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Published on: May 16, 2016
Genetically Engineered Mouse Models Reveal the Importance of Proteases as Osteoarthritis Drug Targets
Rachel E Miller1, Yongzhi Lu, Micky D Tortorella
1Department of Medicine, Section of Rheumatology, Rush University Medical Center, 1611 W. Harrison St., Suite 510, Chicago, IL 60612, USA.
Abstract:
More than two decades of research has revealed a combination of proteases that determine cartilage degradation in osteoarthritis. These include metalloproteinases, which degrade the major macromolecules in cartilage, aggrecan and type II collagen, serine proteases, and cysteine proteases, for example cathepsin K. This review summarizes the function of proteases in osteoarthritis progression, as revealed by studies of genetically engineered mouse models. A brief overview of the biochemical characteristics and features of several important proteases is provided, with the objective of increasing understanding of their function. Published data reveal at least three enzymes to be major targets for osteoarthritis drug development: ADAMTS-5, MMP-13, and cathepsin K. In surgical models of osteoarthritis, mice lacking these enzymes are protected from cartilage damage and, to varying degrees, from bone changes. In-vivo studies targeting these proteases with selective small-molecule inhibitors have been performed for a variety of animal models. Mouse models will provide opportunities for future tests of the therapeutic effect of protease inhibitors, both on progression of structural damage to the joint and on associated pain.
Insights
Proteases drive osteoarthritis progression by degrading cartilage. Targeting specific proteases like ADAMTS-5, MMP-13, and cathepsin K in mouse models shows promise for developing new osteoarthritis drugs.
Area of Science:
- Biochemistry
- Molecular Biology
- Pharmacology
Background:
- Osteoarthritis (OA) involves cartilage degradation mediated by various proteases.
- Key proteases include metalloproteinases (MMPs), serine proteases, and cysteine proteases like cathepsin K.
- Understanding protease function is crucial for OA pathogenesis.
Purpose of the Study:
- To review the role of proteases in OA progression using genetically engineered mouse models.
- To provide biochemical insights into important proteases involved in OA.
- To identify key protease targets for OA drug development.
Main Methods:
- Analysis of genetically engineered mouse models lacking specific protease genes.
- Review of published in-vivo studies using small-molecule inhibitors against target proteases.
- Examination of biochemical characteristics of key proteases.
Main Results:
- Mice deficient in ADAMTS-5, MMP-13, or cathepsin K exhibit protection against cartilage damage in OA models.
- These enzymes are identified as major targets for OA therapeutic development.
- In-vivo studies demonstrate the efficacy of protease inhibitors in preclinical OA models.
Conclusions:
- Targeting specific proteases (ADAMTS-5, MMP-13, cathepsin K) is a viable strategy for OA drug development.
- Mouse models are essential for evaluating the therapeutic potential of protease inhibitors in OA.
- Future research should focus on translating these findings into clinical treatments for OA and associated pain.
