In vivo imaging of protease activity in arthritis: A novel approach for monitoring treatment response

Wunder, Andreas; Tung, Ching–Hsuan; Müller‐Ladner, Ulf; Weissleder, Ralph; Mahmood, Umar

doi:10.1002/art.20379

Cited by 156 publications

(112 citation statements)

References 29 publications

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“…The reduction of protease-activated fluorescence signal in response to methotrexate treatment has been observed in the murine collagen-induced arthritis model (16). However, that study did not include analysis of the correlation between the decrease in protease-activated fluorescence signal and clinical disease indices such as redness, swelling, and ankylosis.…”

Section: Discussionmentioning

confidence: 99%

“…Since we detected increased mRNA levels for cathepsins B and K in arthritic joints, which were inhibited in the ML120B-treated group, we selected an optical probe activated by cathepsin proteases to monitor protease activity in vivo. The Prosense "smart" probe is an enzyme-cleavable fluorescent probe specific for a defined subset of proteases, including cathepsins B and K. Probe fluorescence remains quenched when the probe is administered intravenously, until activation by enzyme cleavage in the target tissue (16). The Prosense probe was injected into control, vehicle-treated, and 60 mg/kg ML120B-treated animals, and an in vivo image was captured and fluorescence intensity in paws quantified ( Figure 5A).…”

Section: Response To Ikk-2 Inhibition In Arthritic Micementioning

confidence: 99%

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Use of molecular imaging to quantify response to IKK‐2 inhibitor treatment in murine arthritis

Izmailova¹,

Paz²,

Alencar³

et al. 2007

Arthritis & Rheumatism

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Objective. The NF-B signaling pathway promotes the immune response in rheumatoid arthritis (RA) and in rodent models of RA. NF-B activity is regulated by the IKK-2 kinase during inflammatory responses. To elucidate how IKK-2 inhibition suppresses disease development, we used a combination of in vivo imaging, transcription profiling, and histopathology technologies to study mice with antibodyinduced arthritis.Methods. ML120B, a potent, small molecule inhibitor of IKK-2, was administered to arthritic animals, and disease activity was monitored. NF-B activity in diseased joints was quantified by in vivo imaging. Quantitative reverse transcriptase-polymerase chain reaction was used to evaluate gene expression in joints. Protease-activated near-infrared fluorescence (NIRF) in vivo imaging was applied to assess the amounts of active proteases in the joints.Results. Oral administration of ML120B suppressed both clinical and histopathologic manifestations of disease. In vivo imaging demonstrated that NF-B activity in inflamed arthritic paws was inhibited by ML120B, resulting in significant suppression of multiple genes in the NF-B pathway, i.e., KC, epithelial neutrophil-activating peptide 78, JE, intercellular adhesion molecule 1, CD3, CD68, tumor necrosis factor ␣, interleukin-1␤, interleukin-6, inducible nitric oxide synthase, cyclooxygenase 2, matrix metalloproteinase 3, cathepsin B, and cathepsin K. NIRF in vivo imaging demonstrated that ML120B treatment dramatically reduced the amount of active proteases in the joints.Conclusion. Our data demonstrate that IKK-2 inhibition in the murine model of antibody-induced arthritis suppresses both inflammation and joint destruction. In addition, this study highlights how gene expression profiling can facilitate the identification of surrogate biomarkers of disease activity and treatment response in an experimental model of arthritis.

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Section: Discussionmentioning

confidence: 99%

Section: Response To Ikk-2 Inhibition In Arthritic Micementioning

confidence: 99%

Use of molecular imaging to quantify response to IKK‐2 inhibitor treatment in murine arthritis

Izmailova¹,

Paz²,

Alencar³

et al. 2007

Arthritis & Rheumatism

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“…These allow examination of protease-activated near-infrared fluorescence, enabling noninvasive acquisition, on a molecular level, of quantitative information about the presence and anatomic location of transgene expression (25) and target enzymes in arthritis research (26).…”

Section: Discussionmentioning

confidence: 99%

High‐resolution multipinhole single‐photon–emission computed tomography in experimental and human arthritis

Ostendorf

Scherer

Wirrwar

et al. 2006

Arthritis & Rheumatism

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Objective. To image inflammatory arthritic lesions in experimental arthritis and in patients with arthritis, using a newly developed high-resolution multipinhole single-photon-emission computed tomography (MPH-SPECT) technique.Methods. Six interleukin-1 receptor antagonistdeficient mice with arthritis of the front and back paws and 2 control BALB/c mice were imaged with MPH-SPECT and scored macroscopically for arthritis. SPECT imaging was performed with a conventional gamma camera upgraded with a pyramidal lead collimator affixed with MPH apertures. All images were reconstructed, and uptake in the paws was quantified in counts/weight and injected activity. To transfer the imaging technique to humans we examined the clinically dominant hand of 6 individuals (3 with established rheumatoid arthritis [RA], 1 with early RA, 1 with osteoarthritis, and 1 healthy control).Results. MPH-SPECT images were highresolution 3-dimensional tomographic images, which allowed exact localization and quantifiable observation of increased bone metabolism. MPH-SPECT counts of inflamed joints in mice correlated with macroscopic scoring and histologic joint analysis postmortem. In humans, MPH-SPECT images depicted a detailed visualization of tracer accumulation in bony structures of hand and finger joints, and were also capable of imaging increased bone metabolism that had appeared normal with other imaging modalities, e.g., magnetic resonance imaging.Conclusion. The MPH-SPECT technique represents a new diagnostic tool in the detection of bone pathology in small-animal arthritis research. Compared with macroscopic scoring, this new method provides a more objective and higher-precision quantifiable measurement of bone reaction, allowing visualization of inflammatory processes of the whole skeleton in vivo. These results suggest that MPH-SPECT may be useful as a diagnostic instrument for monitoring experimental arthritis, with further potential for use in human studies of RA.

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“…In particular, tomographic fluorescence imaging of near-infraredlabeled imaging agents has the potential to be used in drug discovery RAS research by virtue of improved deep tissue penetration, quantitative readout (picomoles rather than relative light intensity), and the pairing with protease-activated NIR imaging agents. This approach has been shown to be effective for the assessment and monitoring of protease activity associated with various diseases, including cancer (20), atherosclerosis (4), lung inflammation, and arthritis (26,33). In a similar fashion, noninvasive imaging and quantification of renin activity in vivo and monitoring of response to therapeutics could have a significant impact on the development of cardiovascular disease-targeted drugs in both preclinical and clinical settings.…”

mentioning

confidence: 99%

A fluorogenic near-infrared imaging agent for quantifying plasma and local tissue renin activity in vivo and ex vivo

Zhang

Preda

Vasquez

et al. 2012

American Journal of Physiology-Renal Physiology

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. A fluorogenic near-infrared imaging agent for quantifying plasma and local tissue renin activity in vivo and ex vivo. Am J Physiol Renal Physiol 303: F593-F603, 2012. First published June 6, 2012; doi:10.1152/ajprenal.00361.2011.-The renin-angiotensin system (RAS) is well studied for its regulation of blood pressure and fluid homeostasis, as well as for increased activity associated with a variety of diseases and conditions, including cardiovascular disease, diabetes, and kidney disease. The enzyme renin cleaves angiotensinogen to form angiotensin I (ANG I), which is further cleaved by angiotensin-converting enzyme to produce ANG II. Although ANG II is the main effector molecule of the RAS, renin is the rate-limiting enzyme, thus playing a pivotal role in regulating RAS activity in hypertension and organ injury processes. Our objective was to develop a near-infrared fluorescent (NIRF) renin-imaging agent for noninvasive in vivo detection of renin activity as a measure of tissue RAS and in vitro plasma renin activity. We synthesized a reninactivatable agent, ReninSense 680 FAST (ReninSense), using a NIRF-quenched substrate derived from angiotensinogen that is cleaved specifically by purified mouse and rat renin enzymes to generate a fluorescent signal. This agent was assessed in vitro, in vivo, and ex vivo to detect and quantify increases in plasma and kidney renin activity in sodium-sensitive inbred C57BL/6 mice maintained on a low dietary sodium and diuretic regimen. Noninvasive in vivo fluorescence molecular tomographic imaging of the ReninSense signal in the kidney detected increased renin activity in the kidneys of hyperreninemic C57BL/6 mice. The agent also effectively detected renin activity in ex vivo kidneys, kidney tissue sections, and plasma samples. This approach could provide a new tool for assessing disorders linked to altered tissue and plasma renin activity and to monitor the efficacy of therapeutic treatments. optical tomography; low-salt diet; hypertension THE RENIN-ANGIOTENSIN SYSTEM (RAS) plays an important role in the regulation of blood volume, electrolyte homeostasis, and systemic vascular resistance, which together affect cardiac output and arterial pressure (11). Renin, a highly specific aspartyl protease, is primarily stored and released from juxtaglomerular (JG) cells within the afferent arterioles of the kidney glomeruli and plays an important regulatory role in RAS function. JG cells can sense a reduction in afferent arteriole pressure in the kidney leading to direct release of renin, and specialized adjacent cells (the macula densa) can also trigger JG renin release upon sensing of decreased plasma sodium chloride in renal tubules or changes in kidney sympathetic nerve signaling. Release of renin into the blood then mediates the first and rate-limiting step of the RAS cascade by cleaving angiotensinogen to generate angiotensin I (ANG I). ANG I is further cleaved by angiotensin-converting enzyme (ACE) to generate bioactive angiotensin II (ANG II), which binds to angiotensin recepto...

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In vivo imaging of protease activity in arthritis: A novel approach for monitoring treatment response

Cited by 156 publications

References 29 publications

Use of molecular imaging to quantify response to IKK‐2 inhibitor treatment in murine arthritis

Use of molecular imaging to quantify response to IKK‐2 inhibitor treatment in murine arthritis

High‐resolution multipinhole single‐photon–emission computed tomography in experimental and human arthritis

A fluorogenic near-infrared imaging agent for quantifying plasma and local tissue renin activity in vivo and ex vivo

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