Transforming Growth Factor-β1 Increases mRNA Levels of Osteoclastogenesis Inhibitory Factor in Osteoblastic/Stromal Cells and Inhibits the Survival of Murine Osteoclast-like Cells

Murakami, Takehiko; Yamamoto, Michiko; Yamamoto, Mikio; Ono, Kohei; Nishikawa, Manabu; Nagata, Noriko; Motoyoshi, Kazuo; Akatsu, Takuhiko

doi:10.1006/bbrc.1998.9723

Cited by 190 publications

(137 citation statements)

References 20 publications

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“…Recently, TGF-␤ was reported to up-regulate OPG expression in osteoblasts (21,22). Interestingly, TGF-␤ down-regulated OPG mRNA expression in HUVECs in a dosedependent manner (Fig.…”

Section: Tgf-␤ Induces Rankl Mrna and Protein Expression In Endothelialmentioning

confidence: 80%

Transforming Growth Factor-β Induces Expression of Receptor Activator of NF-κB Ligand in Vascular Endothelial Cells Derived from Bone

Ishida¹,

Fujita²,

Kitazawa³

et al. 2002

Journal of Biological Chemistry

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Vascular endothelial cells in bone are thought to have significant roles on pathological bone resorption such as bone metastasis and hypercalcemia because this resorption is often seen where blood vessels are abundant. However, the detailed mechanisms have not yet been elucidated. Here, we focused on transforming growth factor-␤ (TGF-␤) and studied its effects on vascular endothelial cells because TGF-␤ is abundantly stored in bone matrix and is released and activated during bone resorption. We found that TGF-␤ up-regulated the expression of receptor activator of NF-B ligand (RANKL) mRNA and protein in bone marrow-derived endothelial cells and in primary vascular endothelial cells but not in osteoblasts. Further analysis revealed that TGF-␤ promoted phosphorylation of cAMP response element-binding protein and p38. Protein kinase A inhibitor KT5720 and p38 inhibitor SB203580 significantly reduced the TGF-␤-induced RANKL expression. Moreover, we found two CRE-like domains in murine RANKL promoter region that were critical for TGF-␤-dependent RANKL expression. Therefore, protein kinase A and p38 signaling pathways are involved in TGF-␤-induced RANKL expression by stimulating transcription factors that bind to the CRE-like domains. Our findings indicate that TGF-␤ stimulates osteoclastogenesis by promoting RANKL expression in endothelial cells under pathological conditions.

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“…Recently, TGF-␤ was reported to up-regulate OPG expression in osteoblasts (21,22). Interestingly, TGF-␤ down-regulated OPG mRNA expression in HUVECs in a dosedependent manner (Fig.…”

Section: Tgf-␤ Induces Rankl Mrna and Protein Expression In Endothelialmentioning

confidence: 80%

Transforming Growth Factor-β Induces Expression of Receptor Activator of NF-κB Ligand in Vascular Endothelial Cells Derived from Bone

Ishida¹,

Fujita²,

Kitazawa³

et al. 2002

Journal of Biological Chemistry

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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. Atkins et al (2001) recently found that OPG treatment of osteolytic giant cell tumor cultures inhibited resorptive activity of These mononuclear cells lack an RB, and contain a Golgi apparatus (Go) and lysosomes (Ly) in the central cytoplasm.…”

Section: Discussionmentioning

confidence: 96%

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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“…OPG/OCIF mRNA and protein levels were stimulated in various human osteoblastic cell systems by 1a,25-(OH) 2 D 3 (21), BMP-2 (21), IL-1a (37) and -b (21), and TNF-a (21, 38) and TNF-b (38). Other studies using murine osteoblastic/stromal cells demonstrated downregulation of OPG/OCIF mRNA levels in marrow stromal cell lines (ST-2, tsJ2) by 1a,25-(OH) 2 D 3 (9, 39), but not in primary osteoblasts (39) as well as down-regulation of OPG/OCIF mRNA levels in primary osteoblasts by 1a,25-(OH) 2 D 3 , IL-1a, and PTH (40). Some of these discrepancies may be due to species differences or may reflect the variability of the cell systems regarding their stage of osteoblastic differentiation.…”

Section: Regulation Of Opg/ocif By Systemic Hormones and Factorsmentioning

confidence: 95%

Osteoprotegerin ligand and osteoprotegerin: novel implications for osteoclast biology and bone metabolism

Hofbauer

1999

European Journal of Endocrinology

112

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Transforming Growth Factor-β1 Increases mRNA Levels of Osteoclastogenesis Inhibitory Factor in Osteoblastic/Stromal Cells and Inhibits the Survival of Murine Osteoclast-like Cells

Cited by 190 publications

References 20 publications

Transforming Growth Factor-β Induces Expression of Receptor Activator of NF-κB Ligand in Vascular Endothelial Cells Derived from Bone

Transforming Growth Factor-β Induces Expression of Receptor Activator of NF-κB Ligand in Vascular Endothelial Cells Derived from Bone

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

Osteoprotegerin ligand and osteoprotegerin: novel implications for osteoclast biology and bone metabolism

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