Osteoclastogenesis Inhibitory Factor Suppresses Osteoclast Survival by Interfering in the Interaction of Stromal Cells with Osteoclast

Akatsu, Takuhiko; Murakami, Takehiko; Nishikawa, Manabu; Ono, Kohei; Shinomiya, Nariyoshi; Tsuda, Eisuke; Mochizuki, Shin-ichi; Yamaguchi, Kyoji; Kinosaki, Masahiko; Higashio, Kanji; Yamamoto, Michiko; Motoyoshi, Kazuo; Nagata, Noriko

doi:10.1006/bbrc.1998.9294

Cited by 114 publications

(94 citation statements)

References 27 publications

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“…These results suggest that OPG affects the later unknown stage of osteoclast differentiation. In this regards, Akatsu et al (1998) reported that OPG inhibited the survival of osteoclasts formed in mouse marrow cultures in a dose-and timedependent manner, and suggested that OPG affected the osteoclast number by promoting apoptosis. also reported that apoptosis of osteoclasts was mediated by up-regulation of OPG, and that this phenomenon was induced by TGF-␤1.…”

Section: Discussionmentioning

confidence: 99%

“…OPG appears to locally and/or systemically inhibit the differentiation of osteoclast precursors into mature osteoclasts, by interrupting the osteoblast-osteoclast precursor interaction (Simonet et al, 1997;Akatsu et al, 1998;Yasuda et al, 1998a, b). OPG also inhibits in vitro osteoclastogenesis elicited through distinct signaling pathways stimulated by 1,25(OH)2D3, PTH, or IL-11 (Simonet et al, 1997;Tsuda et al, 1997;Matsuzaki et al, 1998;Yasuda et al, 1998a).…”

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Osteoclast induction in periodontal tissue during experimental movement of incisors in osteoprotegerin‐deficient mice

et al. 2002

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Osteoprotegerin (OPG) is a novel secreted member of the tumor necrosis factor (TNF) receptor superfamily that negatively regulates osteoclastogenesis. The receptor activator of the NFKB ligand (RANKL) is one of the key regulatory molecules in osteoclast formation and binds to OPG. In this study, it was suggested that OPG and RANKL are involved in alveolar bone remodeling during orthodontic tooth movement. We examined RANKL localization and osteoclast induction in periodontal tissues during experimental movement of incisors in OPG-deficient mice. To produce orthodontic force, an elastic band was inserted between the upper right and left incisors for 2 or 5 days, and the dissected maxillae were examined for cytochemical and immunocytochemical localization of tartrate-resistant acid phosphatase (TRAP), vacuolar-type H ϩ -ATPase, and RANKL. Compared to wild-type OPG (ϩ/ϩ) littermates, TRAP-positive multinucleated cells were markedly induced in the periodontal ligament (PDL) on the compressed side and in the adjacent alveolar bone of OPG-deficient mice. These multinucleated cells exhibited intense vacuolar-type H ϩ -ATPase along the ruffled border membranes. Because of accelerated osteoclastic resorption in OPG-deficient mice, alveolar bone was severely destroyed and partially perforated at 2 and 5 days after force application. In both wild-type and OPG-deficient mice, RANKL expression became stronger at 2 and 5 days after force application than before force application. There was no apparent difference in intensity of RANKL expression between OPG (ϩ/ϩ) littermates and OPGdeficient mice. In both wild-type and OPG-deficient mice, expression of RANKL protein was detected in osteoblasts, fibroblasts, and osteoclasts mostly located in resorption lacunae. These results suggest that during orthodontic tooth movement, RANKL and OPG in the periodontal tissues are important determinants regulating balanced alveolar bone resorption. Anat Rec 266:218 -225, 2002.

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

Osteoclast induction in periodontal tissue during experimental movement of incisors in osteoprotegerin‐deficient mice

et al. 2002

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“…Akatsu et al (1998) reported that OPG inhibited the survival of OCs formed in mouse marrow cultures in a doseand time-dependent manner, and suggested that OPG reduced the number of OCs by promoting apoptosis. Murakami et al (1998) also reported that apoptosis of OCs was mediated by up-regulation of OPG.…”

Section: Discussionmentioning

confidence: 99%

“…Osteoprotegerin (OPG) is a novel secreted member of the tumor necrosis factor (TNF) receptor superfamily that negatively regulates osteoclastogenesis (Simonet et al, 1997;Tsuda et al, 1997;Buccay et al, 1998;Mizuno et al, 1998;Yasuda et al, 1998a, b;Bateman et al, 2000). OPG inhibits, locally or systemically, the differentiation of OC precursors into mature OCs by interrupting osteoblast-OC precursor interaction and decreases ovariectomy-induced bone loss in rats (Simonet et al, 1997; Akatsu et al, 1998;Yasuda et al, 1998a, b). OPG also inhibits in vitro osteoclastogenesis elicited through distinct signaling pathways stimulated by 1,25(OH) 2 D 3 , parathyroid hormone (PTH), or interleukin (IL)-11 (Simonet et al, 1997;Tsuda et al, 1997;Matsuzaki et al, 1998;Yasuda et al, 1998a).…”

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Regulation of osteoclast differentiation and function by receptor activator of NFkB ligand and osteoprotegerin

et al. 2002

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The differentiation and functions of osteoclasts (OCs) are regulated by osteoblast-derived factors. Receptor activator of NFkB ligand (RANKL) is one of the key regulatory molecules in OC formation. Osteoprotegerin (OPG) is a novel secreted member of the TNF receptor superfamily that negatively regulates osteoclastogenesis and binds to RANKL. We examined the biological actions of macrophage-colony-stimulating factor (M-CSF), RANKL, and OPG on the differentiation of OCs isolated from cocultures of mouse osteoblastic cells and bone marrow cells. Preosteoclasts (pOCs) and OCs were characterized by their ultrastructure and the expression of OC markers such as tartrate-resistant acid phosphatase (TRAP) and vacuolar-type H ϩ -ATPase. pOCs formed without any additives expressed TRAP, but showed little resorptive activity on cocultured dentine slices. TRAP-positive pOCs treated with M-CSF began to fuse with each other, but lacked a ruffled border (RB) and showed almost no resorptive activity. pOCs treated with RANKL became TRAP-positive multinucleated cells, which expressed intense vacuolar-type H ϩ -ATPase along the RB membranes and exhibited prominent resorptive activity. Such effects of RANKL on pOCs were completely inhibited by the addition of OPG. OPG inhibited RB formation in mature OCs and reduced their resorptive activity, and also induced apoptosis of some OCs. These results suggest that 1) RANKL induces differentiation of functional OCs from pOCs, 2) M-CSF induces macrophage-like multinucleated cells, but not OCs, 3) OPG inhibits RB formation and resorptive activity in mature OCs, 4) OPG also induces apoptosis of OCs, and 5) RANKL and OPG are, therefore, important regulators of not only the terminal differentiation of OCs but also their resorptive function. Anat Rec 268: 137-146, 2002.

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“…In vitro, OPG inhibits osteoclastogenesis, (9,14) blocks bone resorption by mature osteoclasts, (15,16) and promotes apoptosis of osteoclasts. (17)(18)(19) In vivo, treatment of tumor-bearing mice with OPG, given either at the onset of hypercalcemia or after it had occurred, resulted in a dose-dependent inhibition of tumor-induced increases in bone resorption and hypercalcemia and rapidly normalized blood ionized calcium. (20) Previously, we reported that the appearance of anti-gp46-197 Ab, an antibody recognizing the Asp197 to region, was synchronized with the deterioration of ATL, (21) and proposed that the antibody possibly cross-reacted with human cellular component(s) and that the interaction might be associated with the pathogenesis.…”

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Involvement of molecular mimicry between human T‐cell leukemia virus type 1 gp46 and osteoprotegerin in induction of hypercalcemia

et al. 2009

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Human T-cell leukemia virus type-1 (HTLV-1) causes adult T-cell leukemia/lymphoma (ATL), frequently associated with hypercalcemia and bone destruction. A positive correlation between the appearance of an antibody recognizing the central region (Asp197 to Leu216) on Gp46, gp46-197, and the severity of ATL has been demonstrated. In this study, five male Nihon Hakusyoku rabbits were immunized with a synthetic peptide corresponding to the gp46-197 region to clarify its action and mechanism. Two of the rabbits showed piloerection, anorexia, and somnolence, and died soon after booster administration. The serum calcium level of the dead rabbits was significantly high, compared to those of surviving rabbits. Interestingly, amino acid sequences homologous with gp46-197 were found in the carboxylterminal half of osteoprotegerin (OPG), an osteoclast inhibitory factor. To confirm the effect of the gp46-197 region on osteogenesis in vivo, the peptide was intraperitoneally administered to male Sprague-Dawley rats. The administration of the gp46-197 peptide resulted in a decrease of bone mineral density (BMD), a significant increase of serum calcium level, and inhibition of normal bone growth in both short-and long-term experiments. In rats, femoral growth inhibition by the gp46- A dult T-cell leukemia (ATL), a malignancy of helper/inducer T lymphocytes, is associated with human T-cell leukemia virus type-1 (HTLV-1) infection.(1) ATL clinically shows hypercalcemia and lytic bone lesions in high prevalence, (2) which are known to be mediated by parathyroid hormone-related protein (PTHrP) and lymphokines, such as interleukin 1 (IL-1), IL-6, and macrophage inflammatory protein-1α.(3,4) Several reports revealed that severe combined immunodeficient/beige mice inoculated with a human ATL line developed lymphoma with hypercalcemia, and plasma PTHrP concentrations were markedly increased in mice with lymphoma.(5,6) About 70% of ATL patients show a high serum calcium level throughout the clinical course, particularly in the aggressive stage.(7) It was reported that the overexpression of the receptor activator of the nuclear factor-κB ligand (RANKL) gene is correlated with hypercalcemia in ATL, (8) and it is well known that bisphosphonate is efficient in the treatment of hypercalcemia in ATL patients. RANKL promotes the differentiation and proliferation of osteoclasts. Osteoprotegerin (OPG), a member of the tumor necrosis factor (TNF) receptor superfamily, acts as a decoy receptor for RANKL and neutralizes the effect of RANKL in osteogenesis.(9) Both the gene expression and the protein production of OPG were reported to be stimulated by 17β-estradiol (E 2 ), (10,11) and there was a positive relationship between OPG and serum E 2 level.(12) OPG-overexpressing mice are osteopetrotic, (9) whereas OPG-deficient mice are osteoporotic.Therefore, OPG is known to play a pivotal role in regulating bone mass. In vitro, OPG inhibits osteoclastogenesis, (9,14) blocks bone resorption by mature osteoclasts, (15,16) and promotes apoptosis of osteoclas...

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Osteoclastogenesis Inhibitory Factor Suppresses Osteoclast Survival by Interfering in the Interaction of Stromal Cells with Osteoclast

Cited by 114 publications

References 27 publications

Osteoclast induction in periodontal tissue during experimental movement of incisors in osteoprotegerin‐deficient mice

Osteoclast induction in periodontal tissue during experimental movement of incisors in osteoprotegerin‐deficient mice

Regulation of osteoclast differentiation and function by receptor activator of NFkB ligand and osteoprotegerin

Involvement of molecular mimicry between human T‐cell leukemia virus type 1 gp46 and osteoprotegerin in induction of hypercalcemia

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