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  1. Artikel: The development and function of the skeleton and bone metastases.

    Rodan, Gideon A

    Cancer

    2003  Band 97, Heft 3 Suppl, Seite(n) 726–732

    Abstract: Bone is a frequent site of metastases of the most common tumors, e.g., breast carcinoma and prostate carcinoma. The functions of the skeleton, calcium homeostasis and mechanical support, are carried out by the continuous destruction and rebuilding of ... ...

    Abstract Bone is a frequent site of metastases of the most common tumors, e.g., breast carcinoma and prostate carcinoma. The functions of the skeleton, calcium homeostasis and mechanical support, are carried out by the continuous destruction and rebuilding of small packets of this tissue called bone remodeling. Multinucleated, hemopoietically derived osteoclasts, which are related to macrophages, digest the bone, and mesenchymal-derived osteoblasts rebuild it. This process is kept in balance by finely regulated processes whereby osteoblast lineage cells respond to homeostatic signals and release factors that regulate osteoclast generation and activity. Cells that participate in inflammation and immunity also can stimulate osteoclast formation and lead to bone destruction. Tumor cells most likely subvert these physiologic processes to lodge in bone and cause metastases.
    Mesh-Begriff(e) Bone Neoplasms/physiopathology ; Bone Neoplasms/secondary ; Bone Remodeling/physiology ; Bone and Bones/embryology ; Bone and Bones/physiology ; Breast Neoplasms/pathology ; Female ; Humans ; Male ; Osteoblasts/cytology ; Osteoblasts/physiology ; Osteoclasts/cytology ; Osteoclasts/physiology ; Parathyroid Hormone/physiology ; Prostatic Neoplasms/pathology
    Chemische Substanzen Parathyroid Hormone
    Sprache Englisch
    Erscheinungsdatum 2003-02-01
    Erscheinungsland United States
    Dokumenttyp Journal Article ; Review
    ZDB-ID 1429-1
    ISSN 1097-0142 ; 0008-543X ; 1934-662X
    ISSN (online) 1097-0142
    ISSN 0008-543X ; 1934-662X
    DOI 10.1002/cncr.11147
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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  2. Artikel: Bisphosphonates and primary hyperparathyroidism.

    Rodan, Gideon A

    Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research

    2002  Band 17 Suppl 2, Seite(n) N150–3

    Abstract: Bisphosphonates (BP) are pyrophosphate analogs that include very potent inhibitors of bone resorption. BPs act directly on the osteoclast, suppressing isoprenylation by inhibiting farnesyl diphosphate synthase in the cholesterol pathway, which causes ... ...

    Abstract Bisphosphonates (BP) are pyrophosphate analogs that include very potent inhibitors of bone resorption. BPs act directly on the osteoclast, suppressing isoprenylation by inhibiting farnesyl diphosphate synthase in the cholesterol pathway, which causes osteoclast inactivation. BPs should therefore reduce the bone loss produced by any cause, including hyperparathyroidism and hypercalcemia of malignancy (MIH), caused by parathyroid hormone (PTH) and PTH-related protein (PTHrP), respectively. BPs at higher doses than used in osteoporosis are indeed the treatment of choice for malignancy-induced hypercalcemia. Limited, but convincing, data show that BPs at doses effective in osteoporosis also reverse bone loss associated with mild primary hyperparathyroidism (PHPT).
    Mesh-Begriff(e) Alkyl and Aryl Transferases/antagonists & inhibitors ; Alkyl and Aryl Transferases/metabolism ; Bone Resorption/metabolism ; Carcinoma/drug therapy ; Diphosphonates/pharmacology ; Diphosphonates/therapeutic use ; Geranyltranstransferase ; Humans ; Hypercalcemia/drug therapy ; Hypercalcemia/etiology ; Hyperparathyroidism/complications ; Hyperparathyroidism/drug therapy ; Osteoclasts/drug effects ; Osteoclasts/metabolism ; Osteoporosis/drug therapy ; Parathyroid Hormone/physiology ; Parathyroid Hormone-Related Protein ; Parathyroid Neoplasms/drug therapy ; Peptide Hormones/antagonists & inhibitors ; Peptide Hormones/metabolism
    Chemische Substanzen Diphosphonates ; PTHLH protein, human ; Parathyroid Hormone ; Parathyroid Hormone-Related Protein ; Peptide Hormones ; Alkyl and Aryl Transferases (EC 2.5.-) ; Geranyltranstransferase (EC 2.5.1.10)
    Sprache Englisch
    Erscheinungsdatum 2002-11
    Erscheinungsland United States
    Dokumenttyp Journal Article ; Review
    ZDB-ID 632783-7
    ISSN 1523-4681 ; 0884-0431
    ISSN (online) 1523-4681
    ISSN 0884-0431
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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  3. Artikel: Mechanism of action of bisphosphonates.

    Reszka, Alfred A / Rodan, Gideon A

    Current osteoporosis reports

    2005  Band 1, Heft 2, Seite(n) 45–52

    Abstract: In recent years, substantial progress has been made in understanding the mechanism for bisphosphonate suppression of bone turnover. Bisphosphonates can now be distinguished based on their molecular and cellular mechanisms of action. Simple ... ...

    Abstract In recent years, substantial progress has been made in understanding the mechanism for bisphosphonate suppression of bone turnover. Bisphosphonates can now be distinguished based on their molecular and cellular mechanisms of action. Simple bisphosphonates such as clodronate and etidronate inhibit bone resorption through induction of osteoclast apoptosis. Clodronate, and perhaps etidronate, triggers apoptosis by generating a toxic analog of adenosine triphosphate, which then targets the mitochondria, the energy center within the cell. For nitrogen-containing bisphosphonates, the direct intracellular target is the enzyme farnesyl diphosphate synthase in the cholesterol biosynthetic pathway. Its inhibition suppresses a process called protein geranylgeranylation, which is essential for the basic cellular processes required for osteoclastic bone resorption. Although nitrogen-containing bisphosphonates can induce osteoclast apoptosis, this is not necessary for their inhibition of bone resorption.
    Mesh-Begriff(e) Bone Resorption/prevention & control ; Clodronic Acid/chemistry ; Clodronic Acid/therapeutic use ; Diphosphonates/pharmacology ; Diphosphonates/therapeutic use ; Etidronic Acid/chemistry ; Etidronic Acid/therapeutic use ; Humans ; Osteoporosis/prevention & control ; Sensitivity and Specificity ; Structure-Activity Relationship
    Chemische Substanzen Diphosphonates ; Clodronic Acid (0813BZ6866) ; Etidronic Acid (M2F465ROXU)
    Sprache Englisch
    Erscheinungsdatum 2005-07-15
    Erscheinungsland United States
    Dokumenttyp Comparative Study ; Journal Article ; Review
    ZDB-ID 2186581-4
    ISSN 1544-1873
    ISSN 1544-1873
    DOI 10.1007/s11914-003-0008-5
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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  4. Buch: Calcium and phosphorus metabolism

    Irving, James T. / Bronner, Felix / Rodan, Gideon A.

    1973  

    Verfasserangabe James T. Irving. With chapters by Felix Bronner ; Gideon A. Rodan
    Schlagwörter Phosphorstoffwechsel ; Calciumstoffwechsel
    Schlagwörter Calcium ; Kalziumstoffwechsel ; Phosphatstoffwechsel ; Phosphor ; Phosphate
    Sprache Englisch
    Umfang VIII, 246 S.
    Verlag Acad. Press
    Erscheinungsort New York u.a.
    Erscheinungsland Vereinigte Staaten
    Dokumenttyp Buch
    HBZ-ID HT002755100
    ISBN 0-12-374350-8 ; 978-0-12-374350-3
    Datenquelle Katalog ZB MED Medizin, Gesundheit

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    1975 A 520 bestellbar zur Ausleihe Magazin

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  5. Artikel: Osteoporosis and bisphosphonates.

    Rodan, Gideon A / Reszka, Alfred A

    The Journal of bone and joint surgery. American volume

    2003  Band 85-A Suppl 3, Seite(n) 8–12

    Mesh-Begriff(e) Aged ; Bone Density/drug effects ; Bone Density/physiology ; Bone Remodeling/drug effects ; Bone Remodeling/physiology ; Diphosphonates/adverse effects ; Diphosphonates/chemistry ; Diphosphonates/therapeutic use ; Female ; Humans ; Male ; Middle Aged ; Osteoclasts/drug effects ; Osteoclasts/physiology ; Osteoporosis/drug therapy ; Osteoporosis/physiopathology ; Osteoporosis, Postmenopausal/drug therapy ; Osteoporosis, Postmenopausal/physiopathology ; Structure-Activity Relationship
    Chemische Substanzen Diphosphonates
    Sprache Englisch
    Erscheinungsdatum 2003-08-13
    Erscheinungsland United States
    Dokumenttyp Lecture
    ZDB-ID 220625-0
    ISSN 1535-1386 ; 0021-9355
    ISSN (online) 1535-1386
    ISSN 0021-9355
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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  6. Artikel: Nitrogen-containing bisphosphonate mechanism of action.

    Reszka, Alfred A / Rodan, Gideon A

    Mini reviews in medicinal chemistry

    2004  Band 4, Heft 7, Seite(n) 711–719

    Abstract: The current paradigm for drug discovery requires the identification of a target involved in the disease process (e.g. enzyme or receptor) and the development of an appropriate ligand (activator, inhibitor or selective modulator). Selection of ligands for ...

    Abstract The current paradigm for drug discovery requires the identification of a target involved in the disease process (e.g. enzyme or receptor) and the development of an appropriate ligand (activator, inhibitor or selective modulator). Selection of ligands for clinical development is based on the therapeutic window between efficacy vs. safety and ADME (absorption, distribution, metabolism and elimination) considerations. For bisphosphonates (BPs) the process has not followed that paradigm. BPs have very low absorption and are retained in bone, their target tissue. A few have been used on a limited basis for over 20 years in diseases of rapid bone destruction (e.g. post-menopausal osteoporosis, Paget's disease, bone metastases, etc.), without understanding their molecular mechanism of action. The nitrogen-containing BPs (N-BPs) are the latest and most potent addition to this family of compounds and have the widest use. They have high potency, are specifically targeted to the osteoclast on bone and are used at very low doses (5-10 mg clinically). Over the last four years, there was significant progress in elucidating the mechanism of action of BPs, both lacking and containing nitrogen. This review will focus on the mechanism of action of the N-BPs, specifically alendronate (ALN) and risedronate (RIS), the two agents most widely used. For these and all other N-BPs, the molecular target is the isoprenoid biosynthetic enzyme, farnesyl diphosphate synthase, in the cholesterol biosynthesis pathway. Although inhibition of this enzyme by N-BPs results in the suppression of sterol biosynthesis, it is actually disruption of a branch pathway, isoprenylation, that is responsible for N-BP pharmacological activity. Isoprenylation involves covalent linkage of the 15 or 20 carbon isoprene moiety farnesyl diphosphate or geranylgeranyl diphosphate, respectively, to the carboxy-terminus of regulatory proteins, including the small GTPases Ras, Rac, Rho and Cdc42. The latter three, as well as numerous others, are geranylgeranylated and play a rate-limiting role in the activity of the bone-resorbing osteoclast. This targeted osteoclast inhibition accounts for the potency of the N-BPs and for their ability to elicit the desired therapeutic response of suppressing bone turnover. The occasional gastrointestinal irritation caused by N-BPs appears to be mechanism-based and is also briefly reviewed.
    Mesh-Begriff(e) Alkyl and Aryl Transferases/antagonists & inhibitors ; Animals ; Bone Resorption/drug therapy ; Bone Resorption/enzymology ; Bone Resorption/metabolism ; Cholesterol/biosynthesis ; Diphosphonates/adverse effects ; Diphosphonates/chemistry ; Diphosphonates/pharmacology ; Diphosphonates/therapeutic use ; Geranyltranstransferase ; Humans ; Molecular Structure ; Nitrogen/chemistry ; Osteoclasts/drug effects ; Osteoclasts/enzymology ; Osteoclasts/metabolism ; Protein Prenylation/drug effects
    Chemische Substanzen Diphosphonates ; Cholesterol (97C5T2UQ7J) ; Alkyl and Aryl Transferases (EC 2.5.-) ; Geranyltranstransferase (EC 2.5.1.10) ; Nitrogen (N762921K75)
    Sprache Englisch
    Erscheinungsdatum 2004-09
    Erscheinungsland Netherlands
    Dokumenttyp Journal Article ; Review
    ZDB-ID 2104081-3
    ISSN 1875-5607 ; 1389-5575
    ISSN (online) 1875-5607
    ISSN 1389-5575
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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  7. Artikel: Control of osteoblast function and regulation of bone mass.

    Harada, Shun-ichi / Rodan, Gideon A

    Nature

    2003  Band 423, Heft 6937, Seite(n) 349–355

    Abstract: The skeleton is an efficient 'servo' (feedback-controlled/steady-state) system that continuously integrates signals and responses which sustain its functions of delivering calcium while maintaining strength. In many individuals, bone mass homeostasis ... ...

    Abstract The skeleton is an efficient 'servo' (feedback-controlled/steady-state) system that continuously integrates signals and responses which sustain its functions of delivering calcium while maintaining strength. In many individuals, bone mass homeostasis starts failing in midlife, leading to bone loss, osteoporosis and debilitating fractures. Recent advances, spearheaded by genetic information, offer the opportunity to stop or reverse this downhill course.
    Mesh-Begriff(e) Bone Development/genetics ; Bone and Bones/cytology ; Bone and Bones/physiology ; Homeostasis ; Humans ; Organ Size ; Osteoblasts/cytology ; Osteoblasts/physiology ; Signal Transduction ; Transcription, Genetic
    Sprache Englisch
    Erscheinungsdatum 2003-05-15
    Erscheinungsland England
    Dokumenttyp Journal Article ; Review
    ZDB-ID 120714-3
    ISSN 1476-4687 ; 0028-0836
    ISSN (online) 1476-4687
    ISSN 0028-0836
    DOI 10.1038/nature01660
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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  8. Artikel: Bisphosphonate mechanism of action.

    Reszka, Alfred A / Rodan, Gideon A

    Current rheumatology reports

    2003  Band 5, Heft 1, Seite(n) 65–74

    Abstract: The nitrogen-containing bisphosphonates (N-BPs), alendronate and risedronate, are the only pharmacologic agents shown to prevent spine and nonvertebral fractures associated with postmenopausal and glucocorticoid-induced osteoporosis. At the tissue level, ...

    Abstract The nitrogen-containing bisphosphonates (N-BPs), alendronate and risedronate, are the only pharmacologic agents shown to prevent spine and nonvertebral fractures associated with postmenopausal and glucocorticoid-induced osteoporosis. At the tissue level, this is achieved through osteoclast inhibition, which leads to reduced bone turnover, increased bone mass, and improved mineralization. The molecular targets of bisphosphonates (BPs) have recently been identified. This review will discuss the mechanism of action of BPs, focusing on alendronate and risedronate, which are the two agents most widely studied. They act on the cholesterol biosynthesis pathway enzyme, farnesyl diphosphate synthase. By inhibiting this enzyme in the osteoclast, they interfere with geranylgeranylation (attachment of the lipid to regulatory proteins), which causes osteoclast inactivation. This mechanism is responsible for N-BP suppression of osteoclastic bone resorption and reduction of bone turnover, which leads to fracture prevention.
    Mesh-Begriff(e) Apoptosis ; Bone Resorption/metabolism ; Diphosphonates/chemistry ; Diphosphonates/metabolism ; Diphosphonates/pharmacology ; Humans ; Mevalonic Acid/antagonists & inhibitors ; Osteoclasts/drug effects ; Osteoclasts/metabolism ; Osteoclasts/physiology ; Osteoporosis/metabolism
    Chemische Substanzen Diphosphonates ; Mevalonic Acid (S5UOB36OCZ)
    Sprache Englisch
    Erscheinungsdatum 2003-02-11
    Erscheinungsland United States
    Dokumenttyp Journal Article ; Review
    ZDB-ID 2057357-1
    ISSN 1523-3774
    ISSN 1523-3774
    DOI 10.1007/s11926-003-0085-6
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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  9. Artikel: Involvement of alpha(v)beta3 integrins in osteoclast function.

    Nakamura, Ichiro / Duong, Le T / Rodan, Sevgi B / Rodan, Gideon A

    Journal of bone and mineral metabolism

    2007  Band 25, Heft 6, Seite(n) 337–344

    Abstract: Integrins are heterodimeric adhesion receptors that mediate cell-matrix interaction. Osteoclast exhibits high expression of the alpha(v)beta(3) integrin, which binds to a variety of extracellular matrix proteins including vitronectin, osteopontin, and ... ...

    Abstract Integrins are heterodimeric adhesion receptors that mediate cell-matrix interaction. Osteoclast exhibits high expression of the alpha(v)beta(3) integrin, which binds to a variety of extracellular matrix proteins including vitronectin, osteopontin, and bone sialoprotein. Arg-Gly-Asp (RGD)-containing peptides, RGD-mimetics, and blocking antibodies to alpha(v)beta(3) integrin were shown to inhibit bone resorption in vitro and in vivo, suggesting that this integrin may play an important role in regulating osteoclast function. Several lines of evidence have demonstrated that a number of signaling molecules are involved in the alpha(v)beta(3) integrin-dependent signaling pathway, including c-Src, Pyk2, c-Cbl, and p130(Cas). In this article, we review the history of "alpha(v)beta(3) integrin and osteoclasts" and discuss the involvement of alpha(v)beta(3) integrins in osteoclast function at tissue, cellular, and molecular levels. A better understanding of the role of alpha(v)beta(3) integrin in osteoclastic bone resorption would provide opportunities for developing new therapeutics to treat human bone diseases, including rheumatoid arthritis, osteoporosis, and periodontal disease.
    Mesh-Begriff(e) Animals ; Bone Diseases/therapy ; Humans ; Integrin alphaVbeta3/metabolism ; Osteoclasts/cytology ; Osteoclasts/metabolism ; Receptor Cross-Talk ; Signal Transduction
    Chemische Substanzen Integrin alphaVbeta3
    Sprache Englisch
    Erscheinungsdatum 2007-10-25
    Erscheinungsland Japan
    Dokumenttyp Journal Article ; Review
    ZDB-ID 1295123-7
    ISSN 1435-5604 ; 0914-8779
    ISSN (online) 1435-5604
    ISSN 0914-8779
    DOI 10.1007/s00774-007-0773-9
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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  10. Artikel: Pathogenesis of osteoporosis.

    Raisz, Lawrence G / Rodan, Gideon A

    Endocrinology and metabolism clinics of North America

    2003  Band 32, Heft 1, Seite(n) 15–24

    Abstract: There are many pathways that might lead to decreased bone mass, skeletal fragility, and increased fracture risk in osteoporosis. Some of these have been clearly identified, such as estrogen deficiency. Others that were conceived on the basis of ... ...

    Abstract There are many pathways that might lead to decreased bone mass, skeletal fragility, and increased fracture risk in osteoporosis. Some of these have been clearly identified, such as estrogen deficiency. Others that were conceived on the basis of experimental findings and recent scientific discoveries such as abnormalities of cytokines, bone growth factors, and osteoblast transcription factors remain interesting but speculative. The recent revolution in genomics and proteomics opens new avenues for pursuing in great depth the pathways leading to osteoporosis. Animal models developed largely in rodents can suggest specific factors that can be further studied in primate models and in osteoporotic patients. Identification of specific pathogenetic mechanisms should lead to new approaches to the diagnosis and management of this disorder.
    Mesh-Begriff(e) Animals ; Bone Remodeling/physiology ; Bone and Bones/pathology ; Fractures, Bone/epidemiology ; Humans ; Osteoporosis/etiology ; Osteoporosis/pathology ; Risk Factors
    Sprache Englisch
    Erscheinungsdatum 2003-03-26
    Erscheinungsland United States
    Dokumenttyp Journal Article ; Review
    ZDB-ID 92116-6
    ISSN 1558-4410 ; 0889-8529
    ISSN (online) 1558-4410
    ISSN 0889-8529
    DOI 10.1016/s0889-8529(02)00055-5
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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