The molecular basis of osteoclast differentiation and activation.
Osteoclasts develop from haemopoietic cells of the monocyte-macrophage lineage. Osteoblasts or stromal cells are essentially involved in osteoclastogenesis through cell-cell interaction with osteoclast progenitor cells. Recent findings indicate that osteoblasts/stromal cells express osteoclast differentiation factor (ODF, also called RANKL, TRANCE and OPGL) as a membrane-associated factor in response to several osteotropic factors to support osteoclast differentiation. ODF is a new member of the tumour necrosis factor (TNF) ligand family. Osteoclast precursors, which express RANK, a TNF receptor family member, recognize ODF through cell-cell interactions with osteoblasts/stromal cells, and differentiate into osteoclasts in the presence of macrophage colony-stimulating factor (M-CSF). Osteoclastogenesis inhibitory factor (OCIF, also called OPG), is a secreted TNF receptor, which acts as a decoy receptor for ODF. ODF is responsible for inducing not only differentiation, but also activation of osteoclasts. Interleukin 1 alpha (IL-1 alpha) can be substituted for ODF in inducing the activation of osteoclasts. Recently, it was shown that mouse TNF alpha stimulated the differentiation of M-CSF-dependent mouse bone marrow macrophages into osteoclasts in the presence of M-CSF without any help of osteoblasts/stromal cells. Osteoclast formation induced by TNF alpha was inhibited by antibodies against TNF type 1 receptor (TNFR1) or TNFR2, but not by OCIF. Osteoclasts induced by TNF alpha formed resorption pits on dentine slices only in the presence of IL-1 alpha. These results demonstrate that TNF alpha stimulates osteoclast differentiation through a mechanism independent of the ODF-RANK interaction. TNF alpha and IL-1 alpha may play an important role in pathological bone resorption due to inflammation.
Suda
T
T
Department of Biochemistry, School of Dentistry, Showa University, Tokyo 142-8555, Japan.
Kobayashi
K
K
Jimi
E
E
Udagawa
N
N
Takahashi
N
N
D000818:Animals; D002352:Carrier Proteins / Q000235:genetics / Q000502:physiology; D002454:Cell Differentiation; D003001:Cloning, Molecular; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000502:physiology; D006801:Humans; D016173:Macrophage Colony-Stimulating Factor / Q000502:physiology; D008562:Membrane Glycoproteins / Q000235:genetics / Q000502:physiology; D008954:Models, Biological; D010010:Osteoclasts / Q000166:cytology / Q000502:physiology*; D010012:Osteogenesis; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; D017154:Stromal Cells / Q000166:cytology / Q000502:physiology; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology
D002352:Carrier Proteins; D008562:Membrane Glycoproteins; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; C505686:TNFRSF11A protein, human; C505688:TNFSF11 protein, human; C505687:Tnfrsf11a protein, mouse; C505689:Tnfsf11 protein, mouse; D014409:Tumor Necrosis Factor-alpha; D016173:Macrophage Colony-Stimulating Factor