Mechanisms of interferon-β effects on bone homeostasis

Abraham, Anson K.; Ramanathan, Murali; Weinstock‐Guttman, Bianca; Mager, Donald E.

doi:10.1016/j.bcp.2009.01.007

Cited by 36 publications

(33 citation statements)

References 63 publications

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“…In fact, PQQ repletion is reported to upregulate the JAK/STAT pathways [33]. Further, the number of osteoclasts notably increases in the bone of the IFN-␤ −/− [10] or IFNAR −/− [32] mice, compared to the wild-type mice. Therefore, PQQ is possible to enhance the IFN-␤-dependent JAK/STAT pathway via augmented IFNAR expression.…”

Section: Discussionmentioning

confidence: 99%

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Inhibition of receptor activator of nuclear factor-κB ligand (RANKL)-induced osteoclast formation by pyrroloquinoline quinine (PQQ)

et al. 2012

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Section: Discussionmentioning

confidence: 99%

“…IFN-␤ is produced in response to RANKL and triggers the JAK/STAT signaling via IFNAR [32]. Subsequently, IFN-inducible genes activated by JAK/STAT signaling inhibit the c-Fos expression [10].…”

Section: Discussionmentioning

confidence: 99%

Inhibition of receptor activator of nuclear factor-κB ligand (RANKL)-induced osteoclast formation by pyrroloquinoline quinine (PQQ)

et al. 2012

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“…The binding of IFN-b to its receptor causes a signal cascade through the JAK/STAT pathway, responsible for inhibition of c-fos protein production and osteoclast proliferation and differentiation [60]. IFN-c is involved in the inhibition of RANK-RANKL-induced osteoclastogenesis and constitutes a negative feedback regulation of RANKL signaling.…”

Section: Negative Regulators Of Osteoclastogenesismentioning

confidence: 99%

Osteoclastogenesis and arthritis

et al. 2010

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There is emerging interest for osteoclasts as key players in the erosive and inflammatory events leading to joint destruction in chronic arthritis. In fact, chronic inflammatory joint diseases such as psoriatic arthritis and rheumatoid arthritis are often characterized by destruction of juxta-articular bone and erosions due to the elevated activity of osteoclasts, which are involved in bone resorption. The main step in inflammatory bone erosion is an imbalance between bone resorption and bone formation: osteoclast formation is enhanced by proinflammatory cytokines such as TNF-α, IL-1β, and IL-17 and is not balanced by increased activity of bone-forming osteoblasts. T-cells, stromal cells, and synoviocytes enhance osteoclast formation via expression of RANKL and, under pathologic conditions, of proinflammatory cytokines. In rheumatoid arthritis, accumulation of osteoclasts in synovial tissues and their activation associated with osteoclastogenic cytokines and chemokines at cartilage erosion sites suggest that they could be usefully selected as therapeutic target. In particular, in consideration of the primary role of RANKL and TNF-α in osteoclastogenesis, the control of the production of RANKL and the inhibition of TNF-α represent important strategies for reducing bone damage in this disease.

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“…The TD model that is presented here describes a more explicit biological mechanism for arsenic-induced protective response of cells applying principles of indirect response model theory; a theoretical framework commonly used to describe dynamic coupling of extracellular stimuli to intracellular signaling (Abraham et al, 2009a, 2009b; Foteinou et al, 2009; Ramakrishnan et al, 2002; Vodovotz et al, 2009). So, it addresses the arsenic-induced ROS production, the Nrf2-mediated mammalian antioxidant response, and the concomitant DNA damage in hepatocytes.…”

Section: Approach and Methodsmentioning

confidence: 99%

A semi-mechanistic integrated toxicokinetic–toxicodynamic (TK/TD) model for arsenic(III) in hepatocytes

Stamatelos

Androulakis

Kong

et al. 2013

Journal of Theoretical Biology

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Background A systems engineering approach is presented for describing the kinetics and dynamics that are elicited upon arsenic exposure of human hepatocytes. The mathematical model proposed here tracks the cellular reaction network of inorganic and organic arsenic compounds present in the hepatocyte and analyzes the production of toxicologically potent by-products and the signaling they induce in hepatocytes. Methods and results The present modeling effort integrates for the first time a cellular-level semi-mechanistic toxicokinetic (TK) model of arsenic in human hepatocytes with a cellular-level toxicodynamic (TD) model describing the arsenic-induced reactive oxygen species (ROS) burst, the antioxidant response, and the oxidative DNA damage repair process. The antioxidant response mechanism is described based on the Keap1-independent Nuclear Factor-erythroid 2-related factor 2 (Nrf2) signaling cascade and accounts for the upregulation of detoxifying enzymes. The ROS-induced DNA damage is simulated by coupling the TK/TD formulation with a model describing the multistep pathway of oxidative DNA repair. The predictions of the model are assessed against experimental data of arsenite-induced genotoxic damage to human hepatocytes; thereby capturing in silico the mode of the experimental dose–response curve. Conclusions The integrated cellular-level TK/TD model presented here provides significant insight into the underlying regulatory mechanism of Nrf2-regulated antioxidant response due to arsenic exposure. While computational simulations are in a fair good agreement with relevant experimental data, further analysis of the system unravels the role of a dynamic interplay among the feedback loops of the system in controlling the ROS upregulation and DNA damage response. This TK/TD framework that uses arsenic as an example can be further extended to other toxic or pharmaceutical agents.

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Mechanisms of interferon-β effects on bone homeostasis

Cited by 36 publications

References 63 publications

Inhibition of receptor activator of nuclear factor-κB ligand (RANKL)-induced osteoclast formation by pyrroloquinoline quinine (PQQ)

Inhibition of receptor activator of nuclear factor-κB ligand (RANKL)-induced osteoclast formation by pyrroloquinoline quinine (PQQ)

Osteoclastogenesis and arthritis

A semi-mechanistic integrated toxicokinetic–toxicodynamic (TK/TD) model for arsenic(III) in hepatocytes

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