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

Abstract

INTRODUCTION:

Long-term administration of non-selective matrix metalloproteinase (MMP) inhibitors, such as marimastat, in humans elicits musculoskeletal syndrome (MSS), a syndrome characterized by joint damage including pain, stiffness, and inflammation. This pathology is a significant obstacle to the clinical development of MMP inhibitors and in pre-clinical models MSS can be verified only after terminal histopathology. Consequently, we devised a longitudinal and functional readout of MSS in conscious rats treated with marimastat that was validated against terminal histological assessment.

METHODS:

MSS was induced by minipump infusion of marimastat (5-10mg/kg/day). In marimastat-treated or vehicle-control groups, three possible functional biomarkers were assessed: paw volume (PV), landing foot splay separation (LFSS), and rotarod performance (n=6 rats/group for each endpoint).

RESULTS:

Histologically, fibrosis scores in the synovium and ligament increased from 0 on Day 1 (D1) to 4.6±0.2 and 4.7±0.1, respectively, on D15; growth plate thickness was also elevated from 215.0±6.3μm (D1) to 253.3±8.0μm (D15). While neither PV nor LFSS were correlative with MSS histopathology, marimastat (10mg/kg/day) reduced rotarod performance from 180±0s (D0) to 135±30s (D9) using a constant speed protocol (10rpm, 180s) and from 180±0s (D0) to 96±6s (D6) employing a variable speed protocol (increasing from 5 to 25rpm over 180s).

DISCUSSION:

Results of the present study demonstrate that rotarod performance can be used as a predictive longitudinal, in vivo functional biomarker of MSS concomitant with histological evidence of joint damage to effectively facilitate compound selection during drug discovery. Moreover, for targets with a mechanistic risk for MSS, the model is also conducive to inclusion in secondary pharmacodynamic studies during lead optimization to identify the best (safest) compounds for advancement into clinical trials.

• Authors: Suzanne G Nodop Mazurek, Jun Li, Gerald H Nabozny, Glenn A Reinhart, Akalushi C Muthukumarana, Paul C Harrison, Ryan M Fryer
• Journal: Journal of pharmacological and toxicological methods (J Pharmacol Toxicol Methods) 2011 Jul-Aug Vol. 64 Issue 1 Pg. 89-96 ISSN: 1873-488X [Electronic] United States
• PMID: 21376127 (Publication Type: Journal Article)
• Copyright: Copyright © 2011 Elsevier Inc. All rights reserved.

Chemical References

• Biomarkers, Pharmacological
• Enzyme Inhibitors
• Hydroxamic Acids
• Matrix Metalloproteinase Inhibitors
• marimastat

Topics

• Animals
• Biomarkers, Pharmacological (analysis)
• Drug Evaluation, Preclinical (methods)
• Enzyme Inhibitors (pharmacology, toxicity)
• Hydroxamic Acids (pharmacology, toxicity)
• Joints (drug effects, pathology)
• Longitudinal Studies
• Male
• Matrix Metalloproteinase Inhibitors
• Musculoskeletal Diseases (chemically induced, diagnosis, pathology)
• Musculoskeletal System (drug effects, pathology)
• Rats
• Rats, Sprague-Dawley