Cartilage degradation is fully reversible in the presence of aggrecanase but not matrix metalloproteinase activity

Morten A Karsdal,Claus Christiansen,Suzi H Madsen,Amanda J Fosang,Bodil C Sondergaard,Kim Henriksen

doi:10.1186/ar2434

Abstract

IntroductionPhysiological and pathophysiological cartilage turnover may coexist in articular cartilage. The distinct enzymatic processes leading to irreversible cartilage damage, compared with those needed for continuous self-repair and regeneration, remain to be identified. We investigated the capacity of repair of chondrocytes by analyzing their ability to initiate an anabolic response subsequent to three different levels of catabolic stimulation.MethodsCartilage degradation was induced by oncostatin M and tumour necrosis factor in articular cartilage explants for 7, 11, or 17 days. The catabolic period was followed by 2 weeks of anabolic stimulation (insulin growth factor-I). Cartilage formation was assessed by collagen type II formation (PIINP). Cartilage degradation was measured by matrix metalloproteinase (MMP) mediated type II collagen degradation (CTX-II), and MMP and aggrecanase mediated aggrecan degradation by detecting the 342FFGVG and 374ARGSV neoepitopes. Proteoglycan turnover, content, and localization were assessed by Alcian blue.ResultsCatabolic stimulation resulted in increased levels of cartilage degradation, with maximal levels of 374ARGSV (20-fold induction), CTX-II (150-fold induction), and 342FFGVG (30-fold induction) (P < 0.01). Highly distinct protease activities were found with aggrecanase-mediated aggrecan degradation at early stages, whereas MMP-mediated aggrecan and collagen degradation occurred during later stages. Anabolic treatment increased proteoglycan content at all time points (maximally, 250%; P < 0.001). By histology, we found a complete replenishment of glycosaminoglycan at early time points and pericellular localization at an intermediate time point. In contrast, only significantly increased collagen type II formation (200%; P < 0.01) was observed at early time points.ConclusionCartilage degradation was completely reversible in the presence of high levels of aggrecanase-mediated aggrecan degradation. After induction of MMP-mediated aggrecan and collagen type II degradation, the chondrocytes had impaired repair capacity.

Highlights

Physiological and pathophysiological cartilage turnover may coexist in articular cartilage
Distinct protease activities were found with aggrecanase-mediated aggrecan degradation at early stages, whereas matrix metalloproteinase (MMP)-mediated aggrecan and collagen degradation occurred during later stages
oncostatin M (OSM) and tumour necrosis factor (TNF) induce cartilage degradation, whereas insulin growth factor (IGF) induces cartilage formation A number of studies in different animal species have shown that OSM and TNF in combination induce cartilage degradation in vitro, in part through upregulation of both MMP and aggrecanase activities [6,7,8,9,10,11]

Summary

Introduction

Physiological and pathophysiological cartilage turnover may coexist in articular cartilage. Osteoarthritis (OA) most likely results from altered biomechanical stress that leads to alterations in chondrocyte metabolism [1]. Cartilage turnover normally is maintained by a balance between catabolic and anabolic processes in which compensatory mechanisms in response to altered biomechanical stresses such as altered gait, weight distribution, or traumatic injury [1] ensure homeostasis in normal healthy individuals. Novel drugs designed to promote articular cartilage health should attenuate only pathological turnover and stimulate or maintain physiological turnover. At present, these processes have not been dissociated, most likely due to the lack of experimental systems and molecular tools for assessing cartilage turnover

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