Role of receptor activator of nuclear factor-κB ligand and osteoprotegerin in bone cell biology

被引:447
作者
Hofbauer, LC [1 ]
Heufelder, AE [1 ]
机构
[1] Univ Marburg, Zentrum Innere Med, Div Gastroenterol Endocrinol & Metab, D-35033 Marburg, Germany
来源
JOURNAL OF MOLECULAR MEDICINE-JMM | 2001年 / 79卷 / 5-6期
关键词
osteoprotegerin; receptor activator of NF-kappa B ligand; receptor activator of NF-kappa B; osteoclast; osteoporosis;
D O I
10.1007/s001090100226
中图分类号
Q3 [遗传学];
学科分类号
071007 ; 090102 ;
摘要
Receptor activator of nuclear factor (NF-kappaB) ligand (RANKL), its cellular receptor, receptor activator of NF-kappaB (RANK), and the decoy receptor osteoprotegerin (OPG) constitute a novel cytokine system. RANKL produced by osteoblastic lineage cells and activated T lymphocytes is the essential factor for osteoclast formation, fusion, activation, and survival, thus resulting in bone resorption and bone loss. RANKL activates its specific receptor, RANK located on osteoclasts and dendritic cells, and its signaling cascade involves stimulation of the c-jun, NF-kappaB, and serine/threonine kinase PKB/Akt pathways. The effects of RANKL are counteracted by OPG which acts as a soluble neutralizing receptor. RANKL and OPG are regulated by various hormones (glucocorticoids, vitamin D, estrogen), cytokines (tumor necrosis factor alpha interleukins 1, 4, 6, 11, and 17), and various mesenchymal transcription factors (such as cbfa-1, peroxisome proliferator-activated receptor gamma, and Indian hedgehog). Transgenic and knock-out mice with excessive or defective production of RANKL, RANK, and OPG display the extremes of skeletal phenotypes, osteoporosis and osteopetrosis. Abnormalities of the RANKL/OPG system have been implicated in the pathogenesis of postmenopausal osteoporosis, rheumatoid arthritis, Paget's disease, periodontal disease, benign and malignant bone tumors, bone metastases, and hypercalcemia of malignancy, while administration of OPG has been demonstrated to prevent or mitigate these disorders in animal models. RANKL and OPG are also important regulators of vascular biology and calcification and of the development of a lactating mammary gland during pregnancy, indicating a crucial role for this system in extraskeletal calcium handling. The discovery and characterization of RANKL, RANK, and OPG and subsequent studies have changed the concepts of bone and calcium metabolism, have led to a detailed understanding of the pathogenesis of metabolic bone diseases, and may form the basis of innovative therapeutic strategies.
引用
收藏
页码:243 / 253
页数:11
相关论文
共 143 条
  • [21] Characterization of the intracellular domain of receptor activator of NF-κB (RANK) -: Interaction with tumor necrosis factor receptor-associated factors and activation of NF-κB and c-Jun N-terminal kinase
    Darnay, BG
    Haridas, V
    Ni, J
    Moore, PA
    Aggarwal, BB
    [J]. JOURNAL OF BIOLOGICAL CHEMISTRY, 1998, 273 (32) : 20551 - 20555
  • [22] Activation of NF-κB by RANK requires tumor necrosis factor receptor-associated factor (TRAF) 6 and NF-κB-inducing kinase -: Identification of a novel TRAF6 interaction motif
    Darnay, BG
    Ni, J
    Moore, PA
    Aggarwal, BB
    [J]. JOURNAL OF BIOLOGICAL CHEMISTRY, 1999, 274 (12) : 7724 - 7731
  • [23] Osteoblast maturation suppressed osteoclastogenesis in coculture with bone marrow cells
    Deyama, Y
    Takeyama, S
    Koshikawa, M
    Shirai, Y
    Yoshimura, Y
    Nishikata, M
    Suzuki, K
    Matsumoto, A
    [J]. BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, 2000, 274 (01) : 249 - 254
  • [24] RANK is essential for osteoclast and lymph node development
    Dougall, WC
    Glaccum, M
    Charrier, K
    Rohrbach, K
    Brasel, K
    De Smedt, T
    Daro, E
    Smith, J
    Tometsko, ME
    Maliszewski, CR
    Armstrong, A
    Shen, V
    Bain, S
    Cosman, D
    Anderson, D
    Morrissey, PJ
    Peschon, JJ
    Schuh, J
    [J]. GENES & DEVELOPMENT, 1999, 13 (18) : 2412 - 2424
  • [25] The osteoblast: A sophisticated fibroblast under central surveillance
    Ducy, P
    Schinke, T
    Karsenty, G
    [J]. SCIENCE, 2000, 289 (5484) : 1501 - 1504
  • [26] Osteoprotegerin is a receptor for the cytotoxic ligand TRAIL
    Emery, JG
    McDonnell, P
    Burke, MB
    Deen, KC
    Lyn, S
    Silverman, C
    Dul, E
    Appelbaum, ER
    Eichman, C
    DiPrinzio, R
    Dodds, RA
    James, IE
    Rosenberg, M
    Lee, JC
    Young, PR
    [J]. JOURNAL OF BIOLOGICAL CHEMISTRY, 1998, 273 (23) : 14363 - 14367
  • [27] The osteoclast differentiation factor osteoprotegerin-ligand is essential for mammary gland development
    Fata, JE
    Kong, YY
    Li, J
    Sasaki, T
    Irie-Sasaki, J
    Moorehead, RA
    Elliott, R
    Scully, S
    Voura, EB
    Lacey, DL
    Boyle, WJ
    Khokha, R
    Penninger, JM
    [J]. CELL, 2000, 103 (01) : 41 - 50
  • [28] Fox SW, 2000, J CELL PHYSIOL, V184, P334, DOI 10.1002/1097-4652(200009)184:3<334::AID-JCP7>3.0.CO
  • [29] 2-U
  • [30] Activin A is an essential cofactor for osteoclast induction
    Fuller, K
    Bayley, KE
    Chambers, TJ
    [J]. BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, 2000, 268 (01) : 2 - 7