In Vivo Imaging of Matrix Metalloproteinase 12 and Matrix Metalloproteinase 13 Activities in the Mouse Model of Collagen‐Induced Arthritis

Lim, Ngee Han; Meinjohanns, Ernst; Bou‐Gharios, George; Gompels, Luke; Nuti, Elisa; Rossello, Armando; Devel, Laurent; Dive, Vincent; Meldal, Morten; Nagase, Hideaki

doi:10.1002/art.38295

Cited by 30 publications

(31 citation statements)

References 41 publications

(45 reference statements)

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“…To further confirm that Adamts1 plays a role in regulating collagen and elastin, we used a pharmacological inhibitor of MMP [Lim et al, ]. Incubation of cells with GM6001 alone did not affect collagen or elastin levels, as compared to control cells (Figs.…”

Section: Resultsmentioning

confidence: 99%

Adamts1 Mediates Ethanol‐Induced Alterations in Collagen and Elastin via a FoxO1‐Sestrin3‐AMPK Signaling Cascade in Myocytes

Hong-Brown

Brown

Navaratnarajah

et al. 2014

J of Cellular Biochemistry

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A variety of stressors including alcohol (EtOH) are known to induce collagen production and fibrotic diseases. Matrix metalloproteinases (MMP) play an important role in regulating fibrosis, but little is known regarding the relationship between EtOH and MMPs. In addition, the signaling cascades involved in this process have not been elucidated. We have identified the MMP Adamts1 as a target of EtOH regulation. To characterize the function of Adamts1, we examined EtOH-induced alterations in collagen I and elastin protein levels in C2C12 myocytes. Incubation of myocytes with 100 mM EtOH decreased elastin and increased collagen content, respectively, and these changes were associated with increased O-GLcNAc modification of Adamts1. Conversely, silencing of Adamts1 by siRNA blocked the adverse effects of EtOH on collagen and elastin levels. Similar results were obtained after treatment with a pharmacological inhibitor of MMP. Changes in collagen were due, at least in part, to a decreased interaction of Adamts1 with its endogenous inhibitor TIMP3. The AMPK inhibitor compound C blocked the EtOH-induced stimulation of collagen and O-GLcNAc Adamts1 protein. Changes in AMPK appear linked to FoxO1, since inhibition of FoxO1 blocked the effects of EtOH on AMPK phosphorylation and O-GLcNAc levels. These FoxO-dependent modifications were associated with an upregulation of the FoxO1 transcription target sestrin 3, as well as increased binding of sestrin 3 with AMPK. Collectively, these data indicate that EtOH regulates the collagen I and elastin content in an Adamts1-dependent manner in myocytes. Furthermore, Adamts1 appears to be controlled by the FoxO1-sestrin 3-AMPK signaling cascade.

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Section: Resultsmentioning

confidence: 99%

Adamts1 Mediates Ethanol‐Induced Alterations in Collagen and Elastin via a FoxO1‐Sestrin3‐AMPK Signaling Cascade in Myocytes

Hong-Brown

Brown

Navaratnarajah

et al. 2014

J of Cellular Biochemistry

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“…In high fat-fed apoE −/− mice, RXP470.1 reduces atherosclerotic plaque area and promotes a fibrous plaque phenotype3. More recently, this compound was also shown to block MMP-12 activity in mouse models of inflammation2728 and during viral infection5. The similarity between the effects of RXP470.1 and MMP-12 gene deletion in models of atherosclerosis and viral infection35 suggests that MMP-12 active form is the privileged target for this inhibitor in vivo .…”

Section: Discussionmentioning

confidence: 99%

Optical imaging of MMP-12 active form in inflammation and aneurysm

Razavian

Bordenave

Georgiadis

et al. 2016

Sci Rep

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Matrix metalloproteinase (MMP)-12 plays a key role in the development of aneurysm. Like other members of MMP family, MMP-12 is produced as a proenzyme, mainly by macrophages, and undergoes proteolytic activation to generate an active form. Accordingly, molecular imaging of the MMP-12 active form can inform of the pathogenic process in aneurysm. Here, we developed a novel family of fluorescent probes based on a selective MMP-12 inhibitor, RXP470.1 to target the active form of MMP-12. These probes were stable in complex media and retained the high affinity and selectivity of RXP470.1 for MMP-12. Amongst these, probe 3 containing a zwitterionic fluorophore, ZW800-1, combined a favorable affinity profile toward MMP-12 and faster blood clearance. In vivo binding of probe 3 was observed in murine models of sterile inflammation and carotid aneurysm. Binding specificity was demonstrated using a non-binding homolog. Co-immunostaining localized MMP-12 probe binding to MMP-12 positive areas and F4/80 positive macrophages in aneurysm. In conclusion, the active form of MMP-12 can be detected by optical imaging using RXP470.1-based probes. This is a valuable adjunct for pathophysiology research, drug development, and potentially clinical applications.

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“…We have previously reported an enzyme‐activatable fluorescence resonance energy transfer (FRET) substrate for MMP‐13 and we used this substrate for the detection of MMP‐13 activity in a mouse OA model induced surgically by destabilizing the medial meniscus (DMM). However, due to the limited sensitivity of the probe, it could not discriminate the OA knees from sham‐operated knees until 8 weeks after surgery, when histological damage of the cartilage was apparent .…”

Section: Introductionmentioning

confidence: 99%

In Vivo Imaging of MMP‐13 Activity Using a Specific Polymer‐FRET Peptide Conjugate Detects Early Osteoarthritis and Inhibitor Efficacy

Duro‐Castaño

Lim

Tranchant

et al. 2018

Adv Funct Materials

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Imaging early molecular changes in osteoarthritic (OA) joints is instrumental for the development of disease-modifying drugs. To this end, a fluorescent resonance energy transfer-based peptide probe that is cleavable by matrix metalloproteinase 13 (MMP-13) has been developed. This protease degrades type II collagen, a major matrix component of cartilage. The probe exhibits high catalytic efficiency (k cat /K M = 6.5 × 10 5 m −1 s −1 ) and high selectivity for MMP-13 over a set of nine MMPs. To achieve optimal in vivo pharmacokinetics and tissue penetration, the probe has been further conjugated to a linear l-polyglutamate chain of 30 kDa. The conjugate detects early biochemical events that occur in a surgically induced murine model of OA before major histological changes. The nanometric probe is suitable for the monitoring of in vivo efficacy of an orally bioavailable MMP-13 inhibitor, which effectively blocks cartilage degradation during the development of OA. This new polymer-probe can therefore be a useful tool in detecting early OA, disease progression, and in developing MMP-13-based disease-modifying drugs for OA.

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In Vivo Imaging of Matrix Metalloproteinase 12 and Matrix Metalloproteinase 13 Activities in the Mouse Model of Collagen‐Induced Arthritis

Cited by 30 publications

References 41 publications

Adamts1 Mediates Ethanol‐Induced Alterations in Collagen and Elastin via a FoxO1‐Sestrin3‐AMPK Signaling Cascade in Myocytes

Adamts1 Mediates Ethanol‐Induced Alterations in Collagen and Elastin via a FoxO1‐Sestrin3‐AMPK Signaling Cascade in Myocytes

Optical imaging of MMP-12 active form in inflammation and aneurysm

In Vivo Imaging of MMP‐13 Activity Using a Specific Polymer‐FRET Peptide Conjugate Detects Early Osteoarthritis and Inhibitor Efficacy

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