Transforming Growth Factor-β Stimulates the Production of Osteoprotegerin/Osteoclastogenesis Inhibitory Factor by Bone Marrow Stromal Cells

Takai, Hiroyuki; Kanematsu, Masahiro; Yano, Kouji; Tsuda, Eisuke; Higashio, Kanji; Ikeda, Kyoji; Watanabe, Ken; Yamada, Yoshiji

doi:10.1074/jbc.273.42.27091

Cited by 277 publications

(200 citation statements)

References 38 publications

(59 reference statements)

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“…In addition, mRNA of the TNF receptor, TR1 (identical to OPG), was abundantly expressed in primary osteoclasts, osteogenic sarcoma cell lines, and primary fibroblasts (Kwon et al, 1998). Transforming growth factor (TGF)-␤1 increased OPG mRNA level and the secretion of OPG protein in primary osteoblasts and osteoblastic MC3T3-1 and ST2 cell lines Takai et al, 1998). TGF-␤1 markedly increased the steady-state OPG mRNA level in a dose-dependent manner, but suppressed RANKL mRNA expression and inhibited the formation of TRAP-positive osteoclast-like cells in the presence of 1,25(OH)2D3 (Takai et al, 1998).…”

Section: Discussionmentioning

confidence: 99%

“…Transforming growth factor (TGF)-␤1 increased OPG mRNA level and the secretion of OPG protein in primary osteoblasts and osteoblastic MC3T3-1 and ST2 cell lines Takai et al, 1998). TGF-␤1 markedly increased the steady-state OPG mRNA level in a dose-dependent manner, but suppressed RANKL mRNA expression and inhibited the formation of TRAP-positive osteoclast-like cells in the presence of 1,25(OH)2D3 (Takai et al, 1998). In this regards, expression of TGF-␤1 mRNA and protein was increased in osteoblasts on the stretched side of the PDL during experimental tooth movement .…”

Section: Discussionmentioning

confidence: 99%

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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%

Section: Discussionmentioning

confidence: 99%

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

et al. 2002

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“…TGF-␤ is known to inhibit osteoclastogenesis in the murine neonatal calvaria organ culture system (39). TGF-␤ might inhibit osteoclastogenesis because of the up-regulation of OPG and the down-regulation of RANKL in osteoblasts (21). However, TGF-␤-producing MDA-MB-231 and A549 cells formed osteolytic bone metastasis in vivo.…”

Section: Discussionmentioning

confidence: 99%

“…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: 96%

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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“…Targeted inactivation of the gene encoding M-CSF in mouse models leads to an osteopetrotic phenotype because of complete absence of osteoclasts (Wiktor-Jedrzejczak et al 1990;Marks et al 1992). OPG expression in osteoblasts is controlled by multiple bone metabolic regulators, including vitamin D, prostaglandin E2, tumor necrosis factors (TNFs), and IL-1, and also by TGF-bs and BMPs (Hofbauer et al 1998;Murakami et al 1998;Takai et al 1998;Thirunavukkarasu et al 2001;Wan et al 2001;Sato et al 2009). TGF-b signaling has both positive and negative effects on osteoclastogenesis, which initially led to controversial reports on the role of TGF-b in bone homeostasis.…”

Section: Tgf-b Family Signaling In Connective Tissuesmentioning

confidence: 99%

TGF-β Family Signaling in Connective Tissue and Skeletal Diseases

MacFarlane

Haupt

Dietz

et al. 2017

Cold Spring Harb Perspect Biol

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The transforming growth factor b (TGF-b) family of signaling molecules, which includes TGF-bs, activins, inhibins, and numerous bone morphogenetic proteins (BMPs) and growth and differentiation factors (GDFs), has important functions in all cells and tissues, including soft connective tissues and the skeleton. Specific TGF-b family members play different roles in these tissues, and their activities are often balanced with those of other TGF-b family members and by interactions with other signaling pathways. Perturbations in TGF-b family pathways are associated with numerous human diseases with prominent involvement of the skeletal and cardiovascular systems. This review focuses on the role of this family of signaling molecules in the pathologies of connective tissues that manifest in rare genetic syndromes (e.g., syndromic presentations of thoracic aortic aneurysm), as well as in more common disorders (e.g., osteoarthritis and osteoporosis). Many of these diseases are caused by or result in pathological alterations of the complex relationship between the TGF-b family of signaling mediators and the extracellular matrix in connective tissues.T he transforming growth factor b (TGF-b) family of cytokines comprises the three TGF-b proteins (TGF-b1, TGF-b2, and TGFb3) and related growth and differentiation factors such as activins, inhibins, bone morphogenic proteins (BMPs), and growth and differentiation factors (GDFs). These molecules play critical roles both in normal development and in several pathological conditions, including inflammation, fibrosis, and cancer (reviewed in Li and Flavell 2006;Gordon and Blobe 2008;Ikushima and Miyazono 2010). This review focuses on the role of these proteins in development and homeostasis of the skeleton and other connective tissues (summarized in Fig. 1) and on the diseases that ensue when these pathways are altered. Aberrant signaling in these pathways has been associated with common connective 6 These authors contributed equally to this work.

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Transforming Growth Factor-β Stimulates the Production of Osteoprotegerin/Osteoclastogenesis Inhibitory Factor by Bone Marrow Stromal Cells

Cited by 277 publications

References 38 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

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

TGF-β Family Signaling in Connective Tissue and Skeletal Diseases

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