IFN-γ Enhances Osteoclast Generation in Cultures of Peripheral Blood from Osteopetrotic Patients and Normalizes Superoxide Production

Madyastha, Prema; Yang, Stephen C.; Ries, William L.; Key, L. Lyndon

doi:10.1089/107999000414826

Cited by 45 publications

(41 citation statements)

References 28 publications

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“…A Pit Assay-Bone resorption was determined by a pit assay as described (12). Osteoclasts were isolated from the bone marrow of 4 -6-day-old neonatal mice and placed on bovine bone slices for 0.5-1 h. After removing nonadherent cells by vigorous washing, osteoclasts attached to the bone slices were treated with antisense and sense oligonucleotides for 2 days.…”

Section: Methodsmentioning

confidence: 99%

A New Superoxide-generating Oxidase in Murine Osteoclasts

Yang

Madyastha

Bingel

et al. 2001

Journal of Biological Chemistry

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192

153

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Superoxide production contributes to osteoclastic bone resorption. Evidence strongly indicates that NADPH oxidase is an enzyme system responsible for superoxide generation in osteoclasts. A membranebound subunit, p91, is the catalytic domain of NADPH oxidase. However, osteoclasts from p91 knockout mice still produce superoxide at a rate similar to that observed in wild type mice. This unexpected phenomenon prompted us to examine the osteoclasts for an alternative to the p91-containing oxidase. In this study, the cloning of a NADPH oxidase subunit (Nox 4) with 578 amino acids is reported. Nox 4 has 58% similarity in amino acids with the known p91 subunit of NADPH oxidase. Nox 4 is present and active in osteoclasts. Antisense oligonucleotides of Nox 4 reduced osteoclastic superoxide generation as well as resorption pit formation by osteoclasts. This new oxidase complex was present and functional in osteoclasts from p91 knockout mice, explaining the normal resorptive activity seen in the osteoclasts where no p91 is present.

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Section: Methodsmentioning

confidence: 99%

A New Superoxide-generating Oxidase in Murine Osteoclasts

Yang

Madyastha

Bingel

et al. 2001

Journal of Biological Chemistry

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192

153

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“…However, its effects on osteoclast formation are controversial. IFN-γ also enhances osteoclast generation in cultures of peripheral blood from osteopetrotic patients, in part by normalizing superoxide production (57) and has been shown to be efficacious in the treatment of osteoporosis in humans (58). A recent study analyzed the in vivo effects of IFN-γ in 3 mouse models of bone loss, including ovariectomy, LPS injection, and inflammation induced by silencing TGF-β signaling in T cells.…”

Section: Ranklmentioning

confidence: 99%

Functions of RANKL/RANK/OPG in bone modeling and remodeling

Boyce

Xing

2008

Archives of Biochemistry and Biophysics

1,440

1,058

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The discovery of the RANKL/RANK/OPG system in the mid 1990s for the regulation of bone resorption has led to major advances in our understanding of how bone modeling and remodeling are regulated. It had been known for many years before this discovery that osteoblastic stromal cells regulated osteoclast formation, but it had not been anticipated that they would do this through expression of members of the TNF superfamily: receptor activator of NF-κB ligand (RANKL) and osteoprotegerin (OPG), or that these cytokines and signaling through receptor activator of NF-κB (RANK) would have extensive functions beyond regulation of bone remodeling. RANKL/RANK signaling regulates osteoclast formation, activation and survival in normal bone modeling and remodeling and in a variety of pathologic conditions characterized by increased bone turnover. OPG protects bone from excessive resorption by binding to RANKL and preventing it from binding to RANK. Thus, the relative concentration of RANKL and OPG in bone is a major determinant of bone mass and strength. Here, we review our current understanding of the role of the RANKL/RANK/ OPG system in bone modeling and remodeling. KeywordsBone resorption; osteoclasts; RANKL; RANK; OPG Normal bone modelingWith the exception of the bones of the calvaria, all bones in the mammalian skeleton are preformed in cartilage moulds from mesenchymal progenitors, which under appropriate stimuli also have the potential to differentiate into a variety of tissue types, including fibrous tissue, fat and muscle. Chondrocytes proliferate near the ends of the cartilage moulds to drive their longitudinal growth, while others in the centers of undergo hypertrophic differentiation. The hypertrophic chondrocytes at the periphery of the centers of these moulds are invaded by blood vessels and undergo apoptosis. Some of this hypertrophic cartilage survives as thin islands of cartilage in the centers of ossification in growing bones. Osteoblasts, which differentiate from progenitors in a collar of connective tissue around the middle of the bones where vascular invasion takes place, follow the endothelial cells and lay down bone matrix on the surfaces of these islands of cartilage to form bone struts or trabeculae (1). Osteoclast precursors (OCPs), derived from progenitors in the spleen and liver are attracted from blood in the invading blood vessels close to newly formed bone trabeculae. These osteoclast precursors fuse with one

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“…In contrast, Gao et al (12) recently found that IFN-␥ indirectly stimulates osteoclast formation and bone loss after ovariectomy via antigen-driven T cell activation, resulting in the production of osteoclast-activating factors. Interestingly, IFN-␥ has been used to treat infantile osteopetrosis in which patients suffered from high bone mass secondary to osteoclast dysfunction or osteoblast hyperactivity, but the mechanism of action may be through modulation of the host immune system rather than direct effects on bone cells (13)(14)(15). However, the role of IFN-␥ in the treatment of osteolytic bone metastases has not been elucidated.…”

Section: Ifn-␥mentioning

confidence: 99%

Interferon-γ Targets Cancer Cells and Osteoclasts to Prevent Tumor-associated Bone Loss and Bone Metastases

Hurchla

Deng

et al. 2009

Journal of Biological Chemistry

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Interferon-␥ (IFN-␥ IFN-␥3 is a multifunctional cytokine produced mainly by NK cells and activated T cells that plays a critical role in host immune responses against pathogens and cancer (1). Mice deficient in IFN-␥, the R1 subunit of the IFN-␥ receptor, or the transcription factor STAT1 are more susceptible to spontaneous tumor development (1-3). IFN-␥ has also been found to have direct anti-proliferative and pro-apoptotic effects on tumor cells in animal models (4, 5); however, administration of high dose IFN-␥ to patients with advanced renal and ovarian cancer has had only limited success and failed to improve overall survival (1, 6).IFN-␥ has been shown to regulate bone cell differentiation and function with complex effects on skeletal health. However, the role of IFN-␥ in pathological bone disease is largely controversial. Previously, it has been reported that IFN-␥ can inhibit the critical osteoclast regulator, receptor activator of NFB ligand (RANKL), by activating ubiquitin-mediated degradation of its signaling pathway adaptor protein 8). Mice deficient for IFN-␥ or its receptor develop enhanced bone loss associated with collagen-induced arthritis (9 -11). In contrast, Gao et al. (12) recently found that IFN-␥ indirectly stimulates osteoclast formation and bone loss after ovariectomy via antigen-driven T cell activation, resulting in the production of osteoclast-activating factors. Interestingly, IFN-␥ has been used to treat infantile osteopetrosis in which patients suffered from high bone mass secondary to osteoclast dysfunction or osteoblast hyperactivity, but the mechanism of action may be through modulation of the host immune system rather than direct effects on bone cells (13-15). However, the role of IFN-␥ in the treatment of osteolytic bone metastases has not been elucidated.We evaluated the effects of IFN-␥ in HTLV-1-Tax transgenic mice that develop osteolytic bone tumors and hypercalcemia (16,17). Previously, it was shown that HTLV-1-Taxmice develop increased numbers of soft tissue tumors with enhanced tumor-associated angiogenesis and up-regulation of vascular endothelial growth factor expression; however, the impact on bone metastases and hypercalcemia in these mice * This work was supported, in whole or in part, by National Institutes of Health Grants PPG CA100730 and R01 CA 097250 (to Z. X., M. H., H. D., M. C. E., D. H. F., E. A. H., and K. N. W.), Grant T32 CA09547 (cancer biology training grant to O. U. and M. H.), and Grant RO1 CA100730 (to T. J. R. and W. P. D. and NCRR to S. S.), as well as by the St. Louis Men's Club Against Cancer (to K. N. W.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

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IFN-γ Enhances Osteoclast Generation in Cultures of Peripheral Blood from Osteopetrotic Patients and Normalizes Superoxide Production

Cited by 45 publications

References 28 publications

A New Superoxide-generating Oxidase in Murine Osteoclasts

A New Superoxide-generating Oxidase in Murine Osteoclasts

Functions of RANKL/RANK/OPG in bone modeling and remodeling

Interferon-γ Targets Cancer Cells and Osteoclasts to Prevent Tumor-associated Bone Loss and Bone Metastases

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