Related Experiment Video
Updated: Jul 7, 2026
Standardized Histomorphometric Evaluation of Osteoarthritis in a Surgical Mouse Model
Published on: May 6, 2020
Will the real aggrecanase(s) step up: evaluating the criteria that define aggrecanase activity in osteoarthritis
1Pfizer Global Research and Development, 700 Chesterfield Parkway, St. Louis MO 60013, USA. micky.d.tortorella@pfizer.com
Abstract:
Loss of aggrecan from articular cartilage is an early and critical event in the pathogenesis of osteoarthritis (OA) and is enzymatically mediated by aggrecanase activity. Since the discovery of aggrecanase-1 (ADAMTS-4) and aggrecanase-2 (ADAMTS-5), both members of the "a disintegrin and metalloproteinase with thrombospondin motif" family of proteinases, other members of the family have been reported to have aggrecanase activity, as currently defined, including ADAMTS-1, -8, -9, -15 and -16. Understanding whether these other ADAMTS members are in fact genuine in vivo aggrecanases will be important for the development of therapeutic agents that aim to block aggrecan degradation. The goal of this review is to look at the current definition of "aggrecanase activity", and define its strengths, weaknesses and suitability for determining which ADAMTS, are aggrecanases that participate in aggrecan catabolism in OA. In addition, we propose a more comprehensive definition of aggrecanase activity, based on 6 criteria that encompass both biochemical and biological characteristics of the endogenous aggrecanase activity detected in vitro and in vivo. Finally, using these criteria, we propose which ADAMTSs should be classified as aggrecanases and therefore be considered as drug targets for the development of chondroprotective OA treatments.
Insights
Aggrecan loss in osteoarthritis is driven by aggrecanase activity. This review redefines aggrecanase activity to identify genuine aggrecanases, crucial for developing osteoarthritis treatments.
Area of Science:
- Biochemistry
- Molecular Biology
- Rheumatology
Background:
- Aggrecan degradation in articular cartilage is a key event in osteoarthritis (OA) pathogenesis.
- This degradation is mediated by aggrecanase activity, primarily attributed to ADAMTS-4 and ADAMTS-5.
- Other ADAMTS family members (ADAMTS-1, -8, -9, -15, -16) also exhibit aggrecanase activity, necessitating clarification.
Purpose of the Study:
- To critically evaluate the current definition of "aggrecanase activity" for identifying OA-relevant ADAMTS enzymes.
- To propose a refined, comprehensive definition of aggrecanase activity based on biochemical and biological criteria.
- To identify specific ADAMTS members that qualify as genuine aggrecanases and potential therapeutic targets for OA.
Main Methods:
- Review and analysis of existing literature on aggrecanase activity and ADAMTS proteinases.
- Development of a 6-criterion framework for defining "aggrecanase activity" encompassing in vitro and in vivo characteristics.
- Application of the proposed criteria to classify ADAMTS members based on their role in aggrecan catabolism.
Main Results:
- The current definition of aggrecanase activity has limitations in accurately identifying in vivo aggrecanases.
- A proposed 6-criterion definition provides a more robust framework for classifying aggrecanases.
- Specific ADAMTS members are identified as likely genuine aggrecanases based on the proposed criteria.
Conclusions:
- Accurate identification of aggrecanases involved in OA is essential for targeted drug development.
- The proposed comprehensive definition of aggrecanase activity aids in classifying relevant ADAMTS enzymes.
- This classification will guide the development of chondroprotective therapies for osteoarthritis.
