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Biomechanical thresholds regulate inflammation through the NF-kappaB pathway: experiments and modeling.

Nam J, Aguda BD, Rath B, Agarwal S - PLoS ONE (2009)

Bottom Line: Experimental and computational results indicate that biomechanical signals suppress and induce inflammation at critical thresholds through activation/suppression of the NF-kappaB signaling pathway.These thresholds arise due to the bistable behavior of the networks originating from the positive feedback loop between NF-kappaB and its target genes.These findings lay initial groundwork for the identification of the thresholds in physical activities that can differentiate its favorable actions from its unfavorable consequences on joints.

View Article: PubMed Central - PubMed

Affiliation: Biomechanics and Tissue Engineering Laboratory, College of Dentistry, The Ohio State University, Columbus, OH, USA.

ABSTRACT

Background: During normal physical activities cartilage experiences dynamic compressive forces that are essential to maintain cartilage integrity. However, at non-physiologic levels these signals can induce inflammation and initiate cartilage destruction. Here, by examining the pro-inflammatory signaling networks, we developed a mathematical model to show the magnitude-dependent regulation of chondrocytic responses by compressive forces.

Methodology/principal findings: Chondrocytic cells grown in 3-D scaffolds were subjected to various magnitudes of dynamic compressive strain (DCS), and the regulation of pro-inflammatory gene expression via activation of nuclear factor-kappa B (NF-kappaB) signaling cascade examined. Experimental evidences provide the existence of a threshold in the magnitude of DCS that regulates the mRNA expression of nitric oxide synthase (NOS2), an inducible pro-inflammatory enzyme. Interestingly, below this threshold, DCS inhibits the interleukin-1beta (IL-1beta)-induced pro-inflammatory gene expression, with the degree of suppression depending on the magnitude of DCS. This suppression of NOS2 by DCS correlates with the attenuation of the NF-kappaB signaling pathway as measured by IL-1beta-induced phosphorylation of the inhibitor of kappa B (IkappaB)-alpha, degradation of IkappaB-alpha and IkappaB-beta, and subsequent nuclear translocation of NF-kappaB p65. A mathematical model developed to understand the complex dynamics of the system predicts two thresholds in the magnitudes of DCS, one for the inhibition of IL-1beta-induced expression of NOS2 by DCS at low magnitudes, and second for the DCS-induced expression of NOS2 at higher magnitudes.

Conclusions/significance: Experimental and computational results indicate that biomechanical signals suppress and induce inflammation at critical thresholds through activation/suppression of the NF-kappaB signaling pathway. These thresholds arise due to the bistable behavior of the networks originating from the positive feedback loop between NF-kappaB and its target genes. These findings lay initial groundwork for the identification of the thresholds in physical activities that can differentiate its favorable actions from its unfavorable consequences on joints.

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Mathematical model predictions of RNOS2 and NF-κB nuclear concentration.Predicted (A) RNOS2 and (B) NF-κB concentration in nucleus (Nn) with respect to magnitude of biomechanical stimulation (m) in the absence (P0 = 0, solid lines) or presence (P0 = 25, dotted lines) of inflammatory cytokine at steady states. Initial values of parameters derived from the equilibrium state for P0 = 0 were RP = 0.00944, Pc = 0.000925, P0 = 0.259127, C = 0.001337, RI = 0.011025, Ic = 0.020399, In = 0.011686, Nc = 0.0000426, RNOS2 = 0.000616, Nn = 0.000647, Npc = 0.042536, and Npn = 0.000274; for P0 = 25: RP = 1.06679, Pc = 0.104587, P0 = 29.2808, C = 0.0.0252157, RI = 0.053822, Ic = 0.0892936, In = 0.00196127, Nc = 0.000317215, RNOS2 = 1.05796, Nn = 0.0269191, Npc = 0.0143506, and Npn = 0.00191274.
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pone-0005262-g007: Mathematical model predictions of RNOS2 and NF-κB nuclear concentration.Predicted (A) RNOS2 and (B) NF-κB concentration in nucleus (Nn) with respect to magnitude of biomechanical stimulation (m) in the absence (P0 = 0, solid lines) or presence (P0 = 25, dotted lines) of inflammatory cytokine at steady states. Initial values of parameters derived from the equilibrium state for P0 = 0 were RP = 0.00944, Pc = 0.000925, P0 = 0.259127, C = 0.001337, RI = 0.011025, Ic = 0.020399, In = 0.011686, Nc = 0.0000426, RNOS2 = 0.000616, Nn = 0.000647, Npc = 0.042536, and Npn = 0.000274; for P0 = 25: RP = 1.06679, Pc = 0.104587, P0 = 29.2808, C = 0.0.0252157, RI = 0.053822, Ic = 0.0892936, In = 0.00196127, Nc = 0.000317215, RNOS2 = 1.05796, Nn = 0.0269191, Npc = 0.0143506, and Npn = 0.00191274.

Mentions: The two lines in Figure 6B indicate that the system exhibits bistability for k3eff between 0 and ∼0.024. This phenomenon is characterized by having two stable steady states that coexist for a given set of parameters. The solid curve of Figure 6B explains the origin of the threshold (at m = mth1) observed in the experiment with no initial addition of IL-1β (Fig. 2, solid line), as well as the origin of another threshold mth2 (mth2<mth1), which could not be clearly observed in the experiment. The predicted mth2 is the point where expression of pro-inflammatory gene (NOS2) is completely suppressed in the presence of inflammatory cytokine (Fig. 7A). At k3eff∼0.024, corresponding to m = mth1, synthesis of RNOS2 turns on. At k3,eff = 0, corresponding to m = mth2, synthesis of RNOS2 turns off. These two model-predicted thresholds are shown explicitly in Figure 7A. In Figure 7B, the corresponding levels of nuclear NF-κB concentration (Nn) in steady state are shown. The model predicts that the nuclear localization of NF-κB parallels that of the synthesis of RNOS2 which is a target of active NF-κB as experimentally observed [14].


Biomechanical thresholds regulate inflammation through the NF-kappaB pathway: experiments and modeling.

Nam J, Aguda BD, Rath B, Agarwal S - PLoS ONE (2009)

Mathematical model predictions of RNOS2 and NF-κB nuclear concentration.Predicted (A) RNOS2 and (B) NF-κB concentration in nucleus (Nn) with respect to magnitude of biomechanical stimulation (m) in the absence (P0 = 0, solid lines) or presence (P0 = 25, dotted lines) of inflammatory cytokine at steady states. Initial values of parameters derived from the equilibrium state for P0 = 0 were RP = 0.00944, Pc = 0.000925, P0 = 0.259127, C = 0.001337, RI = 0.011025, Ic = 0.020399, In = 0.011686, Nc = 0.0000426, RNOS2 = 0.000616, Nn = 0.000647, Npc = 0.042536, and Npn = 0.000274; for P0 = 25: RP = 1.06679, Pc = 0.104587, P0 = 29.2808, C = 0.0.0252157, RI = 0.053822, Ic = 0.0892936, In = 0.00196127, Nc = 0.000317215, RNOS2 = 1.05796, Nn = 0.0269191, Npc = 0.0143506, and Npn = 0.00191274.
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pone-0005262-g007: Mathematical model predictions of RNOS2 and NF-κB nuclear concentration.Predicted (A) RNOS2 and (B) NF-κB concentration in nucleus (Nn) with respect to magnitude of biomechanical stimulation (m) in the absence (P0 = 0, solid lines) or presence (P0 = 25, dotted lines) of inflammatory cytokine at steady states. Initial values of parameters derived from the equilibrium state for P0 = 0 were RP = 0.00944, Pc = 0.000925, P0 = 0.259127, C = 0.001337, RI = 0.011025, Ic = 0.020399, In = 0.011686, Nc = 0.0000426, RNOS2 = 0.000616, Nn = 0.000647, Npc = 0.042536, and Npn = 0.000274; for P0 = 25: RP = 1.06679, Pc = 0.104587, P0 = 29.2808, C = 0.0.0252157, RI = 0.053822, Ic = 0.0892936, In = 0.00196127, Nc = 0.000317215, RNOS2 = 1.05796, Nn = 0.0269191, Npc = 0.0143506, and Npn = 0.00191274.
Mentions: The two lines in Figure 6B indicate that the system exhibits bistability for k3eff between 0 and ∼0.024. This phenomenon is characterized by having two stable steady states that coexist for a given set of parameters. The solid curve of Figure 6B explains the origin of the threshold (at m = mth1) observed in the experiment with no initial addition of IL-1β (Fig. 2, solid line), as well as the origin of another threshold mth2 (mth2<mth1), which could not be clearly observed in the experiment. The predicted mth2 is the point where expression of pro-inflammatory gene (NOS2) is completely suppressed in the presence of inflammatory cytokine (Fig. 7A). At k3eff∼0.024, corresponding to m = mth1, synthesis of RNOS2 turns on. At k3,eff = 0, corresponding to m = mth2, synthesis of RNOS2 turns off. These two model-predicted thresholds are shown explicitly in Figure 7A. In Figure 7B, the corresponding levels of nuclear NF-κB concentration (Nn) in steady state are shown. The model predicts that the nuclear localization of NF-κB parallels that of the synthesis of RNOS2 which is a target of active NF-κB as experimentally observed [14].

Bottom Line: Experimental and computational results indicate that biomechanical signals suppress and induce inflammation at critical thresholds through activation/suppression of the NF-kappaB signaling pathway.These thresholds arise due to the bistable behavior of the networks originating from the positive feedback loop between NF-kappaB and its target genes.These findings lay initial groundwork for the identification of the thresholds in physical activities that can differentiate its favorable actions from its unfavorable consequences on joints.

View Article: PubMed Central - PubMed

Affiliation: Biomechanics and Tissue Engineering Laboratory, College of Dentistry, The Ohio State University, Columbus, OH, USA.

ABSTRACT

Background: During normal physical activities cartilage experiences dynamic compressive forces that are essential to maintain cartilage integrity. However, at non-physiologic levels these signals can induce inflammation and initiate cartilage destruction. Here, by examining the pro-inflammatory signaling networks, we developed a mathematical model to show the magnitude-dependent regulation of chondrocytic responses by compressive forces.

Methodology/principal findings: Chondrocytic cells grown in 3-D scaffolds were subjected to various magnitudes of dynamic compressive strain (DCS), and the regulation of pro-inflammatory gene expression via activation of nuclear factor-kappa B (NF-kappaB) signaling cascade examined. Experimental evidences provide the existence of a threshold in the magnitude of DCS that regulates the mRNA expression of nitric oxide synthase (NOS2), an inducible pro-inflammatory enzyme. Interestingly, below this threshold, DCS inhibits the interleukin-1beta (IL-1beta)-induced pro-inflammatory gene expression, with the degree of suppression depending on the magnitude of DCS. This suppression of NOS2 by DCS correlates with the attenuation of the NF-kappaB signaling pathway as measured by IL-1beta-induced phosphorylation of the inhibitor of kappa B (IkappaB)-alpha, degradation of IkappaB-alpha and IkappaB-beta, and subsequent nuclear translocation of NF-kappaB p65. A mathematical model developed to understand the complex dynamics of the system predicts two thresholds in the magnitudes of DCS, one for the inhibition of IL-1beta-induced expression of NOS2 by DCS at low magnitudes, and second for the DCS-induced expression of NOS2 at higher magnitudes.

Conclusions/significance: Experimental and computational results indicate that biomechanical signals suppress and induce inflammation at critical thresholds through activation/suppression of the NF-kappaB signaling pathway. These thresholds arise due to the bistable behavior of the networks originating from the positive feedback loop between NF-kappaB and its target genes. These findings lay initial groundwork for the identification of the thresholds in physical activities that can differentiate its favorable actions from its unfavorable consequences on joints.

Show MeSH
Related in: MedlinePlus