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1
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Ulmer CZ, Kritmetapak K, Singh RJ, Vesper HW, Kumar R. High-Resolution Mass Spectrometry for the Measurement of PTH and PTH Fragments: Insights into PTH Physiology and Bioactivity. J Am Soc Nephrol 2022; 33:1448-1458. [PMID: 35396262 PMCID: PMC9342634 DOI: 10.1681/asn.2022010036] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Full-length parathyroid hormone (PTH 1-84) is crucial for the regulation of calcium and phosphate homeostasis and bone remodeling. PTH 1-84 is metabolized into various PTH fragments, which are measured with varying levels of efficiency by PTH immunoassays. These PTH fragments, which increase in serum as CKD progresses, could potentially modulate the effects of PTH 1-84 and contribute to CKD-associated bone disorders. To obtain a true biologic representation of total PTH bioactivity, it is necessary to measure not only PTH 1-84 but also PTH fragments that are present in circulation. Traditional second-generation PTH immunoassays collectively measure PTH 1-84, PTH fragments, and post-translationally modified PTH 1-84, making it difficult to accurately predict the character of underlying renal osteodystrophy. This review highlights current advances in methods available for PTH measurement and the clinical relevance of PTH fragments in CKD. We emphasize the usefulness of mass spectrometry as a potential reference method for PTH measurement.
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Affiliation(s)
- Candice Z. Ulmer
- Clinical Chemistry Branch, Division of Laboratory Sciences, National Center for Environmental Health, Centers for Disease Control and Prevention, Atlanta, Georgia
| | - Kittrawee Kritmetapak
- Division of Nephrology, Department of Medicine, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand
| | - Ravinder J. Singh
- Immunochemical Core Laboratory, Mayo Clinic, Rochester, Minnesota,Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota
| | - Hubert W. Vesper
- Clinical Chemistry Branch, Division of Laboratory Sciences, National Center for Environmental Health, Centers for Disease Control and Prevention, Atlanta, Georgia
| | - Rajiv Kumar
- Division of Nephrology and Hypertension, Department of Internal Medicine, Mayo Clinic, Rochester, Minnesota,Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, Minnesota
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2
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Rajakumar SA, Papp E, Lee KK, Grandal I, Merico D, Liu CC, Allo B, Zhang L, Grynpas MD, Minden MD, Hitzler JK, Guidos CJ, Danska JS. B cell acute lymphoblastic leukemia cells mediate RANK-RANKL-dependent bone destruction. Sci Transl Med 2021; 12:12/561/eaba5942. [PMID: 32938796 DOI: 10.1126/scitranslmed.aba5942] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2019] [Revised: 06/05/2020] [Accepted: 07/21/2020] [Indexed: 12/20/2022]
Abstract
Although most children survive B cell acute lymphoblastic leukemia (B-ALL), they frequently experience long-term, treatment-related health problems, including osteopenia and osteonecrosis. Because some children present with fractures at ALL diagnosis, we considered the possibility that leukemic B cells contribute directly to bone pathology. To identify potential mechanisms of B-ALL-driven bone destruction, we examined the p53 -/-; Rag2 -/-; Prkdcscid/scid triple mutant (TM) mice and p53 -/-; Prkdcscid/scid double mutant (DM) mouse models of spontaneous B-ALL. In contrast to DM animals, leukemic TM mice displayed brittle bones, and the TM leukemic cells overexpressed Rankl, encoding receptor activator of nuclear factor κB ligand. RANKL is a key regulator of osteoclast differentiation and bone loss. Transfer of TM leukemic cells into immunodeficient recipient mice caused trabecular bone loss. To determine whether human B-ALL can exert similar effects, we evaluated primary human B-ALL blasts isolated at diagnosis for RANKL expression and their impact on bone pathology after their transplantation into NOD.Prkdcscid/scidIl2rgtm1Wjl /SzJ (NSG) recipient mice. Primary B-ALL cells conferred bone destruction evident in increased multinucleated osteoclasts, trabecular bone loss, destruction of the metaphyseal growth plate, and reduction in adipocyte mass in these patient-derived xenografts (PDXs). Treating PDX mice with the RANKL antagonist recombinant osteoprotegerin-Fc (rOPG-Fc) protected the bone from B-ALL-induced destruction even under conditions of heavy tumor burden. Our data demonstrate a critical role of the RANK-RANKL axis in causing B-ALL-mediated bone pathology and provide preclinical support for RANKL-targeted therapy trials to reduce acute and long-term bone destruction in these patients.
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Affiliation(s)
- Sujeetha A Rajakumar
- Program in Genetics and Genome Biology, Hospital for Sick Children, Toronto, Ontario M5G 0A4, Canada.,Department of Medical Biophysics, University of Toronto, Toronto, Ontario M5S 1A8, Canada
| | - Eniko Papp
- Department of Medical Biophysics, University of Toronto, Toronto, Ontario M5S 1A8, Canada.,Program in Developmental and Stem Cell Biology, Hospital for Sick Children, Toronto, Ontario M5G 0A4, Canada
| | - Kathy K Lee
- Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario M5T 3H7, Canada.,Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario M5S 1A8, Canada
| | - Ildiko Grandal
- Program in Developmental and Stem Cell Biology, Hospital for Sick Children, Toronto, Ontario M5G 0A4, Canada
| | - Daniele Merico
- Center for Applied Genomics, Hospital for Sick Children, Toronto, Ontario M5G 0A4, Canada
| | - Careesa C Liu
- Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario M5T 3H7, Canada.,Institute of Biomaterials and Biomedical Engineering, University of Toronto, Toronto, Ontario M5S 1A8, Canada
| | - Bedilu Allo
- Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario M5T 3H7, Canada
| | - Lucia Zhang
- Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario M5T 3H7, Canada.,Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario M5S 1A8, Canada
| | - Marc D Grynpas
- Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario M5T 3H7, Canada.,Institute of Biomaterials and Biomedical Engineering, University of Toronto, Toronto, Ontario M5S 1A8, Canada
| | - Mark D Minden
- Department of Medical Biophysics, University of Toronto, Toronto, Ontario M5S 1A8, Canada.,Princess Margaret Cancer Center, University Health Network, Toronto, Ontario M5G 2M9, Canada
| | - Johann K Hitzler
- Program in Developmental and Stem Cell Biology, Hospital for Sick Children, Toronto, Ontario M5G 0A4, Canada.,Department of Pediatrics, Division of Hematology and Oncology, Hospital for Sick Children, Toronto, Ontario M5G 1X8, Canada
| | - Cynthia J Guidos
- Program in Developmental and Stem Cell Biology, Hospital for Sick Children, Toronto, Ontario M5G 0A4, Canada.,Department of Immunology, University of Toronto, Toronto, Ontario M5S 1A8, Canada
| | - Jayne S Danska
- Program in Genetics and Genome Biology, Hospital for Sick Children, Toronto, Ontario M5G 0A4, Canada. .,Department of Medical Biophysics, University of Toronto, Toronto, Ontario M5S 1A8, Canada.,Department of Immunology, University of Toronto, Toronto, Ontario M5S 1A8, Canada
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3
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Soda N, Sakai N, Kato H, Takami M, Fujita T. Singleton-Merten Syndrome-like Skeletal Abnormalities in Mice with Constitutively Activated MDA5. THE JOURNAL OF IMMUNOLOGY 2019; 203:1356-1368. [PMID: 31366715 DOI: 10.4049/jimmunol.1900354] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/02/2019] [Accepted: 07/01/2019] [Indexed: 12/14/2022]
Abstract
Singleton-Merten syndrome (SMS) is a type I interferonopathy characterized by dental dysplasia, aortic calcification, skeletal abnormalities, glaucoma, and psoriasis. A missense mutation in IFIH1 encoding a cytoplasmic viral RNA sensor MDA5 has recently been identified in the SMS patients as well as in patients with a monogenic form of lupus. We previously reported that Ifih1gs/+ mice express a constitutively active MDA5 and spontaneously develop lupus-like nephritis. In this study, we demonstrate that the Ifih1gs/+ mice also exhibit SMS-like bone abnormalities, including decreased bone mineral density and thin cortical bone. Histological analysis revealed a low number of osteoclasts, low bone formation rate, and abnormal development of growth plate cartilages in Ifih1gs/+ mice. These abnormalities were not observed in Ifih1gs/+ ・Mavs-/- and Ifih1gs/+ ・Ifnar1-/- mice, indicating the critical role of type I IFNs induced by MDA5/MAVS-dependent signaling in the bone pathogenesis of Ifih1gs/+ mice, affecting bone turnover. Taken together, our findings suggest the inhibition of type I IFN signaling as a possible effective therapeutic strategy for bone disorders in SMS patients.
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Affiliation(s)
- Nobumasa Soda
- Laboratory of Molecular Genetics, Institute for Frontier Life and Medical Science, Kyoto University, Kyoto, 606-8507 Japan.,Laboratory of Molecular and Cellular Immunology, Graduate School of Biostudies, Kyoto University, Kyoto, 606-8501 Japan
| | - Nobuhiro Sakai
- Department of Pharmacology, School of Dentistry, Showa University, Tokyo, 142-8555 Japan; and
| | - Hiroki Kato
- Laboratory of Molecular Genetics, Institute for Frontier Life and Medical Science, Kyoto University, Kyoto, 606-8507 Japan.,Institute of Cardiovascular Immunology, University Hospital Bonn, University of Bonn, Bonn, 53127 Germany
| | - Masamichi Takami
- Department of Pharmacology, School of Dentistry, Showa University, Tokyo, 142-8555 Japan; and
| | - Takashi Fujita
- Laboratory of Molecular Genetics, Institute for Frontier Life and Medical Science, Kyoto University, Kyoto, 606-8507 Japan; .,Laboratory of Molecular and Cellular Immunology, Graduate School of Biostudies, Kyoto University, Kyoto, 606-8501 Japan
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4
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Abstract
Bone is a crucial element of the skeletal-locomotor system, but also functions as an immunological organ that harbors hematopoietic stem cells (HSCs) and immune progenitor cells. Additionally, the skeletal and immune systems share a number of regulatory molecules, including cytokines and signaling molecules. Osteoimmunology was created as an interdisciplinary field to explore the shared molecules and interactions between the skeletal and immune systems. In particular, the importance of an inseparable link between the two systems has been highlighted by studies on the pathogenesis of rheumatoid arthritis (RA), in which pathogenic helper T cells induce the progressive destruction of multiple joints through aberrant expression of receptor activator of nuclear factor (NF)-κB ligand (RANKL). The conceptual bridge of osteoimmunology provides not only a novel framework for understanding these biological systems but also a molecular basis for the development of therapeutic approaches for diseases of bone and/or the immune system.
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Affiliation(s)
- Kazuo Okamoto
- Department of Osteoimmunology, Graduate School of Medicine and Faculty of Medicine, The University of Tokyo, Hongo 7-3-1, Bunkyo-ku, Tokyo 113-0033, Japan
| | - Hiroshi Takayanagi
- Department of Immunology, Graduate School of Medicine and Faculty of Medicine, The University of Tokyo, Hongo 7-3-1, Bunkyo-ku, Tokyo 113-0033, Japan
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5
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Wang B, Hao D, Zhang Z, Gao W, Pan H, Xiao Y, He B, Kong L. Inhibition effects of a natural inhibitor on RANKL downstream cellular signalling cascades cross-talking. J Cell Mol Med 2018; 22:4236-4242. [PMID: 29911332 PMCID: PMC6111857 DOI: 10.1111/jcmm.13703] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2018] [Accepted: 04/26/2018] [Indexed: 01/25/2023] Open
Abstract
Myricitrin is a natural occurring flavonoid glycoside that possesses effects on inhibiting nitric oxide (NO) transmission and preventing inflammatory reaction. Although previous study showed the myricitrin possesses antibone loss effects via reducing the expression of IL-6 and partially suppressing reactive oxygen species (ROS) production. However, the effects of myricitrin on nuclear factor-kappaB ligand (RANKL)-stimulated osteoclastogenesis have not yet been further investigated. The current study was aimed to demonstrating the inhibitory effects of myricitrin on RANKL-stimulated osteoclastogenesis and relevant mechanisms. We found myricitrin significantly suppressed osteoclastogenesis suggesting that it may acts on RANKL/RANK induced downstream signal cross cascading in osteoclast precursors. In that, our Western blotting results showed myricitrin significantly attenuated RNAKL/MAPKs (phosphorylation of p38, ERK, JNK) and AKT signal cascading. Complementing previous study, our results suggesting as a natural inhibitor, myricitrin possesses the potential therapeutic effects on inflammatory osteolysis.
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Affiliation(s)
- Biao Wang
- Hong-Hui Hospital, Xi'an Jiaotong University College of Medicine, Xi'an, China
| | - Dingjun Hao
- Hong-Hui Hospital, Xi'an Jiaotong University College of Medicine, Xi'an, China
| | - Zhen Zhang
- Hong-Hui Hospital, Xi'an Jiaotong University College of Medicine, Xi'an, China
| | - Wenjie Gao
- Hong-Hui Hospital, Xi'an Jiaotong University College of Medicine, Xi'an, China
| | - Hu Pan
- Hong-Hui Hospital, Xi'an Jiaotong University College of Medicine, Xi'an, China
| | - Yuan Xiao
- Hong-Hui Hospital, Xi'an Jiaotong University College of Medicine, Xi'an, China
| | - Baorong He
- Hong-Hui Hospital, Xi'an Jiaotong University College of Medicine, Xi'an, China
| | - Lingbo Kong
- Hong-Hui Hospital, Xi'an Jiaotong University College of Medicine, Xi'an, China
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6
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Kim JH, Kim K, Kim I, Seong S, Kim N. c-Src–Dependent and –Independent Functions of Matk in Osteoclasts and Osteoblasts. THE JOURNAL OF IMMUNOLOGY 2018; 200:2455-2463. [DOI: 10.4049/jimmunol.1700582] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/25/2017] [Accepted: 01/17/2018] [Indexed: 11/19/2022]
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7
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Abstract
Bone metastasis is one of the most common forms of metastasis from a number of different primary carcinomas. MicroRNAs (miRNAs) are short, endogenous RNAs that negatively regulate gene expression to control essential pathways, including those involved in bone organogenesis and homeostasis. As these pathways are often hijacked during bone metastasis, it is not surprising that miRNAs can also influence bone metastasis formation. Areas covered: In this review, we first summarize the major signalling pathways involved in normal bone development and bone metastasis. We will then discuss the overall roles of miRNAs in cancer metastasis and highlight the recent findings on the effects of miRNAs in bone metastasis. To this aim, we have performed a literature search in PubMed by using the search words 'miRNAs' and 'bone metastasis', selecting relevant scientific articles published between 2010 and 2016. Seminal publications before 2010 on the metastatic role of miRNAs have also been considered. Expert commentary: With the lack of current diagnostic biomarkers and effective targeted therapies for bone metastasis, the significant role of miRNAs in the regulation of bone homeostasis and bone metastasis may support the future use of miRNAs as diagnostic biomarkers and therapeutic targets.
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Affiliation(s)
- Douglas G Cheung
- a Department of Cancer Biology and Genetics , The Ohio State University , Columbus , Ohio , USA
| | - Marta Buzzetti
- b Biomedical Research Centre, School of Environment and Life Sciences , University of Salford , Salford , UK
| | - Gianpiero Di Leva
- b Biomedical Research Centre, School of Environment and Life Sciences , University of Salford , Salford , UK
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8
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MacFarlane EG, Haupt J, Dietz HC, Shore EM. TGF-β Family Signaling in Connective Tissue and Skeletal Diseases. Cold Spring Harb Perspect Biol 2017; 9:cshperspect.a022269. [PMID: 28246187 DOI: 10.1101/cshperspect.a022269] [Citation(s) in RCA: 86] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
The transforming growth factor β (TGF-β) family of signaling molecules, which includes TGF-βs, activins, inhibins, and numerous bone morphogenetic proteins (BMPs) and growth and differentiation factors (GDFs), has important functions in all cells and tissues, including soft connective tissues and the skeleton. Specific TGF-β family members play different roles in these tissues, and their activities are often balanced with those of other TGF-β family members and by interactions with other signaling pathways. Perturbations in TGF-β family pathways are associated with numerous human diseases with prominent involvement of the skeletal and cardiovascular systems. This review focuses on the role of this family of signaling molecules in the pathologies of connective tissues that manifest in rare genetic syndromes (e.g., syndromic presentations of thoracic aortic aneurysm), as well as in more common disorders (e.g., osteoarthritis and osteoporosis). Many of these diseases are caused by or result in pathological alterations of the complex relationship between the TGF-β family of signaling mediators and the extracellular matrix in connective tissues.
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Affiliation(s)
- Elena Gallo MacFarlane
- McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205
| | - Julia Haupt
- Department of Orthopedic Surgery, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania 19104.,Center for Research in FOP and Related Disorders, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania 19104
| | - Harry C Dietz
- McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205.,Howard Hughes Medical Institute, Bethesda, Maryland 21205
| | - Eileen M Shore
- Department of Orthopedic Surgery, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania 19104.,Center for Research in FOP and Related Disorders, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania 19104.,Department of Genetics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania 19104
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9
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Uehara S, Udagawa N, Mukai H, Ishihara A, Maeda K, Yamashita T, Murakami K, Nishita M, Nakamura T, Kato S, Minami Y, Takahashi N, Kobayashi Y. Protein kinase N3 promotes bone resorption by osteoclasts in response to Wnt5a-Ror2 signaling. Sci Signal 2017; 10:10/494/eaan0023. [DOI: 10.1126/scisignal.aan0023] [Citation(s) in RCA: 46] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
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10
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Suzuki N, Sato M, Nassar HF, Abdel-Gawad FK, Bassem SM, Yachiguchi K, Tabuchi Y, Endo M, Sekiguchi T, Urata M, Hattori A, Mishima H, Shimasaki Y, Oshima Y, Hong CS, Makino F, Tang N, Toriba A, Hayakawa K. Seawater Polluted with Highly Concentrated Polycyclic Aromatic Hydrocarbons Suppresses Osteoblastic Activity in the Scales of Goldfish, Carassius auratus. Zoolog Sci 2017; 33:407-13. [PMID: 27498800 DOI: 10.2108/zs150211] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
We have developed an original in vitro bioassay using teleost scale, that has osteoclasts, osteoblasts, and bone matrix as each marker: alkaline phosphatase (ALP) for osteoblasts and tartrate-resistant acid phosphatase (TRAP) for osteoclasts. Using this scale in vitro bioassay, we examined the effects of seawater polluted with highly concentrated polycyclic aromatic hydrocarbons (PAHs) and nitro-polycyclic aromatic hydrocarbons (NPAHs) on osteoblastic and osteoclastic activities in the present study. Polluted seawater was collected from two sites (the Alexandria site on the Mediterranean Sea and the Suez Canal site on the Red Sea). Total levels of PAHs in the seawater from the Alexandria and Suez Canal sites were 1364.59 and 992.56 ng/l, respectively. We were able to detect NPAHs in both seawater samples. Total levels of NPAHs were detected in the seawater of the Alexandria site (12.749 ng/l) and the Suez Canal site (3.914 ng/l). Each sample of polluted seawater was added to culture medium at dilution rates of 50, 100, and 500, and incubated with the goldfish scales for 6 hrs. Thereafter, ALP and TRAP activities were measured. ALP activity was significantly suppressed by both polluted seawater samples diluted at least 500 times, but TRAP activity did not change. In addition, mRNA expressions of osteoblastic markers (ALP, osteocalcin, and the receptor activator of the NF-κB ligand) decreased significantly, as did the ALP enzyme activity. In fact, ALP activity decreased on treatment with PAHs and NPAHs. We conclude that seawater polluted with highly concentrated PAHs and NPAHs influences bone metabolism in teleosts.
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Affiliation(s)
- Nobuo Suzuki
- 1 Noto Marine Laboratory, Institute of Nature and Environmental Technology, Division of Marine Environmental Studies, Kanazawa University, Housu-gun, Ishikawa 927-0553, Japan
| | - Masayuki Sato
- 1 Noto Marine Laboratory, Institute of Nature and Environmental Technology, Division of Marine Environmental Studies, Kanazawa University, Housu-gun, Ishikawa 927-0553, Japan
| | - Hossam F Nassar
- 2 Environmental Research Division, Water Pollution Control Department, National Research Center, Cairo 12621, Egypt
| | - Fagr Kh Abdel-Gawad
- 2 Environmental Research Division, Water Pollution Control Department, National Research Center, Cairo 12621, Egypt
| | - Samah M Bassem
- 2 Environmental Research Division, Water Pollution Control Department, National Research Center, Cairo 12621, Egypt
| | - Koji Yachiguchi
- 1 Noto Marine Laboratory, Institute of Nature and Environmental Technology, Division of Marine Environmental Studies, Kanazawa University, Housu-gun, Ishikawa 927-0553, Japan
| | - Yoshiaki Tabuchi
- 3 Division of Molecular Genetics Research, Life Science Research Center, University of Toyama, Sugitani, Toyama 930-0194, Japan
| | - Masato Endo
- 4 Department of Marine Biosciences, Division of Marine Science, Tokyo University of Marine Science and Technology, Minato-ku, Tokyo 108-8477, Japan
| | - Toshio Sekiguchi
- 1 Noto Marine Laboratory, Institute of Nature and Environmental Technology, Division of Marine Environmental Studies, Kanazawa University, Housu-gun, Ishikawa 927-0553, Japan
| | - Makoto Urata
- 1 Noto Marine Laboratory, Institute of Nature and Environmental Technology, Division of Marine Environmental Studies, Kanazawa University, Housu-gun, Ishikawa 927-0553, Japan.,5 Institute of Noto SATOUMI Education and Studies, Noto-cho, Ishikawa 927-0553, Japan
| | - Atsuhiko Hattori
- 6 Department of Biology, College of Liberal Arts and Sciences, Tokyo Medical and Dental University, Ichikawa, Chiba 272-0827, Japan
| | - Hiroyuki Mishima
- 7 Department of Medical Hygiene, Kochi Gakuen College, Kochi 780-0955, Japan
| | - Youhei Shimasaki
- 8 Laboratory of Marine Environmental Science, Faculty of Agriculture, Kyushu University, Hakozaki 6-10-1, Higashi-ku, Fukuoka 812-8581, Japan
| | - Yuji Oshima
- 8 Laboratory of Marine Environmental Science, Faculty of Agriculture, Kyushu University, Hakozaki 6-10-1, Higashi-ku, Fukuoka 812-8581, Japan
| | - Chun-Sang Hong
- 9 Hankuk University of Foreign Studies, 81, Oedae-ro, Mohyeon-myeon, Cheoin-gu, Yongin-si, Gyeonggi-do 17035, Korea
| | - Fumiya Makino
- 10 Faculty of Pharmaceutical Sciences, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kakuma, Ishikawa 920-1192, Japan
| | - Ning Tang
- 10 Faculty of Pharmaceutical Sciences, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kakuma, Ishikawa 920-1192, Japan
| | - Akira Toriba
- 10 Faculty of Pharmaceutical Sciences, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kakuma, Ishikawa 920-1192, Japan
| | - Kazuichi Hayakawa
- 1 Noto Marine Laboratory, Institute of Nature and Environmental Technology, Division of Marine Environmental Studies, Kanazawa University, Housu-gun, Ishikawa 927-0553, Japan.,10 Faculty of Pharmaceutical Sciences, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kakuma, Ishikawa 920-1192, Japan
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11
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Lee CJ, Shim KS, Ma JY. Artemisia capillaris Alleviates Bone Loss by Stimulating Osteoblast Mineralization and Suppressing Osteoclast Differentiation and Bone Resorption. THE AMERICAN JOURNAL OF CHINESE MEDICINE 2016; 44:1675-1691. [PMID: 27852127 DOI: 10.1142/s0192415x16500944] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/21/2023]
Abstract
Artemisia capillaris has been used to treat jaundice and relieve high liver-heat in traditional medicine. In this study, we found that the administration of a water extract from A. capillaris (WEAC) to the receptor activator of nuclear factor kappa-B ligand (RANKL)-induced bone loss model significantly prevents osteoporotic bone loss, increasing bone volume/trabecular volume by 22% and trabecular number by 24%, and decreasing trabecular separation by 29%. WEAC stimulated in vitro osteoblast mineralization from primary osteoblasts in association with increasing expression of osterix, nuclear factor of activated T cells cytoplasmic 1, and activator protein-1, as well as phosphorylation of extracellular signal-regulated kinase. In contrast to the anabolic effect of WEAC, WEAC significantly suppressed in vitro osteoclast formation from bone marrow macrophages by inhibiting the RANKL signaling pathways and bone resorption by downregulating the expression of resorption markers. Therefore, this study demonstrated that WEAC has a beneficial effect on bone loss through the regulation of osteoblast mineralization, as well as osteoclast formation and bone resorption. These results suggest that A. capillaris may be a promising herbal candidate for therapeutic agents to treat or prevent osteoporotic bone diseases.
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Affiliation(s)
- Chung-Jo Lee
- 1 KM Application Center, Korea Institute of Oriental Medicine, Dong-gu, Daegu 701-300, Republic of Korea
| | - Ki-Shuk Shim
- 1 KM Application Center, Korea Institute of Oriental Medicine, Dong-gu, Daegu 701-300, Republic of Korea
| | - Jin Yeul Ma
- 1 KM Application Center, Korea Institute of Oriental Medicine, Dong-gu, Daegu 701-300, Republic of Korea
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12
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James AW, LaChaud G, Shen J, Asatrian G, Nguyen V, Zhang X, Ting K, Soo C. A Review of the Clinical Side Effects of Bone Morphogenetic Protein-2. TISSUE ENGINEERING PART B-REVIEWS 2016; 22:284-97. [PMID: 26857241 DOI: 10.1089/ten.teb.2015.0357] [Citation(s) in RCA: 720] [Impact Index Per Article: 80.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Bone morphogenetic protein-2 (BMP-2) is currently the only Food and Drug Administration (FDA)-approved osteoinductive growth factor used as a bone graft substitute. However, with increasing clinical use of BMP-2, a growing and well-documented side effect profile has emerged. This includes postoperative inflammation and associated adverse effects, ectopic bone formation, osteoclast-mediated bone resorption, and inappropriate adipogenesis. Several large-scale studies have confirmed the relative frequency of adverse events associated with the clinical use of BMP-2, including life-threatening cervical spine swelling. In fact, the FDA has issued a warning of the potential life-threatening complications of BMP-2. This review summarizes the known adverse effects of BMP-2, including controversial areas such as tumorigenesis. Next, select animal models that replicate BMP-2's adverse clinical effects are discussed. Finally, potential molecules to mitigate the adverse effects of BMP-2 are reviewed. In summary, BMP-2 is a potent osteoinductive cytokine that has indeed revolutionized the bone graft substitute market; however, it simultaneously has accrued a worrisome side effect profile. Better understanding of these adverse effects among both translational scientists and clinicians will help determine the most appropriate and safe use of BMP-2 in the clinical setting.
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Affiliation(s)
- Aaron W James
- 1 Department of Orthopaedic Surgery and the Orthopaedic Hospital Research Center, UCLA and Orthopaedic Hospital, University of California , Los Angeles, Los Angeles, California.,2 Section of Orthodontics, Division of Growth and Development, School of Dentistry, University of California , Los Angeles, Los Angeles, California.,3 Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California , Los Angeles, Los Angeles, California
| | - Gregory LaChaud
- 1 Department of Orthopaedic Surgery and the Orthopaedic Hospital Research Center, UCLA and Orthopaedic Hospital, University of California , Los Angeles, Los Angeles, California.,2 Section of Orthodontics, Division of Growth and Development, School of Dentistry, University of California , Los Angeles, Los Angeles, California.,3 Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California , Los Angeles, Los Angeles, California
| | - Jia Shen
- 2 Section of Orthodontics, Division of Growth and Development, School of Dentistry, University of California , Los Angeles, Los Angeles, California
| | - Greg Asatrian
- 2 Section of Orthodontics, Division of Growth and Development, School of Dentistry, University of California , Los Angeles, Los Angeles, California
| | - Vi Nguyen
- 3 Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California , Los Angeles, Los Angeles, California
| | - Xinli Zhang
- 2 Section of Orthodontics, Division of Growth and Development, School of Dentistry, University of California , Los Angeles, Los Angeles, California
| | - Kang Ting
- 2 Section of Orthodontics, Division of Growth and Development, School of Dentistry, University of California , Los Angeles, Los Angeles, California
| | - Chia Soo
- 1 Department of Orthopaedic Surgery and the Orthopaedic Hospital Research Center, UCLA and Orthopaedic Hospital, University of California , Los Angeles, Los Angeles, California.,4 Division of Plastic and Reconstructive Surgery, Department of Surgery, David Geffen School of Medicine, University of California , Los Angeles, Los Angeles, California
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13
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LEE WANGHEE, OKOS MARTINR. MODEL-BASED ANALYSIS OF IGF-1 EFFECT ON OSTEOBLAST AND OSTEOCLAST REGULATION IN BONE TURNOVER. J BIOL SYST 2016. [DOI: 10.1142/s0218339016500042] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
Abstract
The main determinant of bone Ca accretion is a bimolecular regulatory network on osteoblast (OB) and osteoclast (OC). Even though IGF-1 is known as an important regulator in bone cell cycle, little has been done to model IGF-1 action in bone cell regulation. Thus, the objective is to develop a mathematical model that depicts the regulatory action of IGF-1 onto the OB and OC interaction, and to evaluate adolescent and adult bone Ca accretion in response to differences in IGF-1 levels. As a result, a dynamic model of OB and OC with two main regulatory systems, i.e., Receptor Activator for Nuclear Factor [Formula: see text]B (RANK)-RANK Ligand (RANKL)-osteoprogerin (OPG) system, and TGF-[Formula: see text], was augmented with the IGF-1, and incorporated into Ca kinetic data to predict exchangeable bone Ca. The developed model could predict a change in OB and OC levels in response to perturbations in regulators, producing results consistent with bone physiology and published experimental data. The model also estimated parametric difference in regulators between adults and adolescents, suggesting that RANKL/OPG in adolescents was about 4 times higher than in adults, while adolescent serum PTH and IGF-1 concentrations were 60% and 220% of those of adults, respectively. This study highlighted the influence of IGF-1 on the regulation of bone cells in positively modulating bone Ca, suggesting that IGF-1 may be an effective target for reducing bone loss by promoting mature OB.
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Affiliation(s)
- WANG-HEE LEE
- Department of Agricultural and Biological Engineering, Purdue University, 225 South University Street, West Lafayette, IN 47907-2093, USA
| | - MARTIN R. OKOS
- Department of Agricultural and Biological Engineering, Purdue University, 225 South University Street, West Lafayette, IN 47907-2093, USA
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14
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Ossola CA, Surkin PN, Mohn CE, Elverdin JC, Fernández-Solari J. Anti-Inflammatory and Osteoprotective Effects of Cannabinoid-2 Receptor Agonist HU-308 in a Rat Model of Lipopolysaccharide-Induced Periodontitis. J Periodontol 2016; 87:725-34. [PMID: 26846967 DOI: 10.1902/jop.2016.150612] [Citation(s) in RCA: 41] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
BACKGROUND Anti-inflammatory and immunologic properties of cannabinoids have been reported in several tissues. Expression of cannabinoid receptor Type 2 was reported in osteoblasts and osteoclasts, suggesting a key role in bone metabolism. The aim of this study is to assess the effect of treatment with cannabinoid-2 receptor agonist HU-308 in the oral health of rats subjected to lipopolysaccharide (LPS)-induced periodontitis. METHODS Twenty-four rats were distributed in four groups (six rats per group): 1) control rats; 2) sham rats; 3) rats submitted to experimental periodontitis (LPS); and 4) rats submitted to experimental periodontitis and treated with HU-308 (LPS+HU). In groups LPS and LPS+HU, periodontitis was induced by LPS (1 mg/mL) injected into the gingival tissue (GT) of maxillary and mandibular first molars and into the interdental space between the first and second molars, 3 days per week for 6 weeks. In group LPS+HU, HU-308 (500 ng/mL) was applied topically to the GT daily. RESULTS Alveolar bone loss resulting from LPS-induced periodontitis was significantly attenuated with HU-308 treatment (LPS+HU), measured by macroscopic and histologic examination. Treatment also reduced gingival production of inflammatory mediators augmented in LPS-injected rats, such as: 1) inducible nitric oxide (iNOS) activity (LPS: 90.18 ± 36.51 pmol/minute/mg protein versus LPS+HU: 16.37 ± 4.73 pmol/minute/mg protein; P <0.05); 2) tumor necrosis factor alpha (LPS: 185.70 ± 25.63 pg/mg protein versus LPS+HU: 95.89 ± 17.47 pg/mg protein; P <0.05); and 3) prostaglandin E2 (PGE2) (LPS: 159.20 ± 38.70 pg/mg wet weight versus LPS+HU: 71.25 ± 17.75 pg/mg wet weight; P <0.05). Additionally, HU-308 treatment prevented the inhibitory effect of LPS-induced periodontitis on the salivary secretory response to pilocarpine. Moreover, iNOS activity and PGE2 content, which were increased by LPS-induced periodontitis in the submandibular gland, returned to control values after HU-308 treatment. CONCLUSION This study demonstrates anti-inflammatory, osteoprotective, and prohomeostatic effects of HU-308 in oral tissues of rats with LPS-induced periodontitis.
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Affiliation(s)
- Cesar A Ossola
- Department of Physiology, Faculty of Dentistry, University of Buenos Aires, Buenos Aires, Argentina
| | - Pablo N Surkin
- Department of Physiology, Faculty of Dentistry, University of Buenos Aires, Buenos Aires, Argentina.,National Council of Scientific and Technical Research (CONICET), Buenos Aires, Argentina
| | - Claudia E Mohn
- Department of Physiology, Faculty of Dentistry, University of Buenos Aires, Buenos Aires, Argentina.,National Council of Scientific and Technical Research (CONICET), Buenos Aires, Argentina
| | - Juan C Elverdin
- Department of Physiology, Faculty of Dentistry, University of Buenos Aires, Buenos Aires, Argentina
| | - Javier Fernández-Solari
- Department of Physiology, Faculty of Dentistry, University of Buenos Aires, Buenos Aires, Argentina.,National Council of Scientific and Technical Research (CONICET), Buenos Aires, Argentina
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15
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Ikeda K, Takeshita S. The role of osteoclast differentiation and function in skeletal homeostasis. J Biochem 2016; 159:1-8. [PMID: 26538571 PMCID: PMC4882648 DOI: 10.1093/jb/mvv112] [Citation(s) in RCA: 105] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2015] [Accepted: 09/27/2015] [Indexed: 11/14/2022] Open
Abstract
Osteoclasts are giant multinucleated cells that differentiate from hematopoietic cells in the bone marrow and carry out important physiological functions in the regulation of skeletal homeostasis as well as hematopoiesis. Osteoclast biology shares many features and components with cells of the immune system, including cytokine-receptor interactions (RANKL-RANK), intracellular signalling molecules (TRAF6) and transcription factors (NFATc1). Although the roles of these molecules in osteoclast differentiation are well known, fundamental questions remain unsolved, including the exact location of the RANKL-RANK interaction and the in vivo temporal and spatial information on the transformation of hematopoietic cells into bone-resorbing osteoclasts. This review focuses on the importance of cell-cell contact and metabolic adaptation for differentiation, relatively overlooked aspects of osteoclast biology and biochemistry.
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Affiliation(s)
- Kyoji Ikeda
- Department of Bone and Joint Disease, National Center for Geriatrics and Gerontology, 7-430 Morioka, Obu, Aichi 474-8511, Japan
| | - Sunao Takeshita
- Department of Bone and Joint Disease, National Center for Geriatrics and Gerontology, 7-430 Morioka, Obu, Aichi 474-8511, Japan
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16
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Kobayashi Y, Uehara S, Udagawa N, Takahashi N. Regulation of bone metabolism by Wnt signals. J Biochem 2015; 159:387-92. [PMID: 26711238 DOI: 10.1093/jb/mvv124] [Citation(s) in RCA: 143] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2015] [Accepted: 10/13/2015] [Indexed: 11/14/2022] Open
Abstract
Wnt ligands play a central role in the development and homeostasis of various organs through β-catenin-dependent and -independent signalling. The crucial roles of Wnt/β-catenin signals in bone mass have been established by a large number of studies since the discovery of a causal link between mutations in the low-density lipoprotein receptor-related protein 5 (Lrp5) gene and alternations in human bone mass. The activation of Wnt/β-catenin signalling induces the expression of osterix, a transcription factor, which promotes osteoblast differentiation. Furthermore, this signalling induces the expression of osteoprotegerin, an osteoclast inhibitory factor in osteoblast-lineage cells to prevent bone resorption. Recent studies have also shown that Wnt5a, a typical non-canonical Wnt ligand, enhanced osteoclast formation. In contrast, Wnt16 inhibited osteoclast formation through β-catenin-independent signalling. In this review, we discussed the current understanding of the Wnt signalling molecules involved in bone formation and resorption.
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Affiliation(s)
| | - Shunsuke Uehara
- Department of Biochemistry, Matsumoto Dental University, 1780 Gohara Hiro-Oka, Shiojiri, Nagano 399-0781, Japan
| | - Nobuyuki Udagawa
- Department of Biochemistry, Matsumoto Dental University, 1780 Gohara Hiro-Oka, Shiojiri, Nagano 399-0781, Japan
| | - Naoyuki Takahashi
- Department of Biochemistry, Matsumoto Dental University, 1780 Gohara Hiro-Oka, Shiojiri, Nagano 399-0781, Japan
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17
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Dai Y, Hu S. Recent insights into the role of autophagy in the pathogenesis of rheumatoid arthritis. Rheumatology (Oxford) 2015; 55:403-10. [PMID: 26342228 DOI: 10.1093/rheumatology/kev337] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2015] [Indexed: 12/19/2022] Open
Abstract
Autophagy appears to play a dual role in eukaryotic cells. It manifests cytoprotective effects through the regulation of catabolic processes and the clearance of pathogens; however, a correlation between autophagy and the pathogenesis of autoimmune/autoinflammatory conditions has recently been described. Autophagy has emerged as a mediator in the pathogenesis of RA. Autophagy may regulate apoptosis resistance and hyperplasia in synovial fibroblasts, promote osteoclastogenesis and stimulate osteoclast-mediated bone resorption through the delivery of citrullinated peptides to MHC compartments, which results in the activation of the innate and adaptive immune response, thereby resulting in RA. Given the likely importance of autophagy in the pathogenesis of RA, here we reviewed the detailed mechanisms concerning the pathogenicity of autophagy and autophagy proteins in RA.
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Affiliation(s)
- Yujie Dai
- Department of Rheumatology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Shaoxian Hu
- Department of Rheumatology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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18
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The regulation of osteoclast differentiation by Wnt signals. BONEKEY REPORTS 2015; 4:713. [PMID: 26157576 DOI: 10.1038/bonekey.2015.82] [Citation(s) in RCA: 42] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/03/2015] [Accepted: 04/24/2015] [Indexed: 01/07/2023]
Abstract
Wnt ligands activate β-catenin-dependent canonical and -independent noncanonical signaling pathways. Wnt regulates many physiological events such as the development of organs and bone metabolism. In contrast, failed signaling leads to pathological conditions including cancer and osteoporosis. Analyses of loss-of-function mutations in the low-density lipoprotein receptor-related protein (Lrp) 5 gene revealed that Lrp5 acted as a co-receptor of Wnt/β-catenin signals and positively regulated bone mass in humans and mice. Many players in Wnt signals including sclerostin, an osteocyte-derived Wnt antagonist, also have since been found to influence bone mass. Bone mass is regulated by the activities of bone-forming osteoblasts, -resorbing osteoclasts and matrix-embedded osteocytes. The roles of Wnt/β-catenin signals in osteoblastogenesis and osteoclastogenesis have been established by the findings of a large number of in vitro and in vivo studies. In contrast, the roles of noncanonical Wnt signals in bone metabolism are only now being examined. In this review, we introduced and discussed recent information on the roles of Wnt signals in bone resorption.
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Kim J, Lee H, Kang KS, Chun KH, Hwang GS. Cordyceps militaris Mushroom and Cordycepin Inhibit RANKL-Induced Osteoclast Differentiation. J Med Food 2015; 18:446-52. [DOI: 10.1089/jmf.2014.3215] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Affiliation(s)
- Jinhee Kim
- Laboratory of Cell Differentiation Research, College of Korean Medicine, Gachon University, Seongnam, Korea
| | - Hyejin Lee
- Laboratory of Cell Differentiation Research, College of Korean Medicine, Gachon University, Seongnam, Korea
| | - Ki Sung Kang
- Laboratory of Cell Differentiation Research, College of Korean Medicine, Gachon University, Seongnam, Korea
| | - Kwang-Hoon Chun
- Gachon Institute of Pharmaceutical Sciences, College of Pharmacy, Gachon University, Incheon, Korea
| | - Gwi Seo Hwang
- Laboratory of Cell Differentiation Research, College of Korean Medicine, Gachon University, Seongnam, Korea
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20
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Gümüş P, Özçaka Ö, Ceyhan-Öztürk B, Akcali A, Lappin DF, Buduneli N. Evaluation of biochemical parameters and local and systemic levels of osteoactive and B-cell stimulatory factors in gestational diabetes in the presence or absence of gingivitis. J Periodontol 2014; 86:387-97. [PMID: 25494659 DOI: 10.1902/jop.2014.140444] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
BACKGROUND Gestational diabetes mellitus (GDM) is defined as varying glucose intolerance, with first onset or recognition in pregnancy. This study evaluates clinical and biochemical parameters in a possible association between GDM and gingivitis. METHODS A total of 167 pregnant females was included in the study. There were 101 females with GDM and 66 females without GDM. Subgroups were created according to the presence or absence of gingival inflammation. Plaque index, bleeding on probing, and probing depth were recorded at four sites per tooth. Serum, saliva, and gingival crevicular fluid (GCF) levels of interleukin (IL)-6, IL-8, soluble receptor activator of nuclear factor-kappa B ligand (sRANKL), osteoprotegerin (OPG), B-cell activating factor (BAFF), and a proliferation-inducing ligand (APRIL) were determined by enzyme-linked immunosorbent assay. Data were analyzed by Kruskal-Wallis and Mann-Whitney U tests and Spearman correlation analysis. RESULTS Age and anthropometric indices were higher in the GDM than non-GDM group (P <0.0001). Clinical periodontal recordings, serum BAFF, IL-8, and saliva sRANKL levels were higher in the GDM group (P <0.05). Saliva IL-6 level was higher in the GDM with gingivitis group than non-GDM with gingivitis group (P = 0.044). Serum and GCF BAFF (P <0.0001), serum, saliva, and GCF APRIL (P <0.0001; P <0.0001; P = 0.032, respectively), GCF OPG (P = 0.036), and serum and saliva sRANKL (P <0.0001) were higher in the GDM with gingivitis group than GDM without gingivitis group. CONCLUSIONS The inflammatory response seems to be more pronounced in females with GDM. The observed increase in both local and systemic levels of inflammatory cytokines may suggest an interaction between gingivitis and GDM.
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Affiliation(s)
- Pınar Gümüş
- Department of Periodontology, School of Dentistry, Ege University, İzmir, Turkey
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21
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Yachiguchi K, Sekiguchi T, Nakano M, Hattori A, Yamamoto M, Kitamura KI, Maeda M, Tabuchi Y, Kondo T, Kamauchi H, Nakabayashi H, Srivastav AK, Hayakawa K, Sakamoto T, Suzuki N. Effects of inorganic mercury and methylmercury on osteoclasts and osteoblasts in the scales of the marine teleost as a model system of bone. Zoolog Sci 2014; 31:330-7. [PMID: 24832906 DOI: 10.2108/zs130265] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
To evaluate the effects of inorganic mercury (InHg) and methylmercury (MeHg) on bone metabolism in a marine teleost, the activity of tartrate-resistant acid phosphatase (TRAP) and alkaline phosphatase (ALP) as indicators of such activity in osteoclasts and osteoblasts, respectively, were examined in scales of nibbler fish (Girella punctata). We found several lines of scales with nearly the same TRAP and ALP activity levels. Using these scales, we evaluated the influence of InHg and MeHg. TRAP activity in the scales treated with InHg (10(-5) and 10(-4) M) and MeHg (10(-6) to 10(-4) M) during 6 hrs of incubation decreased significantly. In contrast, ALP activity decreased after exposure to InHg (10(-5) and 10(-4) M) and MeHg (10(-6) to 10(-4) M) for 18 and 36 hrs, although its activity did not change after 6 hrs of incubation. As in enzyme activity 6 hrs after incubation, mRNA expression of TRAP (osteoclastic marker) decreased significantly with InHg and MeHg treatment, while that of collagen (osteoblastic marker) did not change significantly. At 6 hrs after incubation, the mRNA expression of metallothionein, which is a metal-binding protein in osteoblasts, was significantly increased following treatment with InHg or MeHg, suggesting that it may be involved in the protection of osteoblasts against mercury exposure up to 6 hrs after incubation. To our knowledge, this is the first report of the effects of mercury on osteoclasts and osteoblasts using marine teleost scale as a model system of bone.
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Affiliation(s)
- Koji Yachiguchi
- 1 Noto Marine Laboratory, Institute of Nature and Environmental Technology, Kanazawa University, Housu-gun, Ishikawa 927-0553, Japan
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22
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Kawagishi H, Hota K, Masuda K, Yamaguchi K, Yazawa K, Shibata K, Uzuka N, Matahira Y. Osteoclast-Forming Suppressive Compounds from Makomotake,Zizania latifoliaInfected withUstilago esculenta. Biosci Biotechnol Biochem 2014; 70:2800-2. [PMID: 17090930 DOI: 10.1271/bbb.60376] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
A novel compound (1) and a known one (2) were isolated from Makomotake, Zizania latifolia infected with Ustilago esculenta, as osteoclast-forming suppressive substances.
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Affiliation(s)
- Hirokazu Kawagishi
- Graduate School of Science and Technology, Shizuoka University, Suruga-ku, Shizuoka, Japan.
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23
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Mogi M, Kondo A. The presence of RANKL-OPG complex in human osteosarcoma U2OS. J Immunoassay Immunochem 2014; 34:356-64. [PMID: 23859786 DOI: 10.1080/15321819.2012.741640] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023]
Abstract
A sensitive sandwich enzyme-linked immunosorbent assay (ELISA) for the human receptor activator of nuclear factor κB (RANKL)-osteoprotegerin (OPG) complex was developed by utilizing a monoclonal antibody that recognizes human soluble RANKL as an immobilized capture component and biotinylated human OPG polyclonal antibody. We could quantify the RANKL-OPG complex level (detection limit: 100 pg/mL). Employing this assay system, we demonstrated that the RANKL-OPG complex was constitutively present in the conditioned medium of human osteoblastic sarcoma U2OS, although the complex was not detectable in other human osteoblastic sarcoma cell line, MG-63, HOS, and SaOS-2.
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Affiliation(s)
- Makio Mogi
- Department of Medicinal Biochemistry, School of Pharmacy, Aichi-Gakuin University, Nagoya, Japan.
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Vitamin D endocrine system and osteoclasts. BONEKEY REPORTS 2014; 3:495. [PMID: 24605212 PMCID: PMC3944126 DOI: 10.1038/bonekey.2013.229] [Citation(s) in RCA: 66] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/26/2013] [Accepted: 10/25/2013] [Indexed: 12/16/2022]
Abstract
Vitamin D was discovered as an anti-rachitic agent preventing a failure in bone mineralization, but it is now established that the active form of vitamin D3 (1α,25(OH)2D3) induces bone resorption. Discovery of the receptor activator of nuclear factor -κB ligand (RANKL) uncovered the molecular mechanism by which 1α,25(OH)2D3 stimulates bone resorption. Treating osteoblastic cells with 1α,25(OH)2D3 stimulates RANKL expression, which in turn induces osteoclastogenesis. Nevertheless, active vitamin D compounds such as calcitriol (1α,25(OH)2D3), alfacalcidol (1α(OH)D3) and eldecalcitol (1α,25-dihydroxy-2β-(3-hydroxypropoxy) vitamin D3) have been used as therapeutic drugs for osteoporosis, as they increase bone mineral density (BMD) in osteoporotic patients. Paradoxically, the increase in BMD is caused by the suppression of bone resorption. Several studies have been performed to elucidate the mechanism by which active vitamin D compounds suppress bone resorption in vivo. Our study showed that daily administration of eldecalcitol to mice suppressed neither the number of osteoclast precursors in the bone marrow nor the number of osteoclasts formed in ex vivo cultures. Eldecalcitol administration suppressed RANKL expression in osteoblasts. This review discusses how the difference between in vitro and in vivo effects of active vitamin D compounds on bone resorption is induced.
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Pike JW, Lee SM, Meyer MB. Regulation of gene expression by 1,25-dihydroxyvitamin D3 in bone cells: exploiting new approaches and defining new mechanisms. BONEKEY REPORTS 2014; 3:482. [PMID: 24466413 DOI: 10.1038/bonekey.2013.216] [Citation(s) in RCA: 52] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/01/2013] [Accepted: 09/16/2013] [Indexed: 12/27/2022]
Abstract
The biological actions of 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) serve both to orchestrate calcium and phosphorus homeostasis in higher vertebrates and to regulate a diverse set of cellular functions unrelated to control of mineral metabolism. With regard to bone, mesenchymal lineage cells, including both early and late osteoblasts as well as osteocytes represent classic targets of the vitamin D hormone. Accordingly, much of the early information regarding our current understanding of the mechanism of action of 1,25(OH)2D3, of which gene regulation is central, derives from a broad array of studies in these cell types. Indeed, a gene that provided both the earliest and perhaps the most extensive information regarding this and additional mechanisms was that of osteoblast-specific osteocalcin. Subsequent work has provided much additional detail as to how 1,25(OH)2D3, through the vitamin D receptor (VDR), mediates the modulation of many bone cell genes. In recent years, however, a series of technical advances involving the coupling of chromatin immunoprecipitation (ChIP) to unbiased methodologies that involve next-generation DNA sequencing techniques (ChIP-seq) have opened new avenues in the study of gene regulation. In this review, we summarize early work and then focus on more recent studies that have used ChIP-seq analysis and other approaches to provide insight into not only the regulation of specific genes such as the VDR, TNFSF11 (RANKL), LRP5, CBS and CYP24a1, but overarching genome-wide principles of gene regulation as well. The results of these studies highlight the value of these new approaches and the increased insight that can be gained.
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Affiliation(s)
- J Wesley Pike
- Department of Biochemistry, University of Wisconsin-Madison , Madison, WI, USA
| | - Seong Min Lee
- Department of Biochemistry, University of Wisconsin-Madison , Madison, WI, USA
| | - Mark B Meyer
- Department of Biochemistry, University of Wisconsin-Madison , Madison, WI, USA
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Coupling the activities of bone formation and resorption: a multitude of signals within the basic multicellular unit. BONEKEY REPORTS 2014; 3:481. [PMID: 24466412 DOI: 10.1038/bonekey.2013.215] [Citation(s) in RCA: 444] [Impact Index Per Article: 40.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/09/2013] [Accepted: 09/27/2013] [Indexed: 02/07/2023]
Abstract
Coupling between bone formation and bone resorption refers to the process within basic multicellular units in which resorption by osteoclasts is met by the generation of osteoblasts from precursors, and their bone-forming activity, which needs to be sufficient to replace the bone lost. There are many sources of activities that contribute to coupling at remodeling sites, including growth factors released from the matrix, soluble and membrane products of osteoclasts and their precursors, signals from osteocytes and from immune cells and signaling taking place within the osteoblast lineage. Coupling is therefore a process that involves the interaction of a wide range of cell types and control mechanisms. As bone remodeling occurs at many sites asynchronously throughout the skeleton, locally generated activities comprise very important control mechanisms. In this review, we explore the potential roles of a number of these factors, including sphingosine-1-phosphate, semaphorins, ephrins, interleukin-6 (IL-6) family cytokines and marrow-derived factors. Their interactions achieve the essential tight control of coupling within individual remodeling units that is required for control of skeletal mass.
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Hirose J, Masuda H, Tokuyama N, Omata Y, Matsumoto T, Yasui T, Kadono Y, Hennighausen L, Tanaka S. Bone resorption is regulated by cell-autonomous negative feedback loop of Stat5-Dusp axis in the osteoclast. ACTA ACUST UNITED AC 2013; 211:153-63. [PMID: 24367002 PMCID: PMC3892975 DOI: 10.1084/jem.20130538] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
The transcription factor Stat5 inhibits the bone-resorbing function of osteoclasts, in part by inducing the expression of the phosphatases Dusp1 and Dusp2. Signal transducer and activator of transcription 5 (Stat5) is essential for cytokine-regulated processes such as proliferation, differentiation, and survival in hematopoietic cells. To investigate the role of Stat5 in osteoclasts, we generated mice with an osteoclast-specific conditional deletion of Stat5 (Stat5 conditional knockout [cKO] mice) and analyzed their bone phenotype. Stat5 cKO mice exhibited osteoporosis caused by an increased bone-resorbing activity of osteoclasts. The activity of mitogen-activated protein kinases (MAPKs), in particular extracellular signal–related kinase, was increased in Stat5 cKO osteoclasts, whereas the expression of the MAPK phosphatases dual specificity phosphatase 1 (Dusp1) and Dusp2 was significantly decreased. Interleukin-3 (IL-3) stimulated the phosphorylation and nuclear translocation of Stat5 in osteoclasts, and Stat5 expression was up-regulated in response to receptor activator of nuclear factor κB ligand (RANKL). The results suggest that Stat5 negatively regulates the bone-resorbing function of osteoclasts by promoting Dusp1 and Dusp2 expression, and IL-3 promotes Stat5 activation in osteoclasts.
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Affiliation(s)
- Jun Hirose
- Department of Orthopaedic Surgery, Faculty of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo 113-0033, Japan
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Mechanisms of osteoclast-dependent bone formation. BONEKEY REPORTS 2013; 2:449. [PMID: 24422142 DOI: 10.1038/bonekey.2013.183] [Citation(s) in RCA: 67] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/30/2013] [Accepted: 10/08/2013] [Indexed: 01/14/2023]
Abstract
Should we believe that osteoclasts are only involved in bone resorption? What about their contribution to bone formation? In this article I will review evidence that bone formation can be regulated by osteoclasts. Why is this? Likely because in the physiologic condition of bone remodeling, bone resorption and formation are balanced, and there is no better way to control this equilibrium than through a concerted action between the two cell types. Although the influence of osteoblasts on osteoclastic bone resorption is well documented and consolidated over time, what osteoclasts do to regulate osteoblast activity is still matter of intense investigation. The original hypothesis that all is in the osteoblast-seeking factors stored in the bone matrix, released and activated during bone resorption, is now being challenged by several studies, suggesting that osteoclasts are also capable of producing 'clastokines' that regulate osteoblast performance. Indeed, several of them have been demonstrated to orchestrate osteoclast-osteoblast activities. However, we are probably still at the dawn of a new era, and future work will tell us whether any of these clastokines can be exploited to stimulate bone formation and rebalance bone remodeling in skeletal diseases.
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29
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Ko WK, Cho JY, Moon HJ, Jung MS, Yang NR, Heo SJ, Kim SH, Lee JM, Hwang YS, Bae H, Lee CH, Kwon IK. Spica Prunella extract inhibits phosphorylation of JNK, ERK and IκBα signals during osteoclastogenesis. Food Sci Biotechnol 2013. [DOI: 10.1007/s10068-013-0268-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/26/2022] Open
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Titorencu I, Pruna V, Jinga VV, Simionescu M. Osteoblast ontogeny and implications for bone pathology: an overview. Cell Tissue Res 2013; 355:23-33. [PMID: 24292720 DOI: 10.1007/s00441-013-1750-3] [Citation(s) in RCA: 41] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2013] [Accepted: 10/04/2013] [Indexed: 01/06/2023]
Abstract
Osteoblasts are specialized mesenchyme-derived cells accountable for bone synthesis, remodelling and healing. Differentiation of osteoblasts from mesenchymal stem cells (MSC) towards osteocytes is a multi-step process strictly controlled by various genes, transcription factors and signalling proteins. The aim of this review is to provide an update on the nature of bone-forming osteoblastic cells, highlighting recent data on MSC-osteoblast-osteocyte transformation from a molecular perspective and to discuss osteoblast malfunctions in various bone diseases. We present here the consecutive stages occurring in the differentiation of osteoblasts from MSC, the transcription factors involved and the role of miRNAs in the process. Recent data concerning the pathogenic mechanisms underlying the loss of bone mass and architecture caused by malfunctions in the synthetic activity and metabolism of osteoblasts in osteoporosis, osteogenesis imperfecta, osteoarthritis and rheumatoid arthritis are discussed. The newly acquired knowledge of the ontogeny of osteoblasts will assist in unravelling the abnormalities taking place during their differentiation and will facilitate the prevention and/or treatment of bone diseases by therapy directed against altered molecules and mechanisms.
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Affiliation(s)
- Irina Titorencu
- Regenerative Medicine Department, Institute of Cellular Biology and Pathology "Nicolae Simionescu" of the Romanian Academy, Bucharest, Romania
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Yasuda H. RANKL, a necessary chance for clinical application to osteoporosis and cancer-related bone diseases. World J Orthop 2013; 4:207-217. [PMID: 24147256 PMCID: PMC3801240 DOI: 10.5312/wjo.v4.i4.207] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/06/2013] [Revised: 05/21/2013] [Accepted: 06/20/2013] [Indexed: 02/06/2023] Open
Abstract
Osteoporosis is a common bone disease characterized by reduced bone and increased risk of fracture. In postmenopausal women, osteoporosis results from bone loss attributable to estrogen deficiency. Osteoclast differentiation and activation is mediated by receptor activator of nuclear factor-κB ligand (RANKL), its receptor receptor activator of nuclear factor-κB (RANK), and a decoy receptor for RANKL, osteoprotegerin (OPG). The OPG/RANKL/RANK system plays a pivotal role in osteoclast biology. Currently, a fully human anti-RANKL monoclonal antibody named denosumab is being clinically used for the treatment of osteoporosis and cancer-related bone disorders. This review describes recent advances in RANKL-related research, a story from bench to bedside. First, the discovery of the key factors, OPG/RANKL/RANK, revealed the molecular mechanism of osteoclastogenesis. Second, we established three animal models: (1) a novel and rapid bone loss model by administration of glutathione-S transferase-RANKL fusion protein to mice; (2) a novel mouse model of hypercalcemia with anorexia by overexpression of soluble RANKL using an adenovirus vector; and (3) a novel mouse model of osteopetrosis by administration of a denosumab-like anti-mouse RANKL neutralizing monoclonal antibody. Lastly, anti-human RANKL monoclonal antibody has been successfully applied to the treatment of osteoporosis and cancer-related bone disorders in many countries. This is a real example of applying basic science to clinical practice.
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32
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Martin TJ. Historically significant events in the discovery of RANK/RANKL/OPG. World J Orthop 2013; 4:186-197. [PMID: 24147254 PMCID: PMC3801238 DOI: 10.5312/wjo.v4.i4.186] [Citation(s) in RCA: 49] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/04/2012] [Revised: 01/07/2013] [Accepted: 03/23/2013] [Indexed: 02/06/2023] Open
Abstract
After it was suggested 30 years ago that the osteoblast lineage controlled the formation of osteoclasts, methods were developed that established this to be the case, but the molecular controls were elusive. Over more than a decade much evidence was obtained for signaling mechanisms that regulated the production of a membrane - bound regulator of osteoclastogenesis, in the course of which intercellular communication in bone was revealed in its complexity. The discovery of regulation by tumor necrosis factor ligand and receptor families was made in the last few years of the twentieth century, leading since then to a new physiology of bone, and to exciting drug development.
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Msaouel P, Nandikolla G, Pneumaticos SG, Koutsilieris M. Bone microenvironment-targeted manipulations for the treatment of osteoblastic metastasis in castration-resistant prostate cancer. Expert Opin Investig Drugs 2013; 22:1385-400. [PMID: 24024652 DOI: 10.1517/13543784.2013.824422] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023]
Abstract
INTRODUCTION Most patients with advanced prostate cancer will develop incurable bone metastasis. Although prostate cancer is the quintessential androgen-dependent neoplastic disease in males, the tumor will ultimately become refractory to androgen ablation treatment. Understanding the complex dialog between prostate cancer and the bone microenvironment has allowed the development of promising treatment strategies. AREAS COVERED The present review summarizes the pathophysiology of prostate cancer bone metastasis and provides a concise update on bone microenvironment-targeted therapies for prostate cancer. The current and future prospects and challenges of these strategies are also discussed. EXPERT OPINION A wide variety of signaling pathways, bone turnover homeostatic mechanisms and immunoregulatory networks are potential targets for the treatment of metastatic castration-resistant prostate cancer (mCRPC). Anti-survival factor therapy can enhance the efficacy of existing treatment regimens for mCRPC by exploiting the interaction between the bone microenvironment and androgen signaling networks. In addition, many novel bone microenvironment-targeted strategies have produced promising objective clinical responses. Further elucidation of the complex interactions between prostate cancer cells and the bone stroma will open up new avenues for treatment interventions that can produce sustained cancer suppression.
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Affiliation(s)
- Pavlos Msaouel
- Jacobi Medical Center, Department of Internal Medicine, Albert Einstein College of Medicine , Bronx, NY , USA
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34
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Youn BU, Kim K, Kim JH, Lee J, Moon JB, Kim I, Park YW, Kim N. SLAT negatively regulates RANKL-induced osteoclast differentiation. Mol Cells 2013; 36:252-7. [PMID: 23996528 PMCID: PMC3887978 DOI: 10.1007/s10059-013-0159-x] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2013] [Revised: 07/02/2013] [Accepted: 07/02/2013] [Indexed: 12/25/2022] Open
Abstract
RANKL induces the formation of osteoclasts, which are responsible for bone resorption. Herein, we investigated the role of SWAP-70-like adapter of T cells (SLAT) in RANKL-induced osteoclastogenesis. Expression levels of SLAT were reduced during RANKL-induced osteoclastogenesis. Overexpression of SLAT in BMMs inhibited TRAP-positive multinuclear osteoclast formation and attenuated the expression of NFATc1, which is an important modulator in osteoclastogenesis. Furthermore, silencing of SLAT by RNA interference enhanced osteoclast formation as well as NFATc1 expression. In addition, SLAT was involved in RANKL-induced JNK activation in osteoclasts. Taken together, our data suggest that SLAT acts as a negative modulator of RANKL-induced osteoclastogenesis.
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Affiliation(s)
- Bang Ung Youn
- Department of Pharmacology, Medical Research Center for Gene Regulation, Chonnam National University Medical School, Gwangju 501-746, Korea
| | - Kabsun Kim
- Department of Pharmacology, Medical Research Center for Gene Regulation, Chonnam National University Medical School, Gwangju 501-746, Korea
| | - Jung Ha Kim
- Department of Pharmacology, Medical Research Center for Gene Regulation, Chonnam National University Medical School, Gwangju 501-746, Korea
| | - Jongwon Lee
- Department of Pharmacology, Medical Research Center for Gene Regulation, Chonnam National University Medical School, Gwangju 501-746, Korea
| | - Jang Bae Moon
- Department of Pharmacology, Medical Research Center for Gene Regulation, Chonnam National University Medical School, Gwangju 501-746, Korea
| | - Inyoung Kim
- Department of Pharmacology, Medical Research Center for Gene Regulation, Chonnam National University Medical School, Gwangju 501-746, Korea
| | | | - Nacksung Kim
- Department of Pharmacology, Medical Research Center for Gene Regulation, Chonnam National University Medical School, Gwangju 501-746, Korea
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Lee SA, Park JH, Lee SY. Selective induction of P2Y14 receptor by RANKL promotes osteoclast formation. Mol Cells 2013; 36:273-7. [PMID: 24048691 PMCID: PMC3887970 DOI: 10.1007/s10059-013-0226-3] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2013] [Accepted: 08/26/2013] [Indexed: 11/26/2022] Open
Abstract
The purinergic receptor P2Y, G protein coupled, 14 (P2Y14) receptor for UDP-glucose and other UDP-sugars has been implicated in the regulation of the stem cell compartment as well as neuroimmune function. However, the role of P2Y14 in osteoclast formation is completely unknown. We found that RANKL selectively induced P2Y14 among seven mammalian P2Y receptors when analysed at both the mRNA and protein level, but inhibitors of the mitogenactivated protein (MAP) kinase pathway suppressed induction of P2Y14 proteins. Extracellular addition of UDP-sugars such as UDP-glucose, UDP-galactose, UDP-glucuronic acid, and UDP-N-acetyl glucosamine promoted RANKL-induced osteoclastogenesis, while P2Y14 downregulation by RNA interference inhibited osteoclast formation. Taken together, these results suggest that P2Y14 may act as the receptor for UDP-sugars in osteoclast precusors and may regulate RANKL-induced osteoclastogenesis.
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Affiliation(s)
- Seung Ah Lee
- Department of Life Science and the Research Center for Cellular Homeostasis, Ewha Womans University, Seoul 120-750, Korea
| | - Jin Hee Park
- Department of Life Science and the Research Center for Cellular Homeostasis, Ewha Womans University, Seoul 120-750, Korea
| | - Soo Young Lee
- Department of Life Science and the Research Center for Cellular Homeostasis, Ewha Womans University, Seoul 120-750, Korea
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36
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Nakamichi Y, Udagawa N, Takahashi N. IL-34 and CSF-1: similarities and differences. J Bone Miner Metab 2013; 31:486-95. [PMID: 23740288 DOI: 10.1007/s00774-013-0476-3] [Citation(s) in RCA: 81] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/05/2013] [Accepted: 04/22/2013] [Indexed: 12/12/2022]
Abstract
Colony-stimulating factor-1 (CSF-1) is widely expressed and considered to regulate the development, maintenance, and function of mononuclear phagocyte lineage cells such as monocytes, macrophages, dendritic cells (DCs), Langerhans cells (LCs), microglia, and osteoclasts. Interleukin-34 (IL-34) was recently identified as an alternative ligand for the CSF-1 receptor (CSF-1R) through functional proteomics experiments. It is well established that the phenotype of CSF-1R-deficient (CSF-1R⁻/⁻) mice is more severe than that of mice bearing a spontaneous null mutation in CSF-1 (CSF-1(op/op)). CSF-1R⁻/⁻ mice are severely depleted of macrophages and completely lack LCs, microglia, and osteoclasts during their lifetime. In contrast, CSF-1(op/op) mice exhibit late-onset macrophage development and osteoclastogenesis, whereas they show modestly reduced numbers of microglia and a relatively normal LC development. In contrast, IL-34-deficient (IL-34⁻/⁻) mice show a marked reduction of LCs and a decrease in microglia. IL-34 and CSF-1 display different spatiotemporal expression patterns and have distinct biological functions. In this review, we focus on the functional similarities and differences between IL-34 and CSF-1 in vivo.
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Affiliation(s)
- Yuko Nakamichi
- Institute for Oral Science, Matsumoto Dental University, 1780 Hiro-oka Gobara, Shiojiri, Nagano, 399-0781, Japan,
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37
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Seibel MJ, Cooper MS, Zhou H. Glucocorticoid-induced osteoporosis: mechanisms, management, and future perspectives. Lancet Diabetes Endocrinol 2013; 1:59-70. [PMID: 24622268 DOI: 10.1016/s2213-8587(13)70045-7] [Citation(s) in RCA: 142] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
Glucocorticoids are widely used for their unsurpassed anti-inflammatory and immunomodulatory effects. However, the therapeutic use of glucocorticoids is almost always limited by substantial adverse outcomes such as osteoporosis, diabetes, and obesity. These unwanted outcomes are a major dilemma for clinicians because improvements in the primary disorder seem to be achievable only by accepting substantial adverse effects that are often difficult to prevent or treat. To understand the pathogenesis of glucocorticoid-induced osteoporosis, it is necessary to consider that the actions of glucocorticoids on bone and mineral metabolism are strongly dose and time dependent. At physiological concentrations, endogenous glucocorticoids are key regulators of mesenchymal cell differentiation and bone development, with additional regulatory roles in renal and intestinal calcium handling. However, at supraphysiological concentrations, glucocorticoids affect the same systems in different and often unfavourable ways. For many years, these anabolic and catabolic actions of glucocorticoids on bone were deemed paradoxical. In this Review, we highlight recent advances in our understanding of the mechanisms underlying the physiology and pathophysiology of glucocorticoid action on the skeleton and discuss present and future management strategies for glucocorticoid-induced osteoporosis.
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Affiliation(s)
- Markus J Seibel
- Bone Research Program, Concord Hospital, Concord, Sydney, NSW, Australia; ANZAC Research Institute, Concord Hospital, Concord, Sydney, NSW, Australia; Department of Endocrinology and Metabolism, Concord Hospital, Concord, Sydney, NSW, Australia; Concord Clinical School, Concord Hospital, Concord, Sydney, NSW, Australia.
| | - Mark S Cooper
- Adrenal Steroid Laboratory, Concord Hospital, Concord, Sydney, NSW, Australia; ANZAC Research Institute, Concord Hospital, Concord, Sydney, NSW, Australia; Department of Endocrinology and Metabolism, Concord Hospital, Concord, Sydney, NSW, Australia; Concord Clinical School, Concord Hospital, Concord, Sydney, NSW, Australia
| | - Hong Zhou
- Bone Research Program, Concord Hospital, Concord, Sydney, NSW, Australia; Concord Clinical School, Concord Hospital, Concord, Sydney, NSW, Australia
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38
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Yabumoto T, Miyazawa K, Tabuchi M, Shoji S, Tanaka M, Kadota M, Yoshizako M, Kawatani M, Osada H, Maeda H, Goto S. Stabilization of tooth movement by administration of reveromycin A to osteoprotegerin-deficient knockout mice. Am J Orthod Dentofacial Orthop 2013; 144:368-80. [DOI: 10.1016/j.ajodo.2013.04.016] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2012] [Revised: 04/01/2013] [Accepted: 04/01/2013] [Indexed: 10/26/2022]
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39
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Liu L, Peng B. The Expression of Macrophage Migration Inhibitory Factor Is Correlated with Receptor Activator of Nuclear Factor Kappa B Ligand in Induced Rat Periapical Lesions. J Endod 2013; 39:984-9. [DOI: 10.1016/j.joen.2013.03.001] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2012] [Revised: 03/02/2013] [Accepted: 03/03/2013] [Indexed: 01/02/2023]
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40
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Nicolin V, Narducci P, Bareggi R. Immunolocalization of Protein Kinase C Alpha, Delta, Epsilon, and Zeta During Preosteoclast Diffferentiation Induced by Receptor Activator of NF-Kappa B Ligand and Macrophage-Colony Stimulating Factor. J Histotechnol 2013. [DOI: 10.1179/his.2006.29.3.167] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/31/2022]
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Abstract
It is now well acknowledged that the immune and skeletal systems interact and affect one another during developmental physiology and pathology. With the aid of modern conditional gene targeting and transgenic technologies, this field of interdisciplinary research, known as osteoimmunology, is rapidly advancing. Numerous bone phenotypes have been described in immune-compromised gene-deficient mice and, albeit to a lesser extent, immune deficiencies exist in osteo-compromised gene-deficient mice, suggesting that bone cells themselves actually regulate the development of immune cells directly. In this review, I discuss the essential role of key cytokines, signalling transduction pathways and transcription factors during immune and bone development, and how pathology driven dysregulation of these shared mechanisms can lead to clinical manifestations. Diseases that are within the remit of osteoimmunology continue to cause significant morbidity, for example, rheumatoid arthritis, osteoporosis, multiple myeloma and breast/prostate cancer. The complexity and overlapping cellular and molecular interactions between the immune and bone tissues, mean that despite fervent research of these diseases, it remains a major challenge to discover therapeutics that can specifically target one system without detrimentally affecting the other.
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Affiliation(s)
- Lynett Danks
- Department of Immunology, Graduate School of Medicine and Faculty of Medicine, The University of Tokyo, Japan
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42
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Recht M, Liel MS, Turner RT, Klein RF, Taylor JA. The bone disease associated with factor VIII deficiency in mice is secondary to increased bone resorption. Haemophilia 2013; 19:908-12. [DOI: 10.1111/hae.12195] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/29/2013] [Indexed: 12/01/2022]
Affiliation(s)
- M. Recht
- The Hemophilia Center; Oregon Health & Science University; Portland OR USA
| | - M. S. Liel
- The Hemophilia Center; Oregon Health & Science University; Portland OR USA
- Portland Veterans Affairs Medical Center; Portland OR USA
| | - R. T. Turner
- Skeletal Biology, College of Public Health and Human Sciences; Oregon State University; Corvallis OR USA
| | - R. F. Klein
- Bone and Mineral Research Unit; Division of Endocrinology; Oregon Health & Science University; Portland OR USA
| | - J. A. Taylor
- The Hemophilia Center; Oregon Health & Science University; Portland OR USA
- Portland Veterans Affairs Medical Center; Portland OR USA
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43
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Akman S, Canakci V, Kara A, Tozoglu U, Arabaci T, Dagsuyu İM. Therapeutic Effects of Alpha Lipoic Acid and Vitamin C on Alveolar Bone Resorption After Experimental Periodontitis in Rats: A Biochemical, Histochemical, and Stereologic Study. J Periodontol 2013; 84:666-74. [DOI: 10.1902/jop.2012.120252] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
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44
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Jacome-Galarza CE, Lee SK, Lorenzo JA, LeonardoAguila H. Identification, characterization, and isolation of a common progenitor for osteoclasts, macrophages, and dendritic cells from murine bone marrow and periphery. J Bone Miner Res 2013; 28:1203-13. [PMID: 23165930 PMCID: PMC3625454 DOI: 10.1002/jbmr.1822] [Citation(s) in RCA: 117] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/14/2012] [Revised: 10/18/2012] [Accepted: 11/05/2012] [Indexed: 12/11/2022]
Abstract
Osteoclasts are specialized bone-resorbing cells that derive from monocyte precursors. We have identified three populations of cells with high osteoclastogenic potential in murine bone marrow, which expressed the phenotype B220(-) CD3(-) CD11b(-/low) CD115(+) and either CD117(hi), CD117(intermediate), or CD117(low). We have evaluated these populations for their ability to also generate macrophages and dendritic cells. At a single-cell level, the population expressing higher CD117 levels was able to generate bone-resorbing osteoclasts, phagocytic macrophages, and antigen-presenting dendritic cells in vitro with efficiencies of more than 90%, indicating that there exists a common developmental pathway for these cell types. Cells with osteoclastogenic potential also exist in blood and peripheral hematopoietic organs. Their functional meaning and/or their relationship with bone marrow progenitors is not well established. Hence, we characterized murine peripheral cell populations for their ability to form osteoclasts, macrophages, and dendritic cells in vitro. The spleen and peripheral blood monocyte progenitors share phenotypic markers with bone marrow progenitors but differ in their expression of CD11b, which was low in bone marrow but high in periphery. We propose that circulating monocyte progenitors are derived from a common bone marrow osteoclasts/macrophage/dendritic cell progenitor (OcMDC), which we have now characterized at a clonal level. However, the lineage relationship between the bone marrow and peripheral monocyte progenitors has yet to be defined.
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Affiliation(s)
| | - Sun-Kyeong Lee
- Department of Medicine, University of Connecticut Health Center. Farmington, CT, USA
| | - Joseph A. Lorenzo
- Department of Medicine, University of Connecticut Health Center. Farmington, CT, USA
| | - Hector LeonardoAguila
- Department of Immunology, University of Connecticut Health Center. Farmington, CT, USA
- Department of Medicine, University of Connecticut Health Center. Farmington, CT, USA
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45
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Takahashi A, Kukita A, Li YJ, Zhang JQ, Nomiyama H, Yamaza T, Ayukawa Y, Koyano K, Kukita T. Tunneling nanotube formation is essential for the regulation of osteoclastogenesis. J Cell Biochem 2013; 114:1238-47. [DOI: 10.1002/jcb.24433] [Citation(s) in RCA: 43] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2012] [Accepted: 10/22/2012] [Indexed: 01/19/2023]
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46
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Kim WK, Kim JC, Park HJ, Sul OJ, Lee MH, Kim JS, Choi HS. Platinum nanoparticles reduce ovariectomy-induced bone loss by decreasing osteoclastogenesis. Exp Mol Med 2013; 44:432-9. [PMID: 22525805 PMCID: PMC3406288 DOI: 10.3858/emm.2012.44.7.048] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Abstract
Platinum nanoparticles (PtNP) exhibit remarkable antioxidant activity. There is growing evidence concerning a positive relationship between oxidative stress and bone loss, suggesting that PtNP could protect against bone loss by modulating oxidative stress. Intragastric administration of PtNP reduced ovariectomy (OVX)-induced bone loss with a decreased level of activity and number of osteoclast (OC) in vivo. PtNP inhibited OC formation by impairing the receptor activator of nuclear factor-κB ligand (RANKL) signaling. This impairment was due to a decreased activation of nuclear factor-κB and a reduced level of nuclear factor in activated T-cells, cytoplasmic 1 (NFAT2). PtNP lowered RANKL-induced long lasting reactive oxygen species as well as intracellular concentrations of Ca2+ oscillation. Our data clearly highlight the potential of PtNP for the amelioration of bone loss after estrogen deficiency by attenuated OC formation.
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Affiliation(s)
- Woon-Ki Kim
- Department of Biological Sciences (BK21 Program) and Immunomodulation Research Center, University of Ulsan, Ulsan 680-749, Korea
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47
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Kim J, Park Y, Lee SH, Park Y. trans-10,cis-12 conjugated linoleic acid promotes bone formation by inhibiting adipogenesis by peroxisome proliferator activated receptor-γ-dependent mechanisms and by directly enhancing osteoblastogenesis from bone marrow mesenchymal stem cells. J Nutr Biochem 2013; 24:672-9. [PMID: 22832076 PMCID: PMC3482420 DOI: 10.1016/j.jnutbio.2012.03.017] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2011] [Revised: 03/07/2012] [Accepted: 03/19/2012] [Indexed: 12/14/2022]
Abstract
The bone undergoes continuous remodeling of osteoblastic bone formation and osteoclastic bone resorption to maintain proper bone mass. It is also reported that bone marrow adiposity has a reciprocal role in osteoblasts due to their same origin from mesenchymal stem cells. In addition, one of the key mediators of adipogenesis, peroxisome-proliferator activated receptor-γ (PPARγ), plays a significant role in osteoblastogenesis in bone marrow mesenchymal stem cells. One dietary component that is known to have significant impact on adiposity and bone mass is conjugated linoleic acid (CLA). However, the link between controlling adiposity to improving bone mass by CLA has not been studied intensively. Thus, the purpose of this study is to determine the role of CLA on bone marrow adiposity and bone formation using murine mesenchymal stem cells. The results confirmed that the trans-10,cis-12 CLA, but not the cis-9,trans-11 CLA isomer, significantly inhibited adipogenesis and promoted osteoblastogenesis from mesenchymal stem cells. The inhibition of adipogenesis by the trans-10,cis-12 CLA was mediated by PPARγ; however, the trans-10,cis-12 CLA had a direct effect on osteoblastogenesis which was independent to PPARγ in this model. The trans-10,cis-12 CLA also had significant effects on osteoclastogenesis inhibitory factor, which suggests potential influence of CLA on osteoclastogenesis. Overall, the results suggest that the trans-10,cis-12, but not the cis-9,trans-11 CLA isomer, has a positive impact on bone health by both PPARγ mediated and independent mechanisms in mesenchymal stem cells.
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Affiliation(s)
- Jonggun Kim
- Department of Food Science, University of Massachusetts, Amherst, MA 01003, USA
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48
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Van Phan T, Sul OJ, Ke K, Lee MH, Kim WK, Cho YS, Kim HJ, Kim SY, Chung HT, Choi HS. Carbon monoxide protects against ovariectomy-induced bone loss by inhibiting osteoclastogenesis. Biochem Pharmacol 2013; 85:1145-52. [DOI: 10.1016/j.bcp.2013.01.014] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2012] [Revised: 01/14/2013] [Accepted: 01/15/2013] [Indexed: 12/15/2022]
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49
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Burris TP, Solt LA, Wang Y, Crumbley C, Banerjee S, Griffett K, Lundasen T, Hughes T, Kojetin DJ. Nuclear receptors and their selective pharmacologic modulators. Pharmacol Rev 2013; 65:710-78. [PMID: 23457206 PMCID: PMC11060414 DOI: 10.1124/pr.112.006833] [Citation(s) in RCA: 187] [Impact Index Per Article: 15.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023] Open
Abstract
Nuclear receptors are ligand-activated transcription factors and include the receptors for steroid hormones, lipophilic vitamins, sterols, and bile acids. These receptors serve as targets for development of myriad drugs that target a range of disorders. Classically defined ligands that bind to the ligand-binding domain of nuclear receptors, whether they are endogenous or synthetic, either activate receptor activity (agonists) or block activation (antagonists) and due to the ability to alter activity of the receptors are often termed receptor "modulators." The complex pharmacology of nuclear receptors has provided a class of ligands distinct from these simple modulators where ligands display agonist/partial agonist/antagonist function in a tissue or gene selective manner. This class of ligands is defined as selective modulators. Here, we review the development and pharmacology of a range of selective nuclear receptor modulators.
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Affiliation(s)
- Thomas P Burris
- The Scripps Research Institute, 130 Scripps Way 2A1, Jupiter, FL 33458, USA.
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50
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Kamio N, Kawato T, Tanabe N, Kitami S, Morita T, Ochiai K, Maeno M. Vaspin attenuates RANKL-induced osteoclast formation in RAW264.7 cells. Connect Tissue Res 2013; 54:147-52. [PMID: 23323745 DOI: 10.3109/03008207.2012.761978] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Abstract
Visceral adipose tissue-derived serine protease inhibitor (vaspin), an adipokine that was recently identified in a rat model of type 2 diabetes, has been suggested to have an insulin-sensitizing effect. In this study, we investigated whether vaspin inhibits receptor activator of nuclear factor-κB ligand (RANKL)-induced osteoclastogenesis using two types of osteoclast precursors: RAW264.7 cells and bone marrow cells (BMCs). Vaspin inhibited RANKL-induced osteoclastogenesis in RAW264.7 cells and BMCs. Interestingly, vaspin also inhibited the RANKL-induced expression of nuclear factor of activated T cells c1 (NFATc1) in RAW264.7 cells and BMCs. Furthermore, it inhibited the RANKL-induced upregulation of matrix metalloproteinase-9 and cathepsin K in RAW264.7 cells. Thus, we suggest that vaspin downregulates osteoclastogenesis in part by inhibiting expression of the transcription factor NFATc1.
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Affiliation(s)
- Noriaki Kamio
- Department of Microbiology, Nihon University School of Dentistry, Tokyo, Japan.
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