Functional biomarkers of musculoskeletal syndrome (MSS) for early in vivo screening of selective MMP-13 inhibitors

Mazurek, Suzanne G. Nodop; Li, Jun; Nabozny, Gerald H.; Reinhart, Glenn A.; Muthukumarana, Akalushi; Harrison, Paul C.; Fryer, Ryan M.

doi:10.1016/j.vascn.2011.02.002

Cited by 17 publications

(15 citation statements)

References 13 publications

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“…Bendele (2001a), Bendele (2001b), Bolon et al (2011), Brand (2005), Ghoreschi et al (2011), Greaves (2012), LaBranche et al (2010), LaBranche et al (2012), Liu (2010), Long and Leininger (1999b), Mazurek et al (2011), Melhus (2005), Renkiewicz et al (2003), Rosenberg (2010)…”

Section: Jointmentioning

confidence: 99%

Nonproliferative and Proliferative Lesions of the Rat and Mouse Skeletal Tissues (Bones, Joints, and Teeth)

Fossey

Vahle

Long³

et al. 2016

J Toxicol Pathol

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The INHAND (International Harmonization of Nomenclature and Diagnostic Criteria for Lesions in Rats and Mice) Project (www.toxpath.org/inhand.asp) is an initiative of the Societies of Toxicological Pathology from Europe (ESTP), Great Britain (BSTP), Japan (JSTP) and North America (STP) to develop an internationally accepted nomenclature for proliferative and nonproliferative lesions in laboratory animals. The purpose of this publication is to provide a standardized nomenclature for classifying microscopic lesions observed in the skeletal tissues and teeth of laboratory rats and mice, with color photomicrographs illustrating examples of many common lesions. The standardized nomenclature presented in this document is also available on the internet (http://www.goreni.org/). Sources of material were databases from government, academic and industrial laboratories throughout the world.

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Section: Jointmentioning

confidence: 99%

Nonproliferative and Proliferative Lesions of the Rat and Mouse Skeletal Tissues (Bones, Joints, and Teeth)

Fossey

Vahle

Long³

et al. 2016

J Toxicol Pathol

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“…Examples of 'single-parameter tests' that can be incorporated into repeat-dose toxicity studies include evaluation of the risk of (a) visual dysfunction, assessed using an optomotor method in rodents (Redfern et al 2011a); (b) mydriasis and impaired pupillary light reflex, assessed by measuring pupil diameter in rodents and dogs (Redfern et al 2007); (c) increased or decreased salivation in dogs, measured using a preweighed gauze swab placed in the jowl ); (d) impaired muscle function, assessed by accelerating rotarod performance in rats (Nodop Mazurek et al 2011;; and (e) peripheral neuropathy, assessed by the same method in rats or using a beam walking task (Stanley et al 2005). Such assessments can significantly contribute to decision-making in projects, either in terms of compound progression, design of Phase I clinical trials or development of risk management and mitigation plans.…”

Section: Tests On Specific Neurobehavioural Systemsmentioning

confidence: 99%

Principles of Safety Pharmacology

2015

Handbook of Experimental Pharmacology

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“…In man, these side effects present as musculoskeletal syndrome (MSS), a disorder originating in the shoulder or hands, characterised by musculoskeletal pain and inflammation leading to reduced joint mobility [6]. In pre-clinical animal models, tissue pathologies tend to occur following 14 to 21 days administration of MMPi, appear to be dose-dependent, and are generally reversible on discontinuation of MMPi therapy [7].…”

Section: Introductionmentioning

confidence: 99%

“…Indeed, to date most studies have concentrated on the effects of MMPis at the end-of-treatment once FD is manifest, and following termination, using a variety of time-intensive histological techniques [6]. It is this inability to screen for early FD effects in vivo that led us to consider alternative classes of biomarkers.…”

Section: Introductionmentioning

confidence: 99%

The role of microRNAs in the pathogenesis of MMPi-induced skin fibrodysplasia

et al. 2013

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BackgroundMatrix metalloproteinases (MMPs) are a family of proteolytic enzymes involved in extracellular matrix (ECM) homeostasis. MMPs have been an attractive pharmacological target for a number of indications. However, development has been hampered by the propensity of compounds targeting these enzymes to cause connective-tissue pathologies. The broad-spectrum MMP-inhibitor (MMPi) AZM551248 has been shown to induce such effects in the dog. Histopathological changes were consistent with fibrodysplasia (FD), characterised by fibroblast proliferation and the deposition of collagen in the subcutaneous tissues. We conducted a time-course study administering 20mg/kg/day AZM551248 between 4 and 17 days. Cervical subcutaneous tissue and plasma were sampled during the time-course. miRNA expression profiles in subcutaneous skin specimens following the administration of AZM551248 were determined by high-throughput-sequencing.ResultsAn increasing number of miRNAs were differentially expressed compared with vehicle treated control animals as the study progressed. Several of these were members of the miR-200 family and were significantly attenuated in response to MMPi. As the severity of FD increased at the later time-points, other miRNAs associated with TGFβ synthesis and regulation of the acute inflammatory response were modulated. Evidence indicative of epithelial to mesenchymal transition was present at all study time points. Receiver operator curve (ROC) analysis revealed that miR-21 expression in the cervical subcutaneous tissue was a sensitive and specific biomarker of FD incidence.ConclusionsOur data reveal significant perturbations in canine skin miRNA expression in response to MMPi administration. Furthermore, we have identified dysregulated miRNAs that are associated with processes relevant to the key histopathological events of MMPi-induced FD.

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Functional biomarkers of musculoskeletal syndrome (MSS) for early in vivo screening of selective MMP-13 inhibitors

Cited by 17 publications

References 13 publications

Nonproliferative and Proliferative Lesions of the Rat and Mouse Skeletal Tissues (Bones, Joints, and Teeth)

Nonproliferative and Proliferative Lesions of the Rat and Mouse Skeletal Tissues (Bones, Joints, and Teeth)

Principles of Safety Pharmacology

The role of microRNAs in the pathogenesis of MMPi-induced skin fibrodysplasia

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