Osteoprotegerin Production by Human Osteoblast Lineage Cells Is Stimulated by Vitamin D, Bone Morphogenetic Protein-2, and Cytokines

Hofbauer, Lorenz C.; Dunstan, Colin R.; Spelsberg, Thomas C.; Riggs, B. Lawrence; Khosla, Sundeep

doi:10.1006/bbrc.1998.9394

Cited by 282 publications

(203 citation statements)

References 32 publications

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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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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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“…OPG/OCIF mRNA levels have been detected in various human and murine primary cells and cell lines which, in part, reflect the tissue expression of OPG/OCIF, including various osteoblastic lineage cell lines such as the marrow stromal cell lines ST-2 (9), MC3T3-E1 (9), TF274 (13), and hMS (21), the osteosarcoma cell lines MG-63 (13,14,22,23) and SaOS-2 (23), and various normal human osteoblastic cells lines (hFOB, hFOB/ER-9) (21, 24) as well as primary human trabecular osteoblasts (21,23). Of interest, some of the conditionally immortalized cell lines express tenfold higher OPG/OCIF mRNA levels when cultured under differentiating conditions (21,24).…”

Section: Tissue and Cellular Expression Of Opg/ocifmentioning

confidence: 99%

“…Of interest, some of the conditionally immortalized cell lines express tenfold higher OPG/OCIF mRNA levels when cultured under differentiating conditions (21,24). Among osteoblastic lineage cells, the osteosarcoma cell line MG-63 produces the most abundant amounts of OPG/OCIF (22).…”

Section: Tissue and Cellular Expression Of Opg/ocifmentioning

confidence: 99%

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

Hofbauer

1999

European Journal of Endocrinology

112

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“…The other factor is the HTLV-1 envelope protein Gp46, whose central region inhibits the function of OPG as an antagonist. Recently, E 2 , the most common circulating form of estrogen, has been reported to up-regulate the production of OPG in bone cells, (29) and the OPG expression level in dendritic cells increased in a dose-dependent manner after E 2 treatment. (30) It was also reported that E 2 markedly repressed HTLV-1 Tax-activated transcription via the NF-κB pathway.…”

Section: Discussionmentioning

confidence: 99%

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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Osteoprotegerin Production by Human Osteoblast Lineage Cells Is Stimulated by Vitamin D, Bone Morphogenetic Protein-2, and Cytokines

Cited by 282 publications

References 32 publications

TGF-β Family Signaling in Connective Tissue and Skeletal Diseases

TGF-β Family Signaling in Connective Tissue and Skeletal Diseases

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

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

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