) and parathyroid hormone (PTH) on osteoclastogenesis. We observed a synergistic potentiation of osteoclast progenitor cell differentiation and formation of osteoclasts when DEX was added to either D3- or PTH-treated mouse bone marrow cell (BMC) cultures. Cotreatment of DEX with D3 or PTH increased gene encoding calcitonin receptor (Calcr), acid phosphatase 5, tartrate resistant (Acp5), cathepsin K (Ctsk), and TNF superfamily member 11 (Tnfsf11) mRNA, receptor activator of NF-κB ligand protein (RANKL), numbers of osteoclasts on plastic, and pit formation and release of C-terminal fragment of type I collagen from cells cultured on bone slices. Enhanced RANKL protein expression caused by D3 and DEX was absent in BMC from mice in which the GC receptor (GR) was deleted in stromal cells/osteoblasts. Synergistic interactions between DEX and D3 on RANKL and osteoclast formation were present in BMC from mice with attenuated GR dimerization. These data demonstrate that the GR cooperates with D3 and PTH signaling, causing massive osteoclastogenesis, which may explain the rapid bone loss observed with high dosages of GC treatment.-Conaway, H. H., Henning, P., Lie, A., Tuckermann, J., Lerner, U. H. Glucocorticoids employ the monomeric glucocorticoid receptor to potentiate vitamin D3 and parathyroid hormone-induced osteoclastogenesis.
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Affiliation(s)
- H Herschel Conaway
- Department of Physiology and Biophysics, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA
| | - Petra Henning
- Center for Bone and Arthritis Research, Institute for Medicine, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden
| | - Antia Lie
- Department of Molecular Periodontology, Umeå University, Umeå, Sweden
| | - Jan Tuckermann
- Institute of Comparative Molecular Endocrinology, University of Ulm, Ulm, Germany
| | - Ulf H Lerner
- Center for Bone and Arthritis Research, Institute for Medicine, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden.,Department of Molecular Periodontology, Umeå University, Umeå, Sweden
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11
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Hardy RS, Zhou H, Seibel MJ, Cooper MS. Glucocorticoids and Bone: Consequences of Endogenous and Exogenous Excess and Replacement Therapy. Endocr Rev 2018; 39:519-548. [PMID: 29905835 DOI: 10.1210/er.2018-00097] [Citation(s) in RCA: 150] [Impact Index Per Article: 21.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/14/2018] [Accepted: 06/08/2018] [Indexed: 02/02/2023]
Abstract
Osteoporosis associated with long-term glucocorticoid therapy remains a common and serious bone disease. Additionally, in recent years it has become clear that more subtle states of endogenous glucocorticoid excess may have a major impact on bone health. Adverse effects can be seen with mild systemic glucocorticoid excess, but there is also evidence of tissue-specific regulation of glucocorticoid action within bone as a mechanism of disease. This review article examines (1) the role of endogenous glucocorticoids in normal bone physiology, (2) the skeletal effects of endogenous glucocorticoid excess in the context of endocrine conditions such as Cushing disease/syndrome and autonomous cortisol secretion (subclinical Cushing syndrome), and (3) the actions of therapeutic (exogenous) glucocorticoids on bone. We review the extent to which the effect of glucocorticoids on bone is influenced by variations in tissue metabolizing enzymes and glucocorticoid receptor expression and sensitivity. We consider how the effects of therapeutic glucocorticoids on bone are complicated by the effects of the underlying inflammatory disease being treated. We also examine the impact that glucocorticoid replacement regimens have on bone in the context of primary and secondary adrenal insufficiency. We conclude that even subtle excess of endogenous or moderate doses of therapeutic glucocorticoids are detrimental to bone. However, in patients with inflammatory disorders there is a complex interplay between glucocorticoid treatment and underlying inflammation, with the underlying condition frequently representing the major component underpinning bone damage.
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Affiliation(s)
- Rowan S Hardy
- University of Birmingham, Birmingham, United Kingdom
| | - Hong Zhou
- Bone Research Program, ANZAC Research Institute, Sydney, New South Wales, Australia
| | - Markus J Seibel
- Bone Research Program, ANZAC Research Institute, Sydney, New South Wales, Australia.,Department of Endocrinology and Metabolism, Concord Repatriation General Hospital, Sydney, New South Wales, Australia.,Concord Clinical School, University of Sydney, Sydney, New South Wales, Australia
| | - Mark S Cooper
- Department of Endocrinology and Metabolism, Concord Repatriation General Hospital, Sydney, New South Wales, Australia.,Concord Clinical School, University of Sydney, Sydney, New South Wales, Australia.,Adrenal Steroid Laboratory, ANZAC Research Institute, Sydney, New South Wales, Australia
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12
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Ohlsson C, Nilsson KH, Henning P, Wu J, Gustafsson KL, Poutanen M, Lerner UH, Movérare-Skrtic S. WNT16 overexpression partly protects against glucocorticoid-induced bone loss. Am J Physiol Endocrinol Metab 2018; 314:E597-E604. [PMID: 29406783 DOI: 10.1152/ajpendo.00292.2017] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Therapeutic use of glucocorticoids (GCs) is a major cause of secondary osteoporosis, but the molecular mechanisms responsible for the deleterious effects of GCs in bone are only partially understood. WNT16 is a crucial physiological regulator of bone mass and fracture susceptibility, and we hypothesize that disturbed WNT16 activity might be involved in the deleterious effects of GC in bone. Twelve-week-old female Obl-Wnt16 mice (WNT16 expression driven by the rat procollagen type I α1 promoter) and wild-type (WT) littermates were treated with prednisolone (7.6 mg·kg-1·day-1) or vehicle for 4 wk. We first observed that GC treatment decreased the Wnt16 mRNA levels in bone of female mice (-56.4 ± 6.1% compared with vehicle, P < 0.001). We next evaluated if WNT16 overexpression protects against GC-induced bone loss. Dual-energy X-ray absorptiometry analyses revealed that GC treatment decreased total body bone mineral density in WT mice (-3.9 ± 1.2%, P = 0.028) but not in Obl-Wnt16 mice (+1.3 ± 1.4%, nonsignificant). Microcomputed tomography analyses showed that GC treatment decreased trabecular bone volume fraction (BV/TV) of the femur in WT mice ( P = 0.019) but not in Obl-Wnt16 mice. Serum levels of the bone formation marker procollagen type I N-terminal propeptide were substantially reduced by GC treatment in WT mice (-50.3 ± 7.0%, P = 0.008) but not in Obl-Wnt16 mice (-3.8 ± 21.2%, nonsignificant). However, the cortical bone thickness in femur was reduced by GC treatment in both WT mice and Obl-Wnt16 mice. In conclusion, GC treatment decreases Wnt16 mRNA levels in bone and WNT16 overexpression partly protects against GC-induced bone loss.
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Affiliation(s)
- Claes Ohlsson
- Centre for Bone and Arthritis Research at Institute of Medicine, Sahlgrenska Academy at University of Gothenburg , Gothenburg , Sweden
| | - Karin H Nilsson
- Centre for Bone and Arthritis Research at Institute of Medicine, Sahlgrenska Academy at University of Gothenburg , Gothenburg , Sweden
| | - Petra Henning
- Centre for Bone and Arthritis Research at Institute of Medicine, Sahlgrenska Academy at University of Gothenburg , Gothenburg , Sweden
| | - Jianyao Wu
- Centre for Bone and Arthritis Research at Institute of Medicine, Sahlgrenska Academy at University of Gothenburg , Gothenburg , Sweden
| | - Karin L Gustafsson
- Centre for Bone and Arthritis Research at Institute of Medicine, Sahlgrenska Academy at University of Gothenburg , Gothenburg , Sweden
| | - Matti Poutanen
- Centre for Bone and Arthritis Research at Institute of Medicine, Sahlgrenska Academy at University of Gothenburg , Gothenburg , Sweden
- Institute of Biomedicine and Turku Center for Disease Modeling, University of Turku , Turku , Finland
| | - Ulf H Lerner
- Centre for Bone and Arthritis Research at Institute of Medicine, Sahlgrenska Academy at University of Gothenburg , Gothenburg , Sweden
| | - Sofia Movérare-Skrtic
- Centre for Bone and Arthritis Research at Institute of Medicine, Sahlgrenska Academy at University of Gothenburg , Gothenburg , Sweden
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Li J, Li SH, Wu J, Weisel RD, Yao A, Stanford WL, Liu SM, Li RK. Young Bone Marrow Sca-1 Cells Rejuvenate the Aged Heart by Promoting Epithelial-to-Mesenchymal Transition. Am J Cancer Res 2018; 8:1766-1781. [PMID: 29556355 PMCID: PMC5858499 DOI: 10.7150/thno.22788] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2017] [Accepted: 01/13/2018] [Indexed: 01/13/2023] Open
Abstract
Background: To improve the regenerative capacity of aged individuals, we reconstituted bone marrow (BM) of aged mice with young Sca-1 cells, which repopulated cardiac progenitors and prevented cardiac dysfunction after a myocardial infarction (MI). However, the mechanisms involved were incompletely elucidated. This study aimed to investigate whether young, highly regenerative BM Sca-1 cells exert their cardio-protective effects on the aged heart through reactivation of the epithelial-to-mesenchymal transition (EMT) process. Methods:In vitro, BM Sca-1 cells were co-cultured with epicardial-derived cells (EPDCs) under hypoxia condition; mRNA and protein levels of EMT genes were measured along with cellular proliferation and migration. In vivo, BM Sca-1+ or Sca-1- cells from young mice (2-3 months) were transplanted into lethally-irradiated old mice (20-22 months) to generate chimeras. In addition, Sca-1 knockout (KO) mice were reconstituted with wild type (WT) BM Sca-1+ cells. The effects of BM Sca-1 cell on EMT reactivation and improvement of cardiac function after MI were evaluated. Results:In vitro, BM Sca-1+ cells increased EPDC proliferation, migration, and EMT relative to Sca-1- cells and these effects were inhibited by a TGF-β blocker. In vivo, more young BM Sca-1+ than Sca-1- cells homed to the epicardium and induced greater host EPDC proliferation, migration, and EMT after MI. Furthermore, reconstitution of Sca-1 KO mice with WT Sca-1+ cells was associated with the reactivation of EMT and improved cardiac function after MI. Conclusions: Young BM Sca-1+ cells improved cardiac regeneration through promoting EPDC proliferation, migration and reactivation of EMT via the TGF-β signaling pathway.
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Affiliation(s)
- Jiao Li
- Department of Cardiology, Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, China,Toronto General Research Institute, Division of Cardiovascular Surgery, University Health Network, Toronto, Canada,Division of Cardiac Surgery, Department of Surgery, University of Toronto; Toronto, Canada
| | - Shu-Hong Li
- Toronto General Research Institute, Division of Cardiovascular Surgery, University Health Network, Toronto, Canada
| | - Jun Wu
- Toronto General Research Institute, Division of Cardiovascular Surgery, University Health Network, Toronto, Canada
| | - Richard D. Weisel
- Toronto General Research Institute, Division of Cardiovascular Surgery, University Health Network, Toronto, Canada,Division of Cardiac Surgery, Department of Surgery, University of Toronto; Toronto, Canada
| | - Alina Yao
- Toronto General Research Institute, Division of Cardiovascular Surgery, University Health Network, Toronto, Canada
| | - William L. Stanford
- Regenerative Medicine Program, Ottawa Hospital Research Institute, Department of Cellular and Molecular Medicine, University of Ottawa
| | - Shi-Ming Liu
- Department of Cardiology, Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, China,✉ Corresponding author: Shi-Ming Liu, MD, Department of Cardiology, Second Affiliated Hospital of Guangzhou Medical University, Guangzhou 510260, China. Tel: 86-020-34153522; Fax: 86-20-3415-3709; and Ren-Ke Li, MD, PhD, Toronto Medical Discovery Tower, Room 3-702, 101 College Street, Toronto, Ontario, Canada M5G 1L7. Tel: 1-416-581-7492; Fax: 1-416-581-7493;
| | - Ren-Ke Li
- Toronto General Research Institute, Division of Cardiovascular Surgery, University Health Network, Toronto, Canada,Division of Cardiac Surgery, Department of Surgery, University of Toronto; Toronto, Canada,✉ Corresponding author: Shi-Ming Liu, MD, Department of Cardiology, Second Affiliated Hospital of Guangzhou Medical University, Guangzhou 510260, China. Tel: 86-020-34153522; Fax: 86-20-3415-3709; and Ren-Ke Li, MD, PhD, Toronto Medical Discovery Tower, Room 3-702, 101 College Street, Toronto, Ontario, Canada M5G 1L7. Tel: 1-416-581-7492; Fax: 1-416-581-7493;
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Adriamycin in combination with dexamethasone and octreotide lacks activity on the treatment of a 4T1 metastatic breast cancer model. Anticancer Drugs 2017; 28:489-502. [PMID: 28272098 DOI: 10.1097/cad.0000000000000484] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
The aim of this study was to evaluate whether the palliative treatment for metastatic disease with dexamethasone (DEX) plus octreotide (OCT) can improve the anticancer effects of the standard treatment with adriamycin (ADR) on a 4T1 metastatic breast cancer (MBC) model. 4T1 cells were first characterized for the expression of the somatostatin receptors 1-5 and were then inoculated onto the femur of BALB/C mice. Investigation protocols used 4T1 cell proliferation and invasion assays, analysis of radiographic images of the bone metastatic lesions, and overall survival of the diseased animals. The triple combination treatment regime (ADR+OCT+DEX) was ineffective for growth inhibition and showed an antagonistic effect on ADR activity in the 4T1 cell line in both proliferation and invasion assays. ADR treatment following the administration of the DEX+OCT regimen decreased the anticancer activity of ADR both on the grading of the bone metastatic lesions and on the overall survival of diseased animals. Moreover, the palliation treatment with OCT+DEX and in combination with ADR rather caused disease progression of the metastatic disease and bone lesions in a 4T1 MBC model in vivo. These results suggest that the administration of the DEX+OCT regimen, although may preserve palliative effects, neutralizes or reverses the anticancer effects of ADR on a 4T1 MBC model in vitro and in vivo. The simultaneous use of these drugs should be considered carefully in clinical practice.
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15
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Conaway HH, Henning P, Lie A, Tuckermann J, Lerner UH. Activation of dimeric glucocorticoid receptors in osteoclast progenitors potentiates RANKL induced mature osteoclast bone resorbing activity. Bone 2016; 93:43-54. [PMID: 27596806 DOI: 10.1016/j.bone.2016.08.024] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/24/2016] [Revised: 08/26/2016] [Accepted: 08/30/2016] [Indexed: 01/02/2023]
Abstract
Glucocorticoid (GC) therapy is the greatest risk factor for secondary osteoporosis. Pathogenic mechanisms involve an initial increase in bone resorption followed by decreased bone formation. To gain a better understanding of the resorptive activity of GCs, we have used mouse bone marrow macrophages (BMM) to determine if GCs can directly modulate RANKL stimulated osteoclast formation and/or activity. In agreement with previous studies, experiments performed in plastic wells showed that GCs (dexamethasone, hydrocortisone, and prednisolone) inhibited osteoclast number and size during the initial phases of RANKL stimulated osteoclastogenesis; however, in prolonged cultures, decreased apoptosis was observed and escape from GC induced inhibition occurred with an enhanced number of osteoclasts formed, many with an increased area. When BMM cells were seeded on bone slices, GCs robustly enhanced RANKL stimulated formation of resorption pits and release of CTX without affecting the number or size of osteoclasts formed and with no effect on apoptosis. Stimulation of pit formation was not associated with increased life span of osteoclasts or an effect on mRNA expression of several osteoclastic or osteoclastogenic genes. The potentiation of RANKL induced CTX release by dexamethasone was significantly less in BMM cells from mice with conditional knockout of the osteoclastic glucocorticoid receptor and completely absent in cells from GRdim mice, which carry a point mutation in one dimerizing interface of the GC receptor. These data suggest that: 1. Plastic is a poor medium to use for studying direct effects of GCs on osteoclasts 2. GCs can enhance bone resorption without decreasing apoptosis, and 3. A direct enhancement of RANKL mediated resorption is stimulated by the dimeric GC-receptor.
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Affiliation(s)
- H Herschel Conaway
- Department of Physiology and Biophysics, University of Arkansas for Medical Sciences, Little Rock, AR 72205, United States
| | - Petra Henning
- Centre for Bone and Arthritis Research at Department of Internal Medicine and Clinical Nutrition, Institute for Medicine, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden
| | - Anita Lie
- Department of Molecular Periodontology, Umeå University, Umeå, Sweden
| | - Jan Tuckermann
- Institute of Comparative Molecular Endocrinology, University of Ulm, Ulm, Germany
| | - Ulf H Lerner
- Centre for Bone and Arthritis Research at Department of Internal Medicine and Clinical Nutrition, Institute for Medicine, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden; Department of Molecular Periodontology, Umeå University, Umeå, Sweden.
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16
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Piemontese M, Xiong J, Fujiwara Y, Thostenson JD, O'Brien CA. Cortical bone loss caused by glucocorticoid excess requires RANKL production by osteocytes and is associated with reduced OPG expression in mice. Am J Physiol Endocrinol Metab 2016; 311:E587-93. [PMID: 27460899 PMCID: PMC5142003 DOI: 10.1152/ajpendo.00219.2016] [Citation(s) in RCA: 87] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/09/2016] [Accepted: 07/25/2016] [Indexed: 12/15/2022]
Abstract
Glucocorticoid excess is a major cause of low bone mass and fractures. Glucocorticoid administration decreases cortical thickness and increases cortical porosity in mice, and these changes are associated with increased osteoclast number at the endocortical surface. Receptor activator of NF-κB ligand (RANKL) produced by osteocytes is required for osteoclast formation in cancellous bone as well as the increase in cortical bone resorption caused by mechanical unloading or dietary calcium deficiency. However, whether osteocyte-derived RANKL also participates in the increase in bone resorption caused by glucocorticoid excess is unknown. To address this question, we examined the effects of prednisolone on cortical bone of mice lacking RANKL production in osteocytes. Prednisolone administration increased osteoclast number at the endocortical surface, increased cortical porosity, and reduced cortical thickness in control mice, but none of these effects occurred in mice lacking RANKL in osteocytes. Prednisolone administration did not alter RANKL mRNA abundance but did reduce osteoprotegerin (OPG) mRNA abundance in osteocyte-enriched cortical bone. Similarly, dexamethasone suppressed OPG but did not increase RANKL production in cortical bone organ cultures and primary osteoblasts. These results demonstrate that RANKL produced by osteocytes is required for the cortical bone loss caused by glucocorticoid excess but suggest that the changes in endocortical resorption are driven by reduced OPG rather than elevated RANKL expression.
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Affiliation(s)
- Marilina Piemontese
- Center for Osteoporosis and Metabolic Bone Diseases, University of Arkansas for Medical Sciences, Little Rock, Arkansas; Central Arkansas Veterans Healthcare System, Little Rock, Arkansas
| | - Jinhu Xiong
- Center for Osteoporosis and Metabolic Bone Diseases, University of Arkansas for Medical Sciences, Little Rock, Arkansas; Central Arkansas Veterans Healthcare System, Little Rock, Arkansas
| | - Yuko Fujiwara
- Center for Osteoporosis and Metabolic Bone Diseases, University of Arkansas for Medical Sciences, Little Rock, Arkansas; Central Arkansas Veterans Healthcare System, Little Rock, Arkansas
| | - Jeff D Thostenson
- Department of Biostatistics, University of Arkansas for Medical Sciences, Little Rock, Arkansas; and
| | - Charles A O'Brien
- Center for Osteoporosis and Metabolic Bone Diseases, University of Arkansas for Medical Sciences, Little Rock, Arkansas; Central Arkansas Veterans Healthcare System, Little Rock, Arkansas
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Bernardi S, Bossi F, Toffoli B, Fabris B. Roles and Clinical Applications of OPG and TRAIL as Biomarkers in Cardiovascular Disease. BIOMED RESEARCH INTERNATIONAL 2016; 2016:1752854. [PMID: 27200369 PMCID: PMC4856888 DOI: 10.1155/2016/1752854] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/29/2016] [Revised: 03/28/2016] [Accepted: 04/05/2016] [Indexed: 12/19/2022]
Abstract
Cardiovascular diseases (CVD) remain the major cause of death and premature disability in Western societies. Assessing the risk of CVD is an important aspect in clinical decision-making. Among the growing number of molecules that are studied for their potential utility as CVD biomarkers, a lot of attention has been focused on osteoprotegerin (OPG) and its ligands, which are receptor activator of nuclear factor κB ligand (RANKL) and TNF-related apoptosis-inducing ligand. Based on the existing literature and on our experience in this field, here we review what the possible roles of OPG and TRAIL in CVD are and their potential utility as CVD biomarkers.
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Affiliation(s)
- Stella Bernardi
- Department of Medical, Surgical and Health Sciences, University of Trieste, Cattinara Teaching Hospital, Strada di Fiume, 34149 Trieste, Italy
| | - Fleur Bossi
- Department of Medical, Surgical and Health Sciences, University of Trieste, Cattinara Teaching Hospital, Strada di Fiume, 34149 Trieste, Italy
| | - Barbara Toffoli
- Department of Medical, Surgical and Health Sciences, University of Trieste, Cattinara Teaching Hospital, Strada di Fiume, 34149 Trieste, Italy
| | - Bruno Fabris
- Department of Medical, Surgical and Health Sciences, University of Trieste, Cattinara Teaching Hospital, Strada di Fiume, 34149 Trieste, Italy
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18
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Miyamoto S, Miyamoto Y, Shibata Y, Yoshimura K, Izumida E, Suzuki H, Miyazaki T, Maki K, Kamijo R. In situ quasi-static and dynamic nanoindentation tests on calcified nodules formed by osteoblasts: Implication of glucocorticoids responsible for osteoblast calcification. Acta Biomater 2015; 12:216-226. [PMID: 25448350 DOI: 10.1016/j.actbio.2014.10.038] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2014] [Revised: 10/27/2014] [Accepted: 10/28/2014] [Indexed: 01/06/2023]
Abstract
The functional requirements of regenerated calcified tissues are that they enable the tissues to bear a variety of imposed stress and consequent contact-induced strain without substantial fracture. Here we demonstrate the effects of glucocorticoid hormones such as dexamethasone and hydrocortisone on the nanomechanical properties of calcified nodules formed by mouse osteoblastic MC3T3-E1 cells in differentiation-inducing medium containing ascorbic acid and β-glycerophosphate. Neither cell proliferation nor calcium deposition, evaluated using alizarin red and von Kossa staining, was affected by dexamethasone. On the other hand, calcified nodules formed in the presence of dexamethasone were significantly harder and stiffer than those formed in their absence. In particular, a series of nanoindentation tests revealed that the calcified nodules formed in the presence of dexamethasone showed enhanced stiffness against dynamic strain as compared to a quasi-static load. Furthermore, Raman spectroscopy revealed that dexamethasone and hydrocortisone increased the apatite/matrix ratio and lowered that of carbonate in the nodules. Our results suggest that glucocorticoids are required for in vitro formation by osteoblasts of more mature calcified nodules containing apatite/phosphate.
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Abstract
Among the adverse events of glucocorticoid treatment are bone loss and fractures. Despite available, effective preventive measures, many patients receiving or initiating glucocorticoid therapy are not appropriately evaluated and treated for bone health and fracture risk. Populations with, or at risk of, glucocorticoid-induced osteoporosis (GIOP) to target for these measures are defined on the basis of dose and duration of glucocorticoid therapy and bone mineral density. That patients with GIOP should be treated as early as possible is generally agreed upon; however, diversity remains in intervention thresholds and management guidelines. The FRAX(®) algorithm provides a 10-year probability of fracture that can be adjusted according to glucocorticoid dose. There is no evidence that GIOP and postmenopausal osteoporosis respond differently to treatments. Available anti-osteoporotic therapies such as anti-resorptives including bisphosphonates and the bone anabolic agent teriparatide are effective for the management of GIOP. Prevention with calcium and vitamin D supplementation is less effective than specific anti-osteoporotic treatment. Anti-osteoporotic treatment should be stopped at the time of glucocorticoid cessation, unless the patient remains at increased risk of fracture.
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20
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Malan J, Ettinger K, Naumann E, Beirne OR. The relationship of denosumab pharmacology and osteonecrosis of the jaws. Oral Surg Oral Med Oral Pathol Oral Radiol 2013; 114:671-6. [PMID: 23159111 DOI: 10.1016/j.oooo.2012.08.439] [Citation(s) in RCA: 50] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2012] [Revised: 07/09/2012] [Accepted: 08/06/2012] [Indexed: 01/06/2023]
Abstract
Denosumab is a new bone antiresorptive agent that has received approval by the Food and Drug Administration for use in patients with osteoporosis and metastatic cancer to the bones. Like the bisphosponates that are used as antiresorptive medications, denosumab has been associated with osteonecrosis of the jaws (ONJ). However, because the pharmacodynamics and pharmacokinetics of denosumab differ from that of the bisphosphonates, ONJ related to denosumab may resolve more rapidly with a drug holiday than bisphosphonate-related osteonecrosis of the jaws (BRONJ). This paper describes the management of a patient who developed ONJ while receiving denosumab, reviews the incidence of ONJ associated with denosumab, and compares the pharmacology of denosumab and the bisphosphonates. Because the effects of denosumab on bone turnover are more rapidly reversible than the effects of the bisphosphonates, ONJ related to denosumab may resolve more quickly with a drug holiday than BRONJ.
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21
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Engvall IL, Svensson B, Boonen A, van der Heijde D, Lerner UH, Hafstrom I. Low-dose prednisolone in early rheumatoid arthritis inhibits collagen type I degradation by matrix metalloproteinases as assessed by serum 1CTP--a possible mechanism for specific inhibition of radiological destruction. Rheumatology (Oxford) 2012; 52:733-42. [DOI: 10.1093/rheumatology/kes369] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023] Open
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22
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Tang Y, Xie H, Chen J, Geng L, Chen H, Li X, Hou Y, Lu L, Shi S, Zeng X, Sun L. Activated NF-κB in bone marrow mesenchymal stem cells from systemic lupus erythematosus patients inhibits osteogenic differentiation through downregulating Smad signaling. Stem Cells Dev 2012; 22:668-78. [PMID: 22897816 DOI: 10.1089/scd.2012.0226] [Citation(s) in RCA: 52] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
Osteoporosis in patients with systemic lupus erythematosus (SLE) is thought to be the result of accelerated osteoclastogenesis induced by pro-inflammatory cytokines such as tumor necrosis factor (TNF). However, the molecular mechanisms involved in the osteoblastogenesis in SLE patients are not fully understood. We investigated the bone morphogenetic protein-2 (BMP-2)-induced osteoblastic capacity of bone marrow-derived mesenchymal stem cells (BMMSCs) from SLE patients and the TNF signaling system in determining BMP-2-induced regulatory pathways. It showed that the capacity of osteogenic differentiation of BMMSCs from SLE patients was reduced compared with that from healthy controls. The nuclear factor κB (NF-κB) signaling was activated while the BMP/Smad pathway was repressed in BMMSCs from SLE patients. TNF activated NF-κB pathway and inhibited the phosphorylation of Smad 1/5/8 and BMP-2-induced osteoblastic differentiation in BMMSCs from normal controls, while addition of pyrollidine dithiocarbamate (PDTC), an NF-κB inhibitor, to SLE-BMMSCs could partially reverse these effects. Thus, our findings have shown that the activated NF-κB pathway in SLE-BMMSCs inhibits the BMP-2-induced osteoblastic differentiation through BMP/Smad signaling pathway, suggesting that the impaired osteoblastic differentiation may participate in the pathology of osteoporosis in SLE patients.
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Affiliation(s)
- Yu Tang
- Department of Rheumatology and Immunology, The Affiliated Drum Tower Hospital, Nanjing University Medical School, Nanjing, China
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Kaneko K, Kusunoki N, Hasunuma T, Kawai S. Changes of serum soluble receptor activator for nuclear factor-κB ligand after glucocorticoid therapy reflect regulation of its expression by osteoblasts. J Clin Endocrinol Metab 2012; 97:E1909-17. [PMID: 22791764 PMCID: PMC3462941 DOI: 10.1210/jc.2012-1971] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
CONTEXT Osteoporosis is a serious complication of systemic glucocorticoid therapy. The role of serum soluble receptor activator for nuclear factor-κB ligand (RANKL) in glucocorticoid-induced osteoporosis remains unclear. OBJECTIVE The objective of the study was to clarify the influence of serum soluble RANKL on the osteoprotegerin (OPG)/RANKL/receptor activator for nuclear factor-κB system in patients with systemic autoimmune diseases receiving glucocorticoid therapy. PATIENTS AND METHODS Sixty patients (40 women) with systemic autoimmune diseases who received initial glucocorticoid therapy with prednisolone (30-60 mg/d) plus bisphosphonate therapy were prospectively enrolled. Serum soluble RANKL and OPG levels were measured at 0, 1, 2, 3, and 4 wk after starting glucocorticoid therapy. The effects of dexamethasone on production of RANKL and OPG mRNA and protein by cultured normal human osteoblasts were evaluated by RT-PCR and ELISA, respectively. RESULTS The mean serum soluble RANKL level of the patients was unchanged by glucocorticoid therapy. Because the distribution of serum soluble RANKL was bimodal, the patients were stratified into two groups. Serum soluble RANKL decreased significantly in the higher soluble RANKL group (≥0.16 pmol/liter), whereas it increased significantly in the lower soluble RANKL group. The mean serum OPG level of the patients decreased significantly. Bone mineral density increased in the higher soluble RANKL group after starting glucocorticoid therapy, whereas it decreased in the lower soluble RANKL group. In cultures of unstimulated human osteoblasts, RANKL mRNA expression was increased and OPG mRNA was decreased by dexamethasone. Up-regulation of RANKL and OPG mRNA by IL-6 was suppressed by dexamethasone. CONCLUSION Serum soluble RANKL might be a useful marker of bone remodeling in patients with systemic autoimmune diseases receiving glucocorticoid therapy.
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Affiliation(s)
- Kaichi Kaneko
- Division of Rheumatology, Department of Internal Medicine, School of Medicine, Faculty of Medicine, Toho University, 6-11-1 Omori-Nishi, Ota-ku, Tokyo 143-8541, Japan
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Rizzoli R, Adachi JD, Cooper C, Dere W, Devogelaer JP, Diez-Perez A, Kanis JA, Laslop A, Mitlak B, Papapoulos S, Ralston S, Reiter S, Werhya G, Reginster JY. Management of glucocorticoid-induced osteoporosis. Calcif Tissue Int 2012; 91:225-43. [PMID: 22878667 DOI: 10.1007/s00223-012-9630-5] [Citation(s) in RCA: 54] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/22/2012] [Accepted: 05/29/2012] [Indexed: 01/05/2023]
Abstract
This review summarizes the available evidence-based data that form the basis for therapeutic intervention and covers the current status of glucocorticoid-induced osteoporosis (GIOP) management, regulatory requirements, and risk-assessment options. Glucocorticoids are known to cause bone loss and fractures, yet many patients receiving or initiating glucocorticoid therapy are not appropriately evaluated and treated. An European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis workshop was convened to discuss GIOP management and to provide a report by a panel of experts. An expert panel reviewed the available studies that discussed approved therapeutic agents, focusing on randomized and controlled clinical trials reporting on bone mineral density and/or fracture risk of at least 48 weeks' duration. There is no evidence that GIOP and postmenopausal osteoporosis respond differently to treatments. The FRAX algorithm can be adjusted according to glucocorticoid dose. Available antiosteoporotic therapies such as bisphosphonates and teriparatide are efficacious in GIOP management. Several other agents approved for the treatment of postmenopausal osteoporosis may become available for GIOP. It is advised to stop antiosteoporotic treatment after glucocorticoid cessation, unless the patient remains at increased risk of fracture. Calcium and vitamin D supplementation as an osteoporosis-prevention measure is less effective than specific antiosteoporotic treatment. Fracture end-point studies and additional studies investigating specific subpopulations (pediatric, premenopausal, or elderly patients) would strengthen the evidence base and facilitate the development of intervention thresholds and treatment guidelines.
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Affiliation(s)
- R Rizzoli
- Service of Bone Diseases, Geneva University Hospitals, Geneva, Switzerland.
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Sinningen K, Tsourdi E, Rauner M, Rachner TD, Hamann C, Hofbauer LC. Skeletal and extraskeletal actions of denosumab. Endocrine 2012; 42:52-62. [PMID: 22581255 DOI: 10.1007/s12020-012-9696-x] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/13/2012] [Accepted: 05/02/2012] [Indexed: 01/01/2023]
Abstract
Osteoclasts and osteoblasts define skeletal mass, structure and strength through their respective actions in resorbing and forming bone. This remodeling process is orchestrated by the actions of hormones and growth factors, which regulate a cytokine system comprising the receptor activator of nuclear factor κB ligand (RANKL), its receptor RANK and the soluble decoy receptor osteoprotegerin (OPG). Bone resorption depends on RANKL, which determines osteoclast formation, activity and survival. Importantly, cells of the osteoblastic lineage mainly provide RANKL and therefore, are central in the regulation of osteoclast functions. Catabolic effects of RANKL are inhibited by OPG, a TNF receptor family member that binds RANKL, thereby preventing the activation of its receptor RANK, which is expressed by osteoclast precursors. Because this cytokine network is pivotal for the regulation of bone mass in health and diseases, including osteoporosis, rheumatoid arthritis and malignant bone conditions, it has been successfully used for the generation of a targeted therapy to block osteoclast actions. The clinical approval of denosumab, a fully monoclonal antibody against RANKL, provides a novel option to treat bone diseases with a potent, targeted and reversible inhibitor of bone resorption. Although RANKL is also expressed by endothelial cells, T lymphocytes, synovial fibroblasts and various tumor cells, no meaningful clinical extraskeletal effects have been reported after administration of denosumab. This article summarizes the molecular and cellular basis of the RANKL/RANK/OPG system and presents preclinical and clinical studies on the skeletal actions of denosumab.
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Affiliation(s)
- Kathrin Sinningen
- Division of Endocrinology, Diabetes, and Bone Diseases, Department of Medicine III, Technical University Medical Center, Fetscherstr. 74, 01307, Dresden, Germany.
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Abstract
Long-term corticosteroid treatment is the most common secondary cause of bone loss. Patients treated with long-term corticosteroid therapy may develop osteopenia or osteoporosis, and many have fractures. It is difficult to predict which corticosteroid-treated patients will develop significant skeletal complications because of variability in the underlying diseases treated with corticosteroids, and because of variation in corticosteroid dose over time. Corticosteroid therapy causes an alteration in the ratio between osteoprotegerin (OPG) and receptor activator of nuclear factor κ B (RANK) ligand (RANKL), which leads to early increased bone resorption for the first 3-6 months, with long-term treatment leading primarily to suppression of bone formation. Recently published recommendations advise the use of bisphosphonates or teriparatide in high-risk patients, depending on fracture risk assessed by bone mineral density testing. This article gives an update of current knowledge regarding the pathophysiology, clinical presentation and evaluation, and prevention and treatment of patients with corticosteroid-induced osteoporosis.
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Baek ST, Tallquist MD. Nf1 limits epicardial derivative expansion by regulating epithelial to mesenchymal transition and proliferation. Development 2012; 139:2040-9. [PMID: 22535408 DOI: 10.1242/dev.074054] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
The epicardium is the primary source of coronary vascular smooth muscle cells (cVSMCs) and fibroblasts that reside in the compact myocardium. To form these epicardial-derived cells (EPDCs), the epicardium undergoes the process of epithelial to mesenchymal transition (EMT). Although several signaling pathways have been identified that disrupt EMT, no pathway has been reported that restricts this developmental process. Here, we identify neurofibromin 1 (Nf1) as a key mediator of epicardial EMT. To determine the function of Nf1 during epicardial EMT and the formation of epicardial derivatives, cardiac fibroblasts and cVSMCs, we generated mice with a tissue-specific deletion of Nf1 in the epicardium. We found that mutant epicardial cells transitioned more readily to mesenchymal cells in vitro and in vivo. The mesothelial epicardium lost epithelial gene expression and became more invasive. Using lineage tracing of EPDCs, we found that the process of EMT occurred earlier in Nf1 mutant hearts, with an increase in epicardial cells entering the compact myocardium. Moreover, loss of Nf1 caused increased EPDC proliferation and resulted in more cardiac fibroblasts and cVSMCs. Finally, we were able to partially reverse the excessive EMT caused by loss of Nf1 by disrupting Pdgfrα expression in the epicardium. Conversely, Nf1 activation was able to inhibit PDGF-induced epicardial EMT. Our results demonstrate a regulatory role for Nf1 during epicardial EMT and provide insights into the susceptibility of patients with disrupted NF1 signaling to cardiovascular disease.
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Affiliation(s)
- Seung Tae Baek
- Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390-9148, USA
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Smith CL, Baek ST, Sung CY, Tallquist MD. Epicardial-derived cell epithelial-to-mesenchymal transition and fate specification require PDGF receptor signaling. Circ Res 2011; 108:e15-26. [PMID: 21512159 PMCID: PMC3134964 DOI: 10.1161/circresaha.110.235531] [Citation(s) in RCA: 260] [Impact Index Per Article: 18.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/28/2010] [Accepted: 04/12/2011] [Indexed: 01/06/2023]
Abstract
RATIONALE In early heart development, platelet-derived growth factor (PDGF) receptor expression in the heart ventricles is restricted to the epicardium. Previously, we showed that PDGFRβ is required for coronary vascular smooth muscle cell (cVSMC) development, but a role for PDGFRα has not been identified. Therefore, we investigated the combined and independent roles of these receptors in epicardial development. OBJECTIVE To understand the contribution of PDGF receptors in epicardial development and epicardial-derived cell fate determination. METHODS AND RESULTS By generating mice with epicardial-specific deletion of the PDGF receptors, we found that epicardial epithelial-to-mesenchymal transition (EMT) was defective. Sox9, an SRY-related transcription factor, was reduced in PDGF receptor-deficient epicardial cells, and overexpression of Sox9 restored epicardial migration, actin reorganization, and EMT gene expression profiles. The failure of epicardial EMT resulted in hearts that lacked epicardial-derived cardiac fibroblasts and cVSMC. Loss of PDGFRα resulted in a specific disruption of cardiac fibroblast development, whereas cVSMC development was unperturbed. CONCLUSIONS Signaling through both PDGF receptors is necessary for epicardial EMT and formation of epicardial-mesenchymal derivatives. PDGF receptors also have independent functions in the development of specific epicardial-derived cell fates.
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Affiliation(s)
- Christopher L Smith
- Department of Molecular Biology, MC9148, University of Texas Southwestern Medical Center, Dallas, TX 75390-9148, USA
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van Lierop AHJM, Hamdy NAT, Papapoulos SE. Glucocorticoids are not always deleterious for bone. J Bone Miner Res 2010; 25:2796-800. [PMID: 20549703 DOI: 10.1002/jbmr.151] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
A 23-year-old man with the rare sclerosing bone disorder van Buchem disease presented with progressively worsening headaches that eventually became persistent and associated with papilledema. Increased intracranial pressure was diagnosed, and the patient had a ventriculoperitoneal drain inserted as well as simultaneously receiving treatment with prednisone. Before starting treatment, there was biochemical evidence for increased bone turnover and for steady increases in bone mineral density (BMD) at the spine and total hip despite the patient having reached his peak height of 197 cm at the age of 19 years. Treatment with prednisone for 2 years resulted in biochemical and histologic suppression of bone formation as well as of bone resorption and arrest of further bone accumulation. Our data suggest that glucocorticoids (GCs) may represent an attractive alternative to the high-risk surgical approaches used in the management of patients with progressive sclerosing bone disorders. Our findings also suggest that whereas sclerostin may not be required for the action of GCs on bone formation, it may well be important for the action of GCs on bone resorption. The exact mechanism by which sclerostin may be involved in the regulation of bone resorption is as yet to be explored.
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Affiliation(s)
- Antoon H J M van Lierop
- Department of Endocrinology and Metabolic Diseases, Leiden University Medical Center, Leiden, The Netherlands
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Quinlivan R, Shaw N, Bushby K. 170th ENMC International Workshop: Bone protection for corticosteroid treated Duchenne muscular dystrophy. 27–29 November 2009, Naarden, The Netherlands. Neuromuscul Disord 2010; 20:761-9. [DOI: 10.1016/j.nmd.2010.07.272] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2010] [Revised: 07/04/2010] [Accepted: 07/08/2010] [Indexed: 01/06/2023]
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Eriksen CG, Olsen H, Husted LB, Sørensen L, Carstens M, Søballe K, Langdahl BL. The expression of IL-6 by osteoblasts is increased in healthy elderly individuals: stimulated proliferation and differentiation are unaffected by age. Calcif Tissue Int 2010; 87:414-23. [PMID: 20820764 DOI: 10.1007/s00223-010-9412-x] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/09/2009] [Accepted: 07/19/2010] [Indexed: 01/06/2023]
Abstract
Increasing age is associated with reduced bone mineral content and increased risk of fractures. This is caused by a relative insufficiency of osteoblasts compared with osteoclasts. We therefore wanted to examine the potential differences in proliferation, differentiation, and expression of cytokines between human osteoblasts (hOBs) obtained from young and elderly individuals. Cultures of hOBs were obtained from 11 elderly (73-85 years) and 15 young (21-27 years) healthy individuals. The cells were stimulated with hGH, IGF-I, hGH + IGF-I, and TGF-β1. Proliferation was evaluated by thymidine incorporation, and differentiation was evaluated by alkaline phosphatase, OPG, and PINP production. Expression of IL-6, TGF-β1, OPG, and RANKL was investigated using real-time PCR and three carefully selected housekeeping genes. Combined stimulation with hGH and IGF-I increased proliferation without differences between hOBs obtained from young and elderly individuals. hOBs from young individuals responded to stimulation with vitamin D with a more pronounced increase in alkaline phosphatase: 107 ± 17% vs. 43 ± 5%, P < 0.01. Stimulation with TGF-β1 decreased OPG production by hOBs from elderly individuals but not from young individuals, P < 0.05. hOBs from elderly individuals expressed significantly higher amounts of IL-6 mRNA (P < 0.05) and less OPG and TGF-β1 mRNA (P = 0.08 and P = 0.08, respectively) compared with hOBs from young individuals. In conclusion, hOBs from elderly individuals express more IL-6 mRNA and less OPG and TGF-β1 mRNA than hOBs from young individuals. This could partly explain the reduced bone mass and increased fracture risk seen in the elderly. hOBs from young and elderly individuals responded similarly to short-term stimulation of proliferation and differentiation.
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Affiliation(s)
- Charlotte Grith Eriksen
- Department of Endocrinology and Internal Medicine, Aarhus University Hospital, 8000, Aarhus C, Denmark
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Chen CH, Chen HA, Liao HT, Liu CH, Tsai CY, Chou CT. Soluble receptor activator of nuclear factor-kappaB ligand (RANKL) and osteoprotegerin in ankylosing spondylitis: OPG is associated with poor physical mobility and reflects systemic inflammation. Clin Rheumatol 2010; 29:1155-61. [PMID: 20690034 DOI: 10.1007/s10067-010-1543-y] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2010] [Revised: 06/07/2010] [Accepted: 07/22/2010] [Indexed: 01/06/2023]
Abstract
The objective of the study was to investigate the role of receptor activator of nuclear factor-kappaB ligand (RANKL) and osteoprotegerin (OPG) in ankylosing spondylitis (AS). Serum levels of soluble RANKL (sRANKL) and OPG were measured in 42 AS patients and 26 healthy controls. We evaluated the AS patient's disease activity, functional ability, global assessment, and physical mobility and tested markers of systemic inflammation, erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP) levels. Serum levels of sRANKL [mean (SD), 4.75 (1.88) vs. 3.70 (1.14) pmol/l, p = 0.015] and OPG [mean (SD), 5.18 (1.19) vs. 4.52 (0.85) pmol/l, p = 0.026] were significantly higher in the 42 AS patients than the 26 healthy controls. Interestingly, serum OPG levels correlated significantly with ESR (r = 0.417, p = 0.007), CRP (r = 0.524, p < 0.001), tragus-to-wall distance (r = 0.556, p < 0.001), fingertip-to-floor distance (r = 0.423, p = 0.007), and occiput-to-wall distance (r = 0.465, p = 0.002) and correlated inversely with modified Schober index (r = -0.525, p = 0.001), cervical rotation (r = -0.403, p = 0.022), lateral lumbar flexion (r = -0.587, p < 0.001), and chest expansion (r = -0.553, p < 0.001). Moreover, in the AS patients with higher (> or =4.925 pmol/l, n = 21) serum OPG levels, there were significant increases in the tragus-to-wall distance (p = 0.007), fingertip-to-floor distance (p = 0.023), and CRP levels (p = 0.014) and decreased in the modified Schober index (p = 0.012), lateral lumbar flexion (p = 0.019), and chest expansion (p = 0.005). Serum levels of sRANKL and OPG are increased in the AS patients and may participate in the disease process of AS. Production of OPG has association with poor physical mobility and may reflect systemic inflammation in AS.
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Affiliation(s)
- Chun-Hsiung Chen
- Division of Allergy, Immunology and Rheumatology, Buddhist Tzu Chi General Hospital, Taipei Branch, Taipei, Taiwan
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Byron CR, Barger AM, Stewart AA, Pondenis HC, Fan TM. In vitro expression of receptor activator of nuclear factor-kappaB ligand and osteoprotegerin in cultured equine articular cells. Am J Vet Res 2010; 71:615-22. [PMID: 20513175 DOI: 10.2460/ajvr.71.6.615] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
OBJECTIVE To determine concentrations of receptor activator of nuclear factor-kappaB ligand (RANKL) and osteoprotegerin (OPG) in equine chondrocytes and synoviocytes and to quantify changes in the OPG:RANKL ratio in response to exogenous factors. SAMPLE POPULATION Samples of articular cartilage and synovium with grossly normal appearance obtained from metacarpophalangeal and metatarsophalangeal joints of 5 adult (1- to 8-year-old) horses. PROCEDURES Cell cultures of chondrocytes and synoviocytes were incubated with human recombinant interleukin-1beta (hrIL-1beta; 10 ng/mL), lipopolysaccharide (LPS; 10 microg/mL), or dexamethasone (100nM) for 48 hours. Negative control cultures received no treatment. Cells and spent media were assayed for RANKL and OPG concentrations by use of western blot and immunocytochemical analyses. Spent media were also assayed for OPG concentration by use of an ELISA. RESULTS RANKL and OPG were expressed in equine chondrocytes and synoviocytes in vitro. Cell-associated RANKL and OPG concentrations were not impacted by exogenous factors. Soluble RANKL release into media was significantly increased by hrIL-1beta in chondrocyte but not in synoviocyte cultures. Soluble OPG release into media was significantly increased by hrIL-1beta and LPS in chondrocyte but not in synoviocyte cultures. The soluble OPG:RANKL ratio was significantly increased by LPS in chondrocyte cultures. Dexamethasone decreased OPG expression in synoviocytes. CONCLUSIONS AND CLINICAL RELEVANCE RANKL and OPG proteins were expressed in equine articular cells. Release of these proteins may affect osteoclastogenesis within adjacent subchondral bone. Thus, RANKL and OPG may have use as biomarkers and treatment targets in horses with joint disease.
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Affiliation(s)
- Christopher R Byron
- Department of Veterinary Clinical Medicine, College of Veterinary Medicine, University of Illinois, Urbana, IL 61801, USA.
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Ibañez M, Ortiz AM, Castrejón I, García-Vadillo JA, Carvajal I, Castañeda S, González-Alvaro I. A rational use of glucocorticoids in patients with early arthritis has a minimal impact on bone mass. Arthritis Res Ther 2010; 12:R50. [PMID: 20331862 PMCID: PMC2888199 DOI: 10.1186/ar2961] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2009] [Revised: 11/20/2009] [Accepted: 03/23/2010] [Indexed: 01/01/2023] Open
Abstract
Introduction Glucocorticoid (GC)-induced osteoporosis is a frequent complication in patients with rheumatoid arthritis. However, little information exists about the consequences of GC use in patients with early arthritis. Here we describe the variables underlying the use of GC in early arthritis, as well as its effect on bone-mineral density. Methods Data from 116 patients in our early arthritis register were analyzed (90 women; median age, 52.5 years, interquartile range (IQR, 38.5-66); 6-month median disease duration at entry (IQR, 4-9)). In this register, the clinical and treatment information was recorded systematically, including the cumulative GC dose. Lumbar spine, hip, and forearm bone-mineral density (BMD) measurements were performed at entry and after a 2-year follow-up. A multivariate analysis was performed to establish the variables associated with the use of GCs, as well as those associated with variations in BMD. Results Of the patients with early arthritis studied, 67% received GCs during the 2-year follow-up. GCs were more frequently prescribed to elderly patients, those with higher basal disease activity and disability, and patients with positive rheumatoid factor. When adjusted for these variables, GCs were less frequently prescribed to female patients. The use of GCs was associated with an increase of BMD in the ultradistal region of the forearm, although it induced a significant loss of BMD in the medial region of the forearm. No relevant effect of GC was noted on the BMD measured at other locations. Conclusions The frequent use of GCs as a "bridge therapy" in patients with early arthritis does not seem to be associated with relevant loss of bone mass. Moreover, cumulative GC administration might be associated with an increase of juxtaarticular BMD.
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Affiliation(s)
- Monica Ibañez
- Rheumatology Department, Hospital Son Llàtzer, Carretera Manacor km, 4, Palma de Mallorca, 07198, Spain
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Oelzner P, Fleissner-Richter S, Bräuer R, Hein G, Wolf G, Neumann T. Combination therapy with dexamethasone and osteoprotegerin protects against arthritis-induced bone alterations in antigen-induced arthritis of the rat. Inflamm Res 2010; 59:731-41. [DOI: 10.1007/s00011-010-0184-6] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2009] [Revised: 01/22/2010] [Accepted: 03/01/2010] [Indexed: 01/06/2023] Open
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Camozzi V, Sanguin F, Albigier N, Scaroni C, Mantero F, Zaninotto M, Frigo A, Piccolo M, Luisetto G. Persistent increase of osteoprotegerin levels after cortisol normalization in patients with Cushing's syndrome. Eur J Endocrinol 2010; 162:85-90. [PMID: 19793762 DOI: 10.1530/eje-09-0800] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
OBJECTIVE Osteoprotegerin (OPG) has been identified as a decoy receptor that inhibits osteoclast differentiation and, more recently, as a paracrine regulator of vascular calcification. OPG is suppressed by glucocorticoids (GC); however, results from experimental and clinical studies are not univocal. The aim of this study was to evaluate OPG and bone metabolism in patients with Cushing's syndrome (CS) before and after cure. DESIGN AND METHODS Twenty-six patients with CS (all women, mean age: 39.1+/-11.9 years) and 24 age- and gonadal status-matched healthy women were studied for bone mineral density, bone metabolism, OPG, and receptor activator of nuclear factor-kB ligand at baseline. Twelve patients were also studied 6-18 months after surgery, with persistent normalization of cortisol levels. RESULTS OPG was significantly higher and osteocalcin (OC) was significantly lower in CS patients than in controls (OPG: 4.17+/-1.23 vs 2.95+/-0.79 pmol/l, P=0.00001; OC: 15.0+/-6.1 vs 18.8+/-6.8 ng/ml, P=0.04 in CS and controls respectively). After cure, we found no difference in OPG levels, despite a significant increase in OC levels (from 16.4+/-11 to 37.2+/-15 ng/ml, P=0.03). CONCLUSION Patients with CS showed increased OPG serum levels that remained unchanged after recovery, despite a restoration of bone formation. We speculate that high levels of OPG could reflect the persistent damage of the GCs on cardiovascular system.
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Affiliation(s)
- Valentina Camozzi
- Division of Endocrinology, Department of Medical and Surgical Sciences, University of Padova, Padova, Italy
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Ohlsson C, Mohan S, Sjögren K, Tivesten A, Isgaard J, Isaksson O, Jansson JO, Svensson J. The role of liver-derived insulin-like growth factor-I. Endocr Rev 2009; 30:494-535. [PMID: 19589948 PMCID: PMC2759708 DOI: 10.1210/er.2009-0010] [Citation(s) in RCA: 309] [Impact Index Per Article: 19.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/11/2009] [Accepted: 07/01/2009] [Indexed: 02/08/2023]
Abstract
IGF-I is expressed in virtually every tissue of the body, but with much higher expression in the liver than in any other tissue. Studies using mice with liver-specific IGF-I knockout have demonstrated that liver-derived IGF-I, constituting a major part of circulating IGF-I, is an important endocrine factor involved in a variety of physiological and pathological processes. Detailed studies comparing the impact of liver-derived IGF-I and local bone-derived IGF-I demonstrate that both sources of IGF-I can stimulate longitudinal bone growth. We propose here that liver-derived circulating IGF-I and local bone-derived IGF-I to some extent have overlapping growth-promoting effects and might have the capacity to replace each other (= redundancy) in the maintenance of normal longitudinal bone growth. Importantly, and in contrast to the regulation of longitudinal bone growth, locally derived IGF-I cannot replace (= lack of redundancy) liver-derived IGF-I for the regulation of a large number of other parameters including GH secretion, cortical bone mass, kidney size, prostate size, peripheral vascular resistance, spatial memory, sodium retention, insulin sensitivity, liver size, sexually dimorphic liver functions, and progression of some tumors. It is clear that a major role of liver-derived IGF-I is to regulate GH secretion and that some, but not all, of the phenotypes in the liver-specific IGF-I knockout mice are indirect, mediated via the elevated GH levels. All of the described multiple endocrine effects of liver-derived IGF-I should be considered in the development of possible novel treatment strategies aimed at increasing or reducing endocrine IGF-I activity.
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Affiliation(s)
- Claes Ohlsson
- Division of Endocrinology, Institute of Medicine, Sahlgrenska University Hospital, Göteborg, Sweden.
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Hofbauer LC, Zeitz U, Schoppet M, Skalicky M, Schüler C, Stolina M, Kostenuik PJ, Erben RG. Prevention of glucocorticoid-induced bone loss in mice by inhibition of RANKL. ACTA ACUST UNITED AC 2009; 60:1427-37. [PMID: 19404943 DOI: 10.1002/art.24445] [Citation(s) in RCA: 91] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
OBJECTIVE RANKL has been implicated in the pathogenesis of glucocorticoid-induced osteoporosis. This study was undertaken to evaluate the efficacy of denosumab, a neutralizing monoclonal antibody against human RANKL (hRANKL), in a murine model of glucocorticoid-induced osteoporosis. METHODS Eight-month-old male homozygous hRANKL-knockin mice expressing a chimeric RANKL protein with a humanized exon 5 received 2.1 mg/kg of prednisolone or placebo daily over 4 weeks via subcutaneous slow-release pellets and were additionally treated with phosphate buffered saline or denosumab (10 mg/kg subcutaneously twice weekly). Two groups of wild-type mice were also treated with either prednisolone or vehicle. RESULTS The 4-week prednisolone treatment induced loss of vertebral and femoral volumetric bone mineral density in the hRANKL-knockin mice. Glucocorticoid-induced bone loss was associated with suppressed vertebral bone formation and increased bone resorption, as evidenced by increases in the number of tartrate-resistant acid phosphatase (TRAP)-positive osteoclasts, TRAP-5b protein in bone extracts, serum levels of TRAP-5b, and urinary excretion of deoxypyridinoline. Denosumab prevented prednisolone-induced bone loss by a pronounced antiresorptive effect. Biomechanical compression tests of lumbar vertebrae revealed a detrimental effect of prednisolone on bone strength that was prevented by denosumab. CONCLUSION Our findings indicate that RANKL inhibition by denosumab prevents glucocorticoid-induced loss of bone mass and strength in hRANKL-knockin mice.
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Affiliation(s)
- Lorenz C Hofbauer
- Department of Medicine III, University Hospital Carl Gustav Carus, Technical University of Dresden, Dresden, Germany.
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Haeck IM, Hamdy NAT, Timmer-de Mik L, Lentjes EGWM, Verhaar HJJ, Knol MJ, de Bruin-Weller MS, Bruijnzeel-Koomen CAFM. Low bone mineral density in adult patients with moderate to severe atopic dermatitis. Br J Dermatol 2009; 161:1248-54. [PMID: 19673879 DOI: 10.1111/j.1365-2133.2009.09327.x] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
BACKGROUND Atopic dermatitis (AD) is a chronic inflammatory skin disease commonly treated with topical corticosteroids. The inflammatory nature of this disorder and the use of topical corticosteroids represent potential risk factors for bone loss. OBJECTIVES The aim was to assess the prevalence of osteoporosis and osteopenia in adult patients with moderate to severe AD. In addition, the associations between topical/oral corticosteroid use and bone mineral density (BMD) and between disease activity and BMD were studied. PATIENTS AND METHODS We studied 125 adult patients with moderate to severe AD. Using dual-energy X-ray absorptiometry, BMD was measured at lumbar spine and hips. The cumulative dose of topical and oral corticosteroids was calculated from pharmacy prescription records. Lifestyle parameters were collected by a questionnaire. Biochemical parameters of bone metabolism and disease activity [serum concentration of thymus and activation-regulated chemokine (TARC) levels] were also measured. RESULTS Osteoporosis was documented in six patients (4.8%) and osteopenia in 41 patients (32.8%); 30.4% of the patients had a Z-score <or= -1 (low BMD), with more men (43.8%) than women (16.4%) affected. There was no significant association between low BMD and biochemical parameters of bone metabolism, serum TARC levels and cumulative dose of topical and oral corticosteroids during the 5 years prior to inclusion. CONCLUSIONS We document a Z-score <or= -1 in about one-third of predominantly male patients with moderate to severe AD, being independent of the cumulative dose of topical and corticosteroids used within 5 years prior to study. Whether the relatively high prevalence of low BMD is due to the cumulative dose of topical corticosteroids beyond 5 years prior to the study or the chronicity of the underlying inflammatory process or a combination of these, remains to be established.
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Affiliation(s)
- I M Haeck
- Department of Dermatology and Allergology, University Medical Center Utrecht, Inhouse postnumber G02.124, Utrecht, the Netherlands.
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Tyrovola JB, Spyropoulos MN, Makou M, Perrea D. Root resorption and the OPG/RANKL/RANK system: a mini review. J Oral Sci 2009; 50:367-76. [PMID: 19106463 DOI: 10.2334/josnusd.50.367] [Citation(s) in RCA: 85] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/01/2022]
Abstract
Odontoclastic root resorption is a significant clinical issue in relation to orthodontic tooth movement, and resorption of the roots of primary teeth is an intriguing biological phenomenon. The functional coordination of the OPG/RANKL/RANK system seems to contribute not only to alveolar remodeling, but also to resorption during orthodontic tooth movement and physiological root resorption. Serum OPG and s-RANKL are related to regulation of bone homeostasis by the OPG/RANKL/RANK system, and determination of their concentrations might be useful for predicting the rate of bone remodeling during orthodontic tooth movement, the net effect between bone remodeling and root resorption, and the degree of root resorption. It is therefore rational to speculate that a study of the levels of OPG and s-RANKL in blood and GCF, in relation to the degree of root resorption during orthodontic tooth movement, using healthy experimental animals and a carefully planned and organized experimental design, may be able to answer this intriguing question.
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Affiliation(s)
- Joanna B Tyrovola
- Department of Orthodontics, School of Dentistry, University of Athens, Athens, Greece.
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Leibbrandt A, Penninger JM. RANK/RANKL: regulators of immune responses and bone physiology. Ann N Y Acad Sci 2009; 1143:123-50. [PMID: 19076348 DOI: 10.1196/annals.1443.016] [Citation(s) in RCA: 303] [Impact Index Per Article: 18.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Bone-related diseases, such as osteoporosis and rheumatoid arthritis, affect hundreds of millions of people worldwide and pose a tremendous burden to health care. By deepening our understanding of the molecular mechanisms of bone metabolism and bone turnover, it became possible over the past years to devise new and promising strategies for treating such diseases. In particular, three tumor necrosis factor (TNF) family molecules, the receptor activator of NF-kappaB (RANK), its ligand RANKL, and the decoy receptor of RANKL, osteoprotegerin (OPG), have attracted the attention of scientists and pharmaceutical companies alike. Genetic experiments revolving around these molecules established their pivotal role as central regulators of osteoclast development and osteoclast function. RANK-RANKL signaling not only activates a variety of downstream signaling pathways required for osteoclast development, but crosstalk with other signaling pathways also fine-tunes bone homeostasis both in normal physiology and disease. In addition, RANKL and RANK have essential roles in lymph node formation, establishment of the thymic microenvironment, and development of a lactating mammary gland during pregnancy. Consequently, novel drugs specifically targeting RANK, RANKL, and their signaling pathways in osteoclasts are expected to revolutionize the treatment of various ailments associated with bone loss, such as arthritis, periodontal disease, cancer metastases, and osteoporosis.
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Affiliation(s)
- Andreas Leibbrandt
- IMBA, Institute for Molecular Biotechnology of the Austrian Academy of Sciences, Vienna, Austria
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RANK(L) as a Key Target for Controlling Bone Loss. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2009; 647:130-45. [DOI: 10.1007/978-0-387-89520-8_9] [Citation(s) in RCA: 31] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
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Kearns AE, Khosla S, Kostenuik PJ. Receptor activator of nuclear factor kappaB ligand and osteoprotegerin regulation of bone remodeling in health and disease. Endocr Rev 2008; 29:155-92. [PMID: 18057140 PMCID: PMC2528846 DOI: 10.1210/er.2007-0014] [Citation(s) in RCA: 567] [Impact Index Per Article: 33.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/25/2007] [Accepted: 11/15/2007] [Indexed: 12/13/2022]
Abstract
Osteoclasts and osteoblasts dictate skeletal mass, structure, and strength via their respective roles in resorbing and forming bone. Bone remodeling is a spatially coordinated lifelong process whereby old bone is removed by osteoclasts and replaced by bone-forming osteoblasts. The refilling of resorption cavities is incomplete in many pathological states, which leads to a net loss of bone mass with each remodeling cycle. Postmenopausal osteoporosis and other conditions are associated with an increased rate of bone remodeling, which leads to accelerated bone loss and increased risk of fracture. Bone resorption is dependent on a cytokine known as RANKL (receptor activator of nuclear factor kappaB ligand), a TNF family member that is essential for osteoclast formation, activity, and survival in normal and pathological states of bone remodeling. The catabolic effects of RANKL are prevented by osteoprotegerin (OPG), a TNF receptor family member that binds RANKL and thereby prevents activation of its single cognate receptor called RANK. Osteoclast activity is likely to depend, at least in part, on the relative balance of RANKL and OPG. Studies in numerous animal models of bone disease show that RANKL inhibition leads to marked suppression of bone resorption and increases in cortical and cancellous bone volume, density, and strength. RANKL inhibitors also prevent focal bone loss that occurs in animal models of rheumatoid arthritis and bone metastasis. Clinical trials are exploring the effects of denosumab, a fully human anti-RANKL antibody, on bone loss in patients with osteoporosis, bone metastasis, myeloma, and rheumatoid arthritis.
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Affiliation(s)
- Ann E Kearns
- Endocrine Research Unit, Mayo Clinic College of Medicine, 200 First Street SW, Rochester, MN 55905, USA
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Abstract
Osteopenia and periarticular bony erosion are consequences of chronic inflammatory autoimmune disease due to an imbalance of osteoclast activity relative to new bone formation. Osteoclasts, which are specialized as the only bone resorbing cell type, are differentiated from hematopoietic myeloid precursor cells. Inflammatory signals mediated by multiple types of immune cells and cytokines have significant influence over osteoclast differentiation and function through direct effects on osteoclast precursors and indirect effects via osteoblasts and other cells in the bony microenvironment including synovial cells, stromal cells, osteocytes and chondrocytes. Recent studies have demonstrated that osteoclasts themselves express a number of immune receptors and are regulated similarly to macrophages and dendritic cells, closely related cells in the innate immune system. Though we are only beginning to understand the roles of innate immune receptors in osteoclasts, some of these receptors have been shown to be critical regulators of differentiation and function of osteoclasts. Osteoclasts likely function as the innate immune cells of the bone, thus are highly regulated to appropriately respond to stress and inflammatory changes in their microenvironment.
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Affiliation(s)
- Yalei Wu
- Department of Medicine, University of California, San Francisco, CA, USA
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Weenig RH. Pathogenesis of calciphylaxis: Hans Selye to nuclear factor kappa-B. J Am Acad Dermatol 2008; 58:458-71. [PMID: 18206262 DOI: 10.1016/j.jaad.2007.12.006] [Citation(s) in RCA: 114] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2007] [Revised: 11/30/2007] [Accepted: 12/04/2007] [Indexed: 01/06/2023]
Abstract
The clinical syndrome of calciphylaxis is characterized by arteriolar medial calcification, thrombotic cutaneous ischemia, necrotic skin ulceration, and a high mortality rate. This review integrates calciphylaxis risk factors with the molecular processes governing osseous and extraosseous mineralization. As the pathogenesis of calciphylaxis is better understood, targeted therapies aimed at disease prevention and reversal will follow.
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Affiliation(s)
- Roger H Weenig
- Department of Dermatology, Mayo Clinic, Rochester, Minnesota 55905, USA.
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Zhao B, Takami M, Miyamoto Y, Suzawa T, Yamada A, Mochizuki A, Yasuhara R, Wang X, Inoue T, Namiki O, Sakamoto K, Kamijo R. Characterization of synovial cell clones isolated from rheumatoid arthritis patients: Possible involvement of TNF-α in reduction of osteoprotegerin in synovium. Cytokine 2008; 41:61-70. [DOI: 10.1016/j.cyto.2007.10.013] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2007] [Revised: 10/26/2007] [Accepted: 10/31/2007] [Indexed: 01/06/2023]
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Haaber J, Abildgaard N, Knudsen LM, Dahl IM, Lodahl M, Thomassen M, Kerndrup GB, Rasmussen T. Myeloma cell expression of 10 candidate genes for osteolytic bone disease. Only overexpression of DKK1 correlates with clinical bone involvement at diagnosis. Br J Haematol 2007; 140:25-35. [PMID: 18005268 DOI: 10.1111/j.1365-2141.2007.06871.x] [Citation(s) in RCA: 17] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
Osteolytic bone disease (OBD) in multiple myeloma (MM) is caused by interactions between MM cells and the bone marrow microenvironment and is characterized by increased osteoclastic bone resorption and decreased osteoblastic bone formation. Recently, the role of osteoblast inhibition has come into focus, especially the possible role of overexpression of DKK1, an inhibitor of the Wnt signalling pathway. Further, CKS2, PSME2 and DHFR have also been reported as candidate genes for OBD. We studied the gene expression by quantitative reverse transcription polymerase chain reaction of TNFSF11 (RANKL), TNFSF11A (RANK), TNFRSF11B (OPG), CCL3 (MIP1A), CCL4 (MIP1B), PTHR1 (PTHrp), DKK1, CKS2, PSME2 and DHFR in purified, immunophenotypic FACS-sorted plasma cells from 171 newly diagnosed MM patients, 20 patients with monoclonal gammopathy of undetermined significance and 12 controls. The gene expressions of the analysed genes were correlated with radiographically assessed OBD. Only overexpression of DKK1 was correlated to the degree of OBD. Myeloma cells did not express TNFSF11A, TNFSF11, or TNFRSF11B, and very rarely expressed CCL3 and PTHR11. CCL4, CKS2, PSME2 and DHFR were variably expressed, but the expression of these genes showed no correlation with OBD. In contrast, loss of PSME2 expression in MM plasma cells was significantly correlated with OBD.
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Affiliation(s)
- Jacob Haaber
- Department of Pathology, Odense University Hospital, Odense, Denmark.
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Poulsen RC, Wolber FM, Moughan PJ, Kruger MC. Long chain polyunsaturated fatty acids alter membrane-bound RANK-L expression and osteoprotegerin secretion by MC3T3-E1 osteoblast-like cells. Prostaglandins Other Lipid Mediat 2007; 85:42-8. [PMID: 18077200 DOI: 10.1016/j.prostaglandins.2007.10.004] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2007] [Revised: 06/26/2007] [Accepted: 10/25/2007] [Indexed: 12/11/2022]
Abstract
Inflammation triggers an increase in osteoclast (bone resorbing cell) number and activity. Osteoclastogenesis is largely controlled by a triad of proteins consisting of a receptor (RANK), a ligand (RANK-L) and a decoy receptor (osteoprotegerin, OPG). Whilst RANK is expressed by osteoclasts, RANK-L and OPG are expressed by osteoblasts. The long chain polyunsaturated fatty acid (LCPUFA) arachidonic acid (AA, 20:4n-6) and its metabolite prostaglandin E2 (PGE2), are pro-inflammatory and PGE2 is a potent stimulator of RANKL expression. Various LCPUFAs such as eicosapentaenoic acid (EPA, 20:5n-3), docosahexaenoic acid (DHA, 22:6n-3) and gamma-linolenic acid (GLA, 18:3n-6) have anti-inflammatory activity. We aimed to determine if AA itself can stimulate RANKL expression and whether EPA, DHA and GLA inhibit RANKL expression in osteoblasts. MC3T3-E1/4 osteoblast-like cells were cultured under standard conditions with each of the LCPUFAs (5microg/ml) for 48h. Membrane-bound RANKL expression was measured by flow cytometry and OPG secretion measured by ELISA. In a second experiment, RANKL expression in MC3T3-E1/4 cells was stimulated by PGE2 treatment and the effect of EPA, DHA and GLA on membrane-bound RANKL expression and OPG secretion determined. The percentage of RANKL-positive cells was higher (p<0.05) than controls following treatment with AA or GLA but not after co-treatment with the cyclooxygenase inhibitor, indomethacin. DHA and EPA had no effect on membrane-bound RANKL expression under standard cell culture conditions. Secretion of OPG was lower (p<0.05) in AA-treated cells but not significantly different from controls in GLA, EPA or DHA treated cells. Treatment with prostaglandin E2 (PGE2) resulted in an increase (p<0.05) in the percentage of RANK-L positive cells and a decrease (p<0.05) in mean OPG secretion. The percentage of RANKL positive cells was significantly lower following co-treatment with PGE2 and either DHA or EPA compared to treatment with PGE2 alone. Mean OPG secretion remained lower than controls in cells treated with PGE2 regardless of co-treatment with EPA or DHA. Results from this study suggest COX products of GLA and AA induce membrane-bound RANKL expression in MC3T3-E1/4 cells. EPA and DHA have no effect on membrane-bound RANKL expression in cells cultured under standard conditions however both EPA and DHA inhibit the PGE2-induced increase in RANKL expression in MC3T3-E1/4 cells.
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Affiliation(s)
- Raewyn C Poulsen
- Institute of Food, Nutrition and Human Health, Massey University, Private Bag 11-222, Palmerston North 4442, New Zealand.
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Oelzner P, Franke S, Lehmann G, Eidner T, Müller A, Wolf G, Hein G. Soluble receptor activator of NFkappa B-ligand and osteoprotegerin in rheumatoid arthritis - relationship with bone mineral density, disease activity and bone turnover. Clin Rheumatol 2007; 26:2127-2135. [PMID: 17541498 DOI: 10.1007/s10067-007-0639-5] [Citation(s) in RCA: 17] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2007] [Revised: 04/17/2007] [Accepted: 04/17/2007] [Indexed: 01/06/2023]
Abstract
The aim of our study was to investigate determinants of bone mineral density (BMD) measured by dual X-ray absorptiometry at the lumbar spine (BMD-LS) and at the femoral neck (BMD-FN) in patients with rheumatoid arthritis (RA) with special respect to bone resorbing proinflammatory cytokines and their physiological antagonists. In 142 RA patients the following parameters were measured in parallel with BMD: serum levels of soluble receptor activator of nuclear factor kappa-B-ligand (sRANKL), osteoprotegerin (OPG), interleukin (IL)-6, soluble glycoprotein 130 (sgp130), 25-hydroxyvitamin D3 (25OHD(3)), 1,25-dihydroxyvitamin D3 (1,25[OH](2)D(3)), intact parathyroid hormone, osteocalcin, ionized calcium, renal excretion of pyridinolin and deoxypyridinolin, C-reactive protein, and erythrocyte sedimentation rate (ESR). No significant differences of sRANKL, OPG, IL-6, and spg130 were found between patients with osteoporosis (47.9% of patients), osteopenia (36.6%), and normal BMD (15.5%). However, total sRANKL was significantly higher in postmenopausal women with osteoporosis at FN than in those without (p < 0.05) and showed a negative correlation with BMD-LS in patients older than 60 years (p = 0.01). BMD-LS and BMD-FN (p < 0.001) and total sRANKL (p < 0.01) were negatively related with the age of the patients. Only IL-6 (positive correlation, p < 0.001) and 1,25(OH)(2)D(3) (negative correlation, p < 0.001) but not sRANKL, OPG, and sgp130 were related to disease activity. Using multiple linear regression analysis, menopause was identified as the crucial negative determinant of BMD-LS (R (2) = 0.94, p = 0.001), whereas cumulative glucocorticoid dose (beta = -0.80, p = 0.001) and ESR (beta = -0.44, p = 0.016) were the negative determinants of BMD-FN (R (2) = 0.86, p = 0.001). The results indicate that influences of age and gender must be considered in investigations on the relationship between BMD and sRANKL in RA and that high serum levels of sRANKL seems to be associated with osteoporosis only in subgroups of RA patients.
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Affiliation(s)
- P Oelzner
- Division of Rheumatology and Osteology, Department of Internal Medicine III, Friedrich Schiller University, Jena, Germany.
| | - S Franke
- Division of Rheumatology and Osteology, Department of Internal Medicine III, Friedrich Schiller University, Jena, Germany
| | - G Lehmann
- Division of Rheumatology and Osteology, Department of Internal Medicine III, Friedrich Schiller University, Jena, Germany
| | - T Eidner
- Division of Rheumatology and Osteology, Department of Internal Medicine III, Friedrich Schiller University, Jena, Germany
| | - A Müller
- Division of Rheumatology and Osteology, Department of Internal Medicine III, Friedrich Schiller University, Jena, Germany
| | - G Wolf
- Division of Rheumatology and Osteology, Department of Internal Medicine III, Friedrich Schiller University, Jena, Germany
| | - G Hein
- Division of Rheumatology and Osteology, Department of Internal Medicine III, Friedrich Schiller University, Jena, Germany
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