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

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.

Biglycan and Fibromodulin Have Essential Roles in Regulating Chondrogenesis and Extracellular Matrix Turnover in Temporomandibular Joint Osteoarthritis

“…30 To determine whether overactive TGF-␤1 signaling affects MMP-mediated aggrecan degradation, we measured the amount of aggrecan neo-epitopes released in the culture medium of the explants cultures using an ELISA based on a monoclonal antibody targeting FFGVG sequences. 42 The release of this aggrecan fragment in the Bgn Ϫ/0 Fmod Ϫ/Ϫ explant culture medium was not significantly different from wild-type explant culture medium ( Figure 6B). Therefore, in the absence of Bgn and Fmod, overactive TGF-␤1 signaling accelerated type II collagen, but not aggrecan degradation by increasing MMP expression and activity.…”

Extracellular Matrix Remodeling: The Common Denominator in Connective Tissue DiseasesPossibilities for Evaluation and Current Understanding of the Matrix as More Than a Passive Architecture, but a Key Player in Tissue Failure

“…The degradation products of proteins may be the specific action of pathological-specific enzymes, and there is an accumulating amount of evidence suggesting that different fragments of the same protein may have different physiological and pathophysiological meanings. 278 Lastly, polymerization may both be understood as aggregates of the same protein such as hyperphosphorylated Tau or cross-linked collagens, but also pentameric CRP. Each of these subpools obviously holds unique information.…”

“…Joint degenerative diseases lead to alterations in the metabolism of the articular cartilage and subchondral bone. 278,[304][305][306][307][308][309] Cartilage is for the most part composed of collagen type II, which accounts for 60%-70% of the dry weight of cartilage, and proteoglycans accounting for 10% of the dry weight, of which aggrecan is the most abundant. 310 Since type II collagen is the most abundant protein in cartilage, several different degradation fragments of collagen type II have been indicated as useful for monitoring degenerative diseases of the cartilage.…”

GP130 cytokines and bone remodelling in health and disease

“…For example, local over-expression of OSM in the mouse knee joint induces changes to the joint that resemble OA, including cartilage destruction and periosteal bone formation similar to osteophytes (98,99). OSM also induces proteoglycan loss and cartilage damage ex-vivo (97,100). Interestingly, decreased sclerostin expression was observed in bone from OA patients compared to normal or RA patients (91).…”