Interferon-α, unlike interferon-γ, does not cause bone loss in the rat

Goodman, Grant R.; Dissanayake, Imara; Gorodetsky, Ella; Zhou, Hua; Ma, Yang; Jee, Webster S. S.; Epstein, Sol

doi:10.1016/s8756-3282(99)00182-9

Cited by 27 publications

(17 citation statements)

References 24 publications

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“…However it is the first time, according to our knowledge, that these markers are studied in patients in the plateau phase of MM under the combination of pamidronate and IFN-a. It has been reported recently that the administration of low dose IFN-ot (1.6 x 106 IU/m 2) in rats resulted in a significant increase in OSC [13]. On the other hand, pamidronate has an inhibiting effect on apoptosis of primary murine osteoblastic cells isolated from calvaria [30], whereas long-term oral pamidronate treatment does not seem to affect osteoblastic function [31].…”

Section: Discussionmentioning

confidence: 98%

“…NTx is the marker of bone resorption with the greatest decline after therapy with bisphosphonates, although with a high longterm variability [ 19]. IFN-c~ is used for maintenance treatment in MM and has been shown to decrease bone resorption both in vivo and in vitro [13]. IFN-oL also downregulates the expression of a parathyroid hormone (PTH)/PTH-related peptide [20] which increases the number of committed mononuclear osteoclast progenitors as well as mature osteoclasts [21].…”

Section: Discussionmentioning

confidence: 99%

“…Both in vitro and in vivo studies have demonstrated that IFN-a decreases bone resorption, and it has been reported that the administration of low dose IFN-a in rats resulted in a statistically significant increase in serum osteocalcin (OSC) [13]. OSC and bone alkaline phosphatase (BAP) are the most sensitive and specific markers of bone formation [14].…”

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confidence: 99%

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Pamidronate increases markers of bone formation in patients with multiple myeloma in plateau phase under interferon-alpha treatment

et al. 2001

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Bisphosphonates are potent inhibitors of osteoclastic activity and reduce the disease-related skeletal complications when they are used in combination with chemotherapy in patients with multiple myeloma (MM). Pamidronate also inhibits apoptosis of primary osteoblastic cells and probably induces apoptosis on human MM cells and osteoclasts. It has been reported that interferon-alpha (IFN-alpha) decreases bone resorption and that low doses of IFN-alpha result in a significant increase in serum osteocalcin (OSC). The aim of this study was to determine the effects of pamidronate treatment on biochemical markers of bone resorption [cross-linked N-telopeptides of type I collagen (NTx)], bone formation [bone alkaline phosphatase (BAP) and OSC], disease activity [beta2-microglobulin, CRP, paraprotein], and interleukin-6 (IL-6) in patients with MM in plateau phase under IFN-alpha maintenance. The above parameters were evaluated in 28 patients (13 M, 15 F, median age 70 years) during maintenance treatment, before the addition of pamidronate and after 1, 3, 6, 9, 12, and 14 months of the combined therapy. The addition of pamidronate to maintenance treatment resulted in a significant reduction of NTx, IL-6, beta2-microglobulin, CRP from the 3rd month and paraprotein from the 6th month of treatment, whereas BAP and OSC were significantly increased from the 6th month. These changes continued during the 14-month follow-up of the combined treatment. Multivariate analysis showed a significant negative correlation between changes of BAP and OSC and the patients' age. The greater increase of the bone formation markers was observed in younger patients. These results suggest that, in addition to the inhibition of osteoclastic activity, pamidronate in combination with IFN-alpha was shown to induce bone formation in patients with MM in the plateau phase.

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Section: Discussionmentioning

confidence: 98%

Section: Discussionmentioning

confidence: 99%

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Pamidronate increases markers of bone formation in patients with multiple myeloma in plateau phase under interferon-alpha treatment

et al. 2001

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“…Addition of recombinant IFN-γ (rIFN-γ) rescues the defect in osteoclastogenesis in peripheral white blood cells from malignant osteopetrosis patients in vitro (8). Systemic administration of rIFN-γ causes loss of bone volume in rats (16,17). Moreover, mice lacking IFN-γ production are protected against infection-induced alveolar bone loss (18), and IFN-γ receptor -/-(IFN-γR -/-) mice fail to undergo ovariectomy-induced (ovx-induced) bone loss (2).…”

Section: Introductionmentioning

confidence: 99%

IFN-γ stimulates osteoclast formation and bone loss in vivo via antigen-driven T cell activation

Gao¹,

Grassi²,

Ryan³

et al. 2007

J. Clin. Invest.

405

388

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T cell-produced cytokines play a pivotal role in the bone loss caused by inflammation, infection, and estrogen deficiency. IFN-γ is a major product of activated T helper cells that can function as a pro-or antiresorptive cytokine, but the reason why IFN-γ has variable effects in bone is unknown. Here we show that IFN-γ blunts osteoclast formation through direct targeting of osteoclast precursors but indirectly stimulates osteoclast formation and promotes bone resorption by stimulating antigen-dependent T cell activation and T cell secretion of the osteoclastogenic factors RANKL and TNF-α. Analysis of the in vivo effects of IFN-γ in 3 mouse models of bone loss -ovariectomy, LPS injection, and inflammation via silencing of TGF-β signaling in T cells -reveals that the net effect of IFN-γ in these conditions is that of stimulating bone resorption and bone loss. In summary, IFN-γ has both direct anti-osteoclastogenic and indirect pro-osteoclastogenic properties in vivo. Under conditions of estrogen deficiency, infection, and inflammation, the net balance of these 2 opposing forces is biased toward bone resorption. Inhibition of IFN-γ signaling may thus represent a novel strategy to simultaneously reduce inflammation and bone loss in common forms of osteoporosis.

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“…A group and less than 0.01 for the antibodies group (Scheffé's method applied after single-factor analysis of variance 17,18 These cytokines play an important role in the regulation of bone metabolism. [24][25][26] For example, IL-1, tumor necrosis factor (TNF)-a, and TNF-b are potent stimulators of bone resorption and also affect osteoblast metabolism. INF-g preferentially inhibits cytokine-stimulated resorption of bone.…”

Section: Bone Volumes Induced By Adhbmp4 and Adhbmp9 In Different Groupsmentioning

confidence: 99%

Local immunomodulation with CD4 and CD8 antibodies, but not cyclosporine A, improves osteogenesis induced by ADhBMP9 gene therapy

Hankins

et al. 2005

Gene Ther

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This study was designed to see if immunosuppression achieved using local application of cyclosporine A (Cs. A) or CD4 and CD8 antibodies would improve bone formation following intramuscular injections of human BMP-4 and BMP-9 adenoviral vectors (ADhBMP4 and ADhBMP9) in Sprague-Dawley rats. Cs. A was injected into the thigh muscle. After 2 days, ADhBMP4, ADhBMP9, and the antibodies were separately injected into the left and right rear legs. At this time, the number of CD4+/CD3+ cells was significantly lower and the number of CD8+/CD3+ cells higher in the Cs. A group than in the control group (Po0.01). The total number of white blood cells 3 days following injection of CD4 and CD8 antibodies was significantly lower than that before the injection (Po0.01). At 4 weeks after the viral and antibody injections, mean bone volumes at the ADhBMP9 treatment sites were 0.2970.01 cm 3 in the viral control group, 0.1770.03 cm 3 in the Cs. A-ADhBMPs group, and 0.5970.07 cm 3 in the antibodies-ADhBMPs group. ADhBMP4 did not induce new bone formation in any group. This study demonstrates that local immunomodulation may improve the osteogenic potential of bone morphogenetic protein gene therapy in the clinical setting.

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Interferon-α, unlike interferon-γ, does not cause bone loss in the rat

Cited by 27 publications

References 24 publications

Pamidronate increases markers of bone formation in patients with multiple myeloma in plateau phase under interferon-alpha treatment

Pamidronate increases markers of bone formation in patients with multiple myeloma in plateau phase under interferon-alpha treatment

IFN-γ stimulates osteoclast formation and bone loss in vivo via antigen-driven T cell activation

Local immunomodulation with CD4 and CD8 antibodies, but not cyclosporine A, improves osteogenesis induced by ADhBMP9 gene therapy

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