+1 Recommend
0 collections
      • Record: found
      • Abstract: found
      • Article: found
      Is Open Access

      Effects of diacerein at the molecular level in the osteoarthritis disease process

      Read this article at

          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.


          In osteoarthritis (OA), the alterations in joint tissues are numerous and involve morphological, biochemical and metabolic changes and an upregulation of the inflammatory pathways. The focus of this article is a brief narrative review of the effects of diacerein, an antirheumatic drug from the anthraquinone chemical class, and its active metabolite, rhein, on the factors that participate in the complex interaction between OA tissues and cells leading to the progression of joint structural changes.

          Related collections

          Most cited references 60

          • Record: found
          • Abstract: found
          • Article: not found

          Deletion of active ADAMTS5 prevents cartilage degradation in a murine model of osteoarthritis.

          Human osteoarthritis is a progressive disease of the joints characterized by degradation of articular cartilage. Although disease initiation may be multifactorial, the cartilage destruction appears to be a result of uncontrolled proteolytic extracellular matrix destruction. A major component of the cartilage extracellular matrix is aggrecan, a proteoglycan that imparts compressive resistance to the tissue. Aggrecan is cleaved at a specific 'aggrecanase' site in human osteoarthritic cartilage; this cleavage can be performed by several members of ADAMTS family of metalloproteases. The relative contribution of individual ADAMTS proteases to cartilage destruction during osteoarthritis has not been resolved. Here we describe experiments with a genetically modified mouse in which the catalytic domain of ADAMTS5 (aggrecanase-2) was deleted. After surgically induced joint instability, there was significant reduction in the severity of cartilage destruction in the ADAMTS5 knockout mice compared with wild-type mice. This is the first report of a single gene deletion capable of abrogating the course of cartilage destruction in an animal model of osteoarthritis. These results demonstrate that ADAMTS5 is the primary 'aggrecanase' responsible for aggrecan degradation in a murine model of osteoarthritis, and suggest rational strategies for therapeutic intervention in osteoarthritis.
            • Record: found
            • Abstract: found
            • Article: not found

            ADAMTS5 is the major aggrecanase in mouse cartilage in vivo and in vitro.

             A Fourie,  T Meeker,  C. East (2005)
            Aggrecan is the major proteoglycan in cartilage, endowing this tissue with the unique capacity to bear load and resist compression. In arthritic cartilage, aggrecan is degraded by one or more 'aggrecanases' from the ADAMTS (a disintegrin and metalloproteinase with thrombospondin motifs) family of proteinases. ADAMTS1, 8 and 9 have weak aggrecan-degrading activity. However, they are not thought to be the primary aggrecanases because ADAMTS1 null mice are not protected from experimental arthritis, and cleavage by ADAMTS8 and 9 is highly inefficient. Although ADAMTS4 and 5 are expressed in joint tissues, and are known to be efficient aggrecanases in vitro, the exact contribution of these two enzymes to cartilage pathology is unknown. Here we show that ADAMTS5 is the major aggrecanase in mouse cartilage, both in vitro and in a mouse model of inflammatory arthritis. Our data suggest that ADAMTS5 may be a suitable target for the development of new drugs designed to inhibit cartilage destruction in arthritis, although further work will be required to determine whether ADAMTS5 is also the major aggrecanase in human arthritis.
              • Record: found
              • Abstract: found
              • Article: not found

              Osteoarthritis chondrocytes die by apoptosis. A possible pathway for osteoarthritis pathology.

              To determine which kind of cell death occurs in cartilage from patients with osteoarthritis (OA). Seven normal and 16 OA cartilage samples were collected at autopsy or during joint replacement surgery, respectively. A piece of cartilage was cryopreserved until histologic studies were done. The rest of the cartilage was used to isolate chondrocytes. Apoptotic chondrocytes were analyzed by light and fluorescence microscopy using nuclear 4',6-diamidino-2-phenylindole dihydrochloride stain. Apoptotic chondrocytes were quantified by fluorescence-activated cell sorter (FACS) analysis. The TUNEL technique was used to study histologic apoptosis in situ. Superficial cartilage was processed for ultrastructural study by electron microscopy. OA chondrocytes displayed nuclear and cytoplasmic changes consistent with apoptotic cell death. FACS analysis showed that the OA cartilage had a higher proportion of apoptotic chondrocytes than did normal tissue (51% versus 11%; P < 0.01). In situ study of DNA fragmentation in the cartilage showed that apoptotic cells were located in the superficial and middle zones. Ultrastructural analysis of the superficial OA cartilage revealed some empty lacunae, lysosomal-like structures, matrix vesicle-like structures, fragmented chondrocytes, and nuclear condensation. Chondrocytes in OA cartilage demonstrated morphologic changes that are characteristic features of apoptosis. This mechanism of cell death plays an important role in the pathogenesis of OA and could be targeted for new treatment strategies.

                Author and article information

                Ther Adv Musculoskelet Dis
                Ther Adv Musculoskelet Dis
                Therapeutic Advances in Musculoskeletal Disease
                SAGE Publications (Sage UK: London, England )
                April 2010
                : 2
                : 2
                : 95-104
                Osteoarthritis Research Unit, University of Montreal Hospital Research Centre (CRCHUM), Notre-Dame Hospital, 1560 Sherbrooke Street East, Montreal, Quebec H2L 4M1, Canada, jm@
                Arthritis Centre, University of Montreal, Head, Arthritis Division (CHUM) Director, Osteoarthritis Research Unit, University of Montreal Hospital Research Centre (CRCHUM), Notre-Dame Hospital, Montreal, Canada
                © The Author(s), 2010.

                This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 3.0 License ( which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access page (

                Custom metadata
                95 Review Effects of diacerein at the molecular level in the osteoarthritis disease process SAGE Publications, Inc. 201010.1177/1759720X09359104 © The Author(s), 2010. 2010 The Author(s) JohanneMartel-Pelletier Osteoarthritis Research Unit, University of Montreal Hospital Research Centre (CRCHUM), Notre-Dame Hospital, 1560 Sherbrooke Street East, Montreal, Quebec H2L 4M1, Canada, Jean-PierrePelletier Arthritis Centre, University of Montreal, Head, Arthritis Division (CHUM) Director, Osteoarthritis Research Unit, University of Montreal Hospital Research Centre (CRCHUM), Notre-Dame Hospital, Montreal, Canada In osteoarthritis (OA), the alterations in joint tissues are numerous and involve morphological, biochemical and metabolic changes and an upregulation of the inflammatory pathways. The focus of this article is a brief narrative review of the effects of diacerein, an antirheumatic drug from the anthraquinone chemical class, and its active metabolite, rhein, on the factors that participate in the complex interaction between OA tissues and cells leading to the progression of joint structural changes. cartilage diacerein osteoarthritis rhein subchondral bone synovial membrane Introduction Osteoarthritis (OA) is a condition that represents a pathological imbalance in the degradative and reparative processes of the articular tissues. Although we still do not completely understand what initiates the degeneration of the articular tissues, significant progress has been made with respect to the pathogenesis of the disease. There is now evidence of a global cross-talk between the joint tissues, with the diffusion of catabolic fac- tors from the synovial membrane and subchon- dral bone to the cartilage. Although OA is characterized by a degeneration of articular cartilage, at the clinical stage of the disease this is accompanied by changes in the synovial membrane where an inflammatory reac- tion is often observed [Martel-Pelletier et al. 2005]. In addition, a complex relationship between the subchondral bone and the cartilage is currently regarded as a major pathophysiologi- cal factor in the progression of OA. Indeed, some continuity between subchondral bone and carti- lage in OA has been demonstrated, which sug- gests a cross-talk between these tissues [Martel-Pelletier et al. 2007]. One hypothesis regarding the pathological devel- opment of OA at the clinical stage of the disease can be summarized as follows [Martel-Pelletier et al. 2005]. The cartilage matrix is first broken down by proteolytic enzymes. Matrix fragments are released into the fluid, which can promote inflammation in the synovial membrane. The inflammation of the membrane, through the synthesis of mediators, creates a vicious circle, in which the cartilage matrix is further degraded, subsequently provoking more inflam- mation. Several soluble mediators have been identified in articular tissues from arthritic dis- eases and studies have shown that inflammation in knee OA is primarily due to the presence of the cytokine interleukin-1β (IL-1β). Thus, IL-1β(3 plays a fundamental role in the pathophysiology of OA, in which its catabolic effects are multiple: this cytokine is able to stimulate its own produc- tion, to increase the synthesis of catabolic factors as well as chondrocyte apoptosis, and to decrease some of the cartilage macromolecule synthesis. Therefore, targeting this cytokine and related fac- tors is of great importance in therapeutic approaches to OA. Diacerein/rhein The current therapies for OA, including the non- steroidal anti-inflammatory drugs (NSAIDs), although effective against the disease symptoms, are palliative and do not stop the disease progres- sion. There are, however, promising agents and compounds that have been shown to reduce the severity of the disease as well as the symptoms. Among them is diacerein, a drug belonging to the anthraquinone chemical class that is employed in the treatment of OA. This article is a brief review of how its mecha- nism of action differs from that of a classic NSAID. Contrary to a classic NSAID that targets 96 Table 1. Summary of the effects of diacerein/rhein on articular joint tissues/cells. ADAMTS, disintegrin and metalloproteinase domain with thrombospondin motifs; COX-2, cyclooxygenase-2; ICE, IL-1 converting enzyme; IL-1β, interleukin-1β; IL-1 RI, IL-1 receptor type I; iNOS, inducible nitric oxide synthase; MMP, metal- ~ loprotease; NO, nitric oxide; P~E , prostaglandin E ; uPA, urokinase-type plasminogen activator. ~22~ cyclo-oxygenase (COX)-2, an enzyme responsi- ble for prostaglandin production, diacerein is known to act on the IL-1β system. Pharmacokinetics of diacerein/rhein Diacerein in the body is entirely converted into rhein before reaching the systemic circulation. Rhein is either eliminated by the renal route or conjugated in the liver to rhein glucuronide and rhein sulfate. In turn, these metabolites are mainly eliminated by the kidneys [Nicolas et al. 1998]. Data also showed that the pharmacoki- netics of diacerein are about the same in young healthy volunteers and elderly people, both after a single dose of 50 mg or twice daily for a total dose of 100 mg or 150 mg [Nicolas et al. 1998; Fedeli, 1988; Petitjean et al. 1991]. Pharmacoki- netic studies of diacerein performed on healthy volunteers revealed that the plasma peak concen- tration of rhein after an oral administration was 10—5 M [Nicolas et al. 1998; Spencer and Wilde, 1997]. Moreover, a further study [Segré, 1988, reported in Sanchez et al. 2003], showed that fol- lowing daily administration of oral diacerein at 50 mg every 12 hours for 1 month, rhein reaches the synovial fluid at concentrations of 10—6—10—5 M. In in vitro studies, the concentrations most used varied between 10—7 M and 10—4 M. The majority of the studies employed concentrations around 10—5 M, which is in the higher range reached in the synovial fluid. However, as treatment with dia- cerein is characterized by a slow onset of action, with a maximal clinical effect being reached after a few months (about 3 months), the concentrations utilized for in vitro studies thus mimic the effect observed in vivo attained after months of treatment. Effects on cartilage and synovial membrane cells IL-1β (Figure 1). Evaluation of the effects of dia- cerein and its active metabolite, rhein, on the production of IL-1β in human OA synovial mem- brane and cartilage showed that both drugs sig- nificantly decreased the synthesis of this cytokine (Table 1) [Martel-Pelletier et al. 1998]. IL-1β is synthesized in the cell as a biologically inactive precursor, which requires a proteolytic cleavage to permit the activation of the cytokine and the exiting of the cell. This is achieved through a highly selective protease, the IL-1-converting enzyme (ICE), also named caspase-1. Hence, the action of ICE on IL-1β(3 appears to be a key limiting factor for the secre- tion and activity of this cytokine. ICE has been shown to be expressed and synthesized by both human synovial membrane and cartilage and its levels are elevated during the OA process [Saha et al. 1999]. Diacerein and rhein markedly and significantly decreased ICE production in carti- lage [Moldovan et al. 2000]. The biological activation of cells by cytokines is mediated through an association with specific cell surface receptors. For IL-1β, this occurs through binding to two types of specific membrane recep- tors, types I and II; type I was shown to be responsible for mediating the signal. The levels 97 Figure 1. Effect of diacerein/rhein on the IL-1 system. Diacerein/rhein reduces the level of IL-1 receptors leading to fewer receptors to form heterodimer complexes. Following the association of IL-1 with its specific cell surface receptor complex, there is an activation of downstream signalling pathways involving some MAP kinases. In OA articular tissues, rhein has been shown to reduce numerous genes including cytokines, nitric oxide (NO), metalloproteases (MMPs), a disintegrin and metalloproteinase domain with thrombospondin motifs (ADAMTS), etc., through the inhibition of the MEK/ERK intracellular cascade. IL-1β is produced as a precursor which is cleaved at the cell membrane by the IL-1 converting enzyme (ICE) which releases IL-1β as an active cytokine into the extracellular matrix. Rhein reduces the production of ICE leading to a reduction in IL-1βp activation. The grey color indicates that lesser amounts of the factors are produced. The figure is from and reproduced with permission of TRB Chemedica International. MEK = mitogen-activated protein kinase (MAP kinase ), ERK = extracellular-signal-regulated kinase. of this receptor type were also found to be mark- edly increased in OA chondrocytes and synovial fibroblasts, thus potentializing the effect of IL-1β(3 activity [Sadouk et al. 1995; Martel-Pelletier et al. 1992; McCollum et al. 1991]. Investigation of the effects of diacerein and rhein on the binding and receptor levels in human OA chondrocytes showed that, at therapeutic concentrations, the drugs significantly inhibited the IL-1 binding level. Analysis of the competitive binding experi- ments revealed that both treated and untreated OA chondrocytes had similar IL-1 binding affi- nities, but that the receptor density, or number of receptors, was significantly reduced by both drugs [Martel-Pelletier et al. 1998]. Degradative enzymes. Further investigations were then directed to major catabolic pathways induced by IL-1β involved in the OA pathological process. In cartilage, the enzymatic matrix break- down is a key feature in the progression of the disease. The loosening of the collagen network as well as the alterations in the aggrecan (proteo- glycan) result from an increase in the amount of enzymes belonging to the MMP (metallopro- teases) and ADAMTS (disintegrin and metallo- proteinase domain with thrombospondin motifs) families. In regard to collagen degradation, three collagenases, MMP-1, MMP-8, and MMP-13, have been identified in humans, with high produc- tion levels found in OA. MMP-1 and MMP-13 are the major enzymes that account for collagen type II degradation in pathological cartilage. Moreover, it has been shown that in OA MMP-13 is produced during the remodelling phase, not only in the cartilage but also in the subchondral bone. Stromelysin-1 or MMP-3 is also considered an important enzyme in cartilage matrix turnover as, in addition to cleaving the pro- teoglycans, it is implicated in the enzymatic cas- cade responsible for the activation of proMMP-1. With regard to the proteoglycans, also found in OA articular tissues are aggrecan fragments with a proteolytic cleavage at the Glu373-Ala374 bond of the interglobular domain, between the G1 and G2 domains. The enzymes responsible for such cleavage belong to a subgroup of the ADAM family, the ADAMTS, and are named aggreca- nases. Two such enzymes have been reported to be present in cartilage, ADAMTS-4 and ADAMTS-5. Recent studies in mice demon- strated that of the two aggrecanases, ADAMTS-5 is the predominant one involved in the OA degradative process [Stanton et al. 2005; Glasson et al. 2005]; however, in humans this still needs to be confirmed. 98 Data showed that diacerein and rhein significantly inhibited the IL-1β-stimulated MMP-3 and col- lagenase activity [Alvarez-Soria et al. 2008; Legendre et al. 2007; Sanchez et al. 2003; Tamura and Ohmori, 2001; Martel-Pelletier et al. 1998]. On the ADAMTS, both drugs decreased the IL-1β-stimulated ADAMTS-4 and ADAMTS-5 and a marked inhibition was found with rhein [Legendre et al. 2007]. Nitric oxide. Nitric oxide (NO) is produced through the activity of inducible nitric oxide synthase (iNOS) and is a major catabolic factor involved in the pathophysiology of OA. IL-1β is a very potent stimulator of NO. In OA, NO is involved in the promotion of cartilage catabolism and reduction in anabolism via a number of mechanisms. In brief, this factor reduces carti- lage macromolecular synthesis and increases MMP activity, COX-2/prostaglandin E2 (PGE2) production, and apoptosis. Both diacerein and rhein treatments markedly and significantly decreased IL-1β-induced NO production [Sanchez et al. 2003; Pelletier et al. 1998]. Interestingly, in one experiment [Pelletier et al. 1998], in which an NSAID was used as compara- tor, data revealed that only a slight inhibition was obtained for the NSAID, and that occurred at a high concentration. This finding, among others, illustrates that these two classes of drugs have different mechanisms of action. Additional experiments also showed that diacerein and rhein reduced both the expression and produc- tion levels of iNOS [Pelletier et al. 1998]. Prostaglandin E2 and cyclooxygenase-2. The effect of diacerein was also investigated on PGE2 and on COX, as the latter is involved in one of the key steps in the synthesis of this prostanoid. As is well known, the spontaneous synthesis of PGE2 or COX-2 in chondrocytes is low and their produc- tion is markedly increased following IL-1β treat- ment. In contrast to the effects of NSAIDs that reduce PGE2 and COX-2, rhein and diacerein upregulate PGE2 and COX-2 production [Sanchez et al. 2003; Pelletier et al. 1998]. These data correlate with other studies done with diacer- ein on other cell types [Alvarez-Soria et al. 2008; Pomarelli et al. 1980]. Although such elevation could appear detrimental in the context of OA, it is of interest that a metabolite of COX-2, 15-deoxy PGJ2 (15d-PGJ2), displays anti-inflammatory properties. 15d-PGJ2 is a ligand of a nuclear receptor that exerts its effects possibly through binding to the peroxisome proliferator-activated receptor γ (PPARγ). The PPARs are a family of ligand-activated tran- scription factors, which, following ligand binding, heterodimerize with the retinoic X receptor (RXR) [Fahmi et al. 2002a]. This complex binds to PPAR-responsive elements (PPREs) in the pro- moter regions of target genes, thus inducing anti-inflammatory effects. Therefore, increasing COX-2 levels could lead to the formation of this metabolite, which would activate the PPARγ and abrogate the IL-1β-induced production of cata- bolic factors. Treatment of human chondrocytes with 15d-PGJ2 resulted in the inhibition of IL-1β-induced NO and MMP-13 as well as pro- teoglycan degradation [Fahmi et al. 2001, 2002a, 2002b; Bordji et al. 2000]. Moreover, this PPARγ ligand also completely inhibited the effects of two other pro-inflammatory cytokines, tumor necrosis factor (TNF)-α and IL-17, on these cells. Similarly, PPARγ activators suppressed IL-1β-induced MMP-1 expression and produc- tion in human OA synovial fibroblasts [Fahmi et al. 2002c] and IL-1β and TNF-α expression in rheumatoid synovial fibroblasts [Ji et al. 2001]. In rat synovial fibroblasts, which also express PPARγ, 15d-PGJ2 dose-dependently pre- vented lipopolysaccharide (LPS)-induced iNOS, COX-2, IL-1 and TNF-α expression [Simonin et al. 2002]. The protective effect of PPARγ acti- vators has also been demonstrated in several animal models of arthritis including a guinea pig model of OA [Kobayashi et al. 2005]. Data showed that diacerein and rhein increased the activation of PPARγ (authors’ personal data). Thus, the effect of increasing COX-2 might not be as damaging as it might seem, as the increased level could lead to the formation of a metabolite that would, in turn, activate a nuclear receptor with anticatabolic effects. Apoptosis. The role of chondrocyte death by apoptosis in cartilage degradation is likely an important local factor contributing to the loss of matrix, and it has been reported that apoptosis is implicated in the loss of chondrocytes in OA [Blanco et al. 1998]. The involvement of the cas- pase cascade in cell death by apoptosis is well documented, and the caspases-3, -8, and -9 are the primary enzymes involved in cell apoptosis. These enzymes induce cell death by a number of mechanisms, including DNA fragmentation and inactivation of the proteins that protect cells against apoptosis. Data showed that rhein at a physiological concentration did not affect caspases-3/7, but at a concentration of about 99 10 times the physiological concentration, it induced a marked decrease in the activity of these enzymes in both synovial fibroblasts and chondrocytes [Legendre et al. 2009]. However, these authors also showed that DNA fragmenta- tion was not induced by rhein at any of the con- centrations used. Cartilage matrix macromolecules. Data showed that diacerein and rhein decreased the inhibitory effect of IL-1 on the synthesis of collagen and proteoglycans [Domagala et al. 2006; Sanchez et al. 2003; Pujol et al. 2000; Yaron et al. 1999]. It was further suggested that this may occur through the stimulation of transforming growth factor (TGF)-β1 expression [Felisaz et al. 1999], as diacerein counteracts the IL-1β downregula- tion of matrix synthesis [Redini et al. 1988]. Effects on subchondral bone Investigations were also performed on the effects of diacerein on subchondral bone. It is currently suggested that alterations in the subchondral bone may be more intimately related to the OA process and are not merely a consequence of the disease. Indeed, although cartilage degradation charac- terizes OA, there is evidence that the remodelling of subchondral bone is a contributing factor. Interestingly, although it was originally thought that the calcified cartilage layer was an impenetra- ble structure, in OA the presence of channels and microcracks between the subchondral region and the uncalcified cartilage has been demonstrated as well as vascularization in the subchondral bone [Sokoloff, 1993], which could favour the diffusion of factors from the subchondral bone region to the basal layer of cartilage and be responsible for the cartilage remodelling in the deep zone. In addi- tion, recent work indicates that biological and morphological disturbances occur in this tissue very early on in the OA process, which may con- tribute to the initial events of the pathological pro- cess. However, human OA subchondral bone osteoblasts demonstrate an altered metabolic activity or phenotype compared to normal, in which elevated levels of the bone markers alkaline phosphatase and osteocalcin, and enzymes includ- ing the urokinase/plasmin system and MMP-13, for example, are found [Massicotte et al. 2002; Hilal et al. 1998, 1999]. Moreover, data also demonstrated that human OA subchondral bone, although showing sclerosis at a later stage, undergoes phases of bone resorption [Kwan Tat et al. 2008], and emerging data indicate a general- ized undermineralization of OA subchondral bone [Couchourel et al. 2009]. Thus, therapeutic strategies aimed at modifying the metabolism of subchondral bone may be indicated in the treat- ment of OA. Evaluation of the effects of diacerein and rhein on OA subchondral bone (Table 1) osteoblasts revealed that on the cell biomarkers, these drugs dose-dependently inhibited vitamin D3- induced osteocalcin release [Pelletier et al. 2001]. This is interesting, as abnormally elevated osteocalcin levels have been observed in the sub- chondral bone of OA patients, and osteocalcin is believed to be involved in the local modulation of bone formation. Specifically, osteocalcin retards bone formation/mineralization. As OA subchon- dral bone is undermineralized, reducing osteocal- cin would favour a more mineralized tissue. Of the metabolic factors, the production of urokinase-type plasminogen activator (uPA) by osteoblasts is inhibited by these drugs [Pelletier et al. 2001]. This reduction in uPA activity could retard bone formation by preventing the release of trapped growth factors, thus preventing fur- ther sclerosis. Moreover, the production of MMP-13 in this tissue is also inhibited by diacer- ein and rhein [Boileau et al. 2008]. This is impor- tant as MMP-13 acts directly to resorb bone; therefore, reducing the MMP-13 level would contribute to curbing bone resorption. In bone biology, osteoblasts and osteoclasts con- tribute either alone or in combination to the remodelling process. The disturbance between the activities of these two cells is suggested to be responsible for the development of an altered bone metabolism. Investigation of diacerein and rhein on some parameters of the osteoclasts revealed that both drugs reduced not only MMP-13 but also cathepsin K [Boileau et al. 2008]. These data are important because, in osteoclasts, MMP-13 is known to work in con- junction with cathepsin K in the induction of bone resorption; therefore, the reduction in activ- ity of these two enzymes would impact the bal- ance between bone resorption and formation. Exploration of the effect of these drugs on osteo- clast survival and differentiation showed that they effectively block not only the survival of mature osteoclasts but also the differentiation and prolif- eration of pre-osteoclasts into mature osteoclasts, the final effect being a reduction in the number of osteoclasts. Although further studies are needed to fully elucidate the precise mechanism of action of diacerein and rhein on osteoclasts, it may be 100 related to their effect on PGE2, the levels of which, as mentioned above, are increased by these drugs in many cell types including human subchondral bone osteoblasts [Pelletier et al. 2001]. Hence, it has been reported that high PGE2 levels inhibited bone resorption and that human OA subchondral bone osteoblasts expres- sing low levels of PGE2 enhanced the formation of osteoclasts, whereas those expressing higher levels did not [Kwan Tat et al. 2008]. Effects on signalling pathways The intracellular mechanisms by which these drugs exert their effect appear to occur through the down-regulation of the activation of some MAP kinases. Although other signalling path- ways have been found for the different cells including the activation of c-Jun N-terminal kinase (JNK) on chondrocytes [Legendre et al. 2007; Martin et al. 2003] and p38 on osteoblasts [Boileau et al. 2008], it appears that on all artic- ular cells, rhein reduces the catabolic pathways of OA through inhibition of MEK/ERK signalling [Boileau et al. 2008; Legendre et al. 2007; Domagala et al. 2006; Martin et al. 2003]. In vivo effects on the OA process in animal models and human clinical studies The effect of diacerein was also studied in vivo in OA animal models, and data from studies on dif- ferent animal models concur with those obtained in vitro with human articular cells. Indeed, in OA animal models, the drug has been shown to decrease the disease severity as well as the col- lagenase levels in the cartilage of dogs and rabbits [Brandt, 2006; Smith et al. 1999; Brandt et al. 1997; Mazieres et al. 1993, 1996], IL-1β and the loss of hydroxyproline and proteoglycans in mouse cartilage [Colville-Nash, 2002; Moore et al. 1997, 1998], iNOS and apoptosis in dog cartilage [Pelletier et al. 2003], and subchondral bone remodelling in sheep and rats [Tamura et al. 2002; Hwa et al. 2001; Ghosh et al. 1998]. Moreover, the conclusion of a meta-analysis [Rintelen et al. 2006] and data from a Cochrane review [Fidelix et al. 2006] indicate that oral dia- cerein demonstrated a good safety profile, was associated with significant improvement in symp- toms of patients with hip and knee OA, had similar efficacy to NSAIDs but with a carry-over effect once treatment was stopped, and reduced NSAID consumption. In addition, an in vivo study in humans with hip OA showed that this drug demonstrates a structure-modifying effect [Dougados et al. 2001]. Conclusion The data from basic research both in vitro and in vivo in animals provide evidence that diacerein treatment could impact the abnormal metabo- lism of OA articular tissues and cells by reducing the major catabolic processes, with a coherent body of evidence of its effect in clinical studies. Importantly, although an in vivo struc- ture-modifying effect has been shown in humans with hip OA [Dougados et al. 2001], studies on the tissue structure need to be done in knee OA. Even though such studies in knee OA have been impaired due to the imaging tools (X-ray) being unsatisfactory and having significant limitations, in recent years important advances have been made in the quantitative assessment of global structural changes in knee OA with the use of magnetic resonance imaging (MRI) to assess car- tilage volume and thickness as well as synovial membrane and subchondral bone lesions [Raynauld et al. 2003, 2004, 2006, 2008a, 2008b; Pelletier et al. 2007, 2008; Berthiaume et al. 2005]. Such technology allows the analysis of OA disease progression over time and reduces the number of patients needed in clinical trials, improves retention of these patients, and reduces the overall costs and the length of clinical trials. In conclusion, the current pharmacological man- agement of OA is based primarily on the use of analgesics, NSAIDs, and antiCOX-2s. Although studies have confirmed the efficacy of NSAIDs and antiCOX-2s as symptomatic treatments for OA, these drugs have not proven to positively affect the natural course of OA in humans. The development of pharmacological agents capable of modifying the OA disease process is now cru- cial. In this context, basic research has shown that diacerein is an attractive candidate. Acknowledgements The authors thank Virginia Wallis for her assis- tance with the manuscript preparation. Conflict of interest statement JMP and JPP have received grants from Laboratoires Negma-Lerads, Toussus-le-Noble, France and from TRB Chemedica International S.A., Geneva, Switzerland, as well as being 101 speakers for these two companies at international and local congresses and meetings. References Alvarez-Soria, M.A., Herrero-Beaumont, G., Sanchez-Pernaute, O., Bellido, M. and Largo, R. ( 2008) Diacerein has a weak effect on the catabolic pathway of human osteoarthritis synovial fibroblast-comparison to its effects on osteoarthritic chondrocytes. Rheumatology (Oxford) 47: 627-633. Berthiaume, M.J., Raynauld, J.P., Martel-Pelletier, J., Labonté, F., Beaudoin, G., Bloch, D.A. et al. (2005) Meniscal tear and extrusion are strongly associated with the progression of knee osteoarthritis as assessed by quantitative magnetic resonance imaging. Ann Rheum Dis 64: 556-563. Blanco, F.J., Guitian, R., Vazquez-Martul, E., de Toro, F.J. and Galdo, F. (1998) Osteoarthritis chondrocytes die by apoptosis. A possible pathway for osteoarthritis pathology. Arthritis Rheum 41: 284-289. Boileau, C., Tat, S.K., Pelletier, J.P., Cheng, S. and Martel-Pelletier, J. ( 2008) Diacerein inhibits the synthesis of resorptive enzymes and reduces osteoclastic differentiation/survival in osteoarthritic subchondral bone: a possible mechanism for a protective effect against subchondral bone remodelling. Arthritis Res Ther 10: R71. Bordji, K., Grillasca, J.P., Gouze, J.N., Magdalou, J., Schohn, H., Keller, J.M. et al. (2000) Evidence for the presence of peroxisome proliferator-activated receptor (PPAR) alpha and gamma and retinoid Z receptor in cartilage. PPARgamma activation modulates the effects of interleukin-1beta on rat chondrocytes . J Biol Chem 275: 12243-12250. Brandt, K.D. ( 2006) Studies in animal models of osteoarthritis as predictors of a structure-modifying effect of diacerhein in humans with osteoarthritis . Biorheology 43: 589-594. Brandt, K.D., Smith, G., Kang, S.Y., Myers, S., O’Connor, B. and Albrecht, M. ( 1997) Effects of diacerhein in an accelerated canine model of osteoarthritis. Osteoarthritis Cartilage 5: 438-449. Colville-Nash, P.R. ( 2002) Comparison of the pharmacologic effect of diacerein and a selective COX-2 inhibitor in the mouse induced-granuloma model. Presse Med 31: 4S16-4S17 (abstract). Couchourel, D., Aubry, I., Delalandre, A., Lavigne, M., Martel-Pelletier, J., Pelletier, J.-P. et al. (2009) Altered mineralization of human osteoarthritic osteoblasts is due to abnormal collagen type 1 production. Arthritis Rheum 60: 1438-1450. Domagala, F., Martin, G., Bogdanowicz, P., Ficheux, H. and Pujol, J.P. ( 2006) Inhibition of interleukin-1beta-induced activation of MEK/ERK pathway and DNA binding of NF-kappaB and AP-1: potential mechanism for Diacerein effects in osteoarthritis. Biorheology 43: 577-587. Dougados, M., Nguyen, M., Berdah, L., Mazieres, B., Vignon, E. and Lequesne, M. ( 2001) Evaluation of the structure-modifying effects of diacerein in hip osteoarthritis: ECHODIAH, a three-year, placebo-controlled trial. Evaluation of the Chondromodulating Effect of Diacerein in OA of the Hip. Arthritis Rheum 44: 2539-2547. Fahmi, H., Di Battista, J.A., Pelletier, J.P., Mineau, F., Ranger, P. and Martel-Pelletier, J. ( 2001) Peroxisome proliferator-activated receptor gamma activators inhibit interleukin-1beta-induced nitric oxide and matrix metalloproteinase 13 production in human chondrocytes. Arthritis Rheum 44: 595-607. Fahmi, H., Pelletier, J.P. and Martel-Pelletier, J. ( 2002a) PPARgamma ligands as modulators of inflammatory and catabolic responses on arthritis. An overview. J Rheumatol 29: 3-14. Fahmi, H., Pelletier, J.P., Mineau, F. and Martel-Pelletier, J. ( 2002b) 15d-PGJ(2) is acting as a ‘dual agent’ on the regulation of COX-2 expression in human osteoarthritic chondrocytes. Osteoarthritis Cartilage 10: 845-848. Fahmi, H., Pelletier, J.P., Di Battista, J.A., Cheung, H.S., Fernandes, J. and Martel-Pelletier, J. ( 2002c) Peroxisome proliferator-activated receptor gamma acitvators inhibit MMP-1 production in human synovial fibroblasts by reducing the activity of the activator protein 1. Osteoarthritis Cartilage 10: 100-108. Fedeli, S. ( 1988) Livelli plasmatici di Diacerina nell’huomo anziano dopo somministrazioni repetute del farmaco a posologie diverse. Laboratoires NEGMA-PROTER. Study report, July 1988. Felisaz, N., Boumediene, K., Ghayor, C., Herrouin, J.F., Bogdanowicz, P., Galerra, P. et al. (1999) Stimulating effect of diacerein on TGF-beta1 and beta2 expression in articular chondrocytes cultured with and without interleukin-1 . Osteoarthritis Cartilage 7: 255-264. Fidelix, T.S., Soares, B.G. and Trevisani, V.F. ( 2006) Diacerein for osteoarthritis. Cochrane Database Syst Rev CD005117. Ghosh, P., Xu, A., Hwa, S.Y., Burkhardt, D. and Little, C. ( 1998) Evaluation of the effects of diacerhein in the sheep model of arthritis. Rev Prat 48: S24-S30. Glasson, S.S., Askew, R., Sheppard, B., Carito, B., Blanchet, T., Ma, H.L. et al. (2005) Deletion of active ADAMTS5 prevents cartilage degradation in a murine model of osteoarthritis. Nature 434: 644-648. Hilal, G., Martel-Pelletier, J., Pelletier, J.P., Ranger, P. and Lajeunesse, D. ( 1998) Osteoblast-like cells from human subchondral osteoarthritic bone demonstrate an altered phenotype in vitro: possible role in subchondral bone sclerosis. Arthritis Rheum 41: 891-899. 102 Hilal, G., Martel-Pelletier, J., Pelletier, J.P., Duval, N. and Lajeunesse, D. ( 1999) Abnormal regulation of urokinase plasminogen activator by insulin-like growth factor 1 in human osteoarthritic subchondral osteoblasts . Arthritis Rheum 42: 2112-2122. Hwa, S.Y., Burkhardt, D., Little, C. and Ghosh, P. ( 2001) The effects of orally administered diacerein on cartilage and subchondral bone in an ovine model of osteoarthritis. J Rheumatol 28: 825-834. Ji, J.D., Cheon, H., Jun, J.B., Choi, S.J., Kim, Y.R., Lee, Y.H. et al. (2001) Effects of peroxisome proliferator-activated receptor-gamma (PPAR-gamma) on the expression of inflammatory cytokines and apoptosis induction in rheumatoid synovial fibroblasts and monocytes. J Autoimmun 17: 215-221. Kobayashi, T., Notoya, K., Naito, T., Unno, S., Nakamura, A., Martel-Pelletier, J. et al. (2005) Pioglitazone, a peroxisome proliferator-activated receptor gamma agonist, reduces the progression of experimental osteoarthritis in guinea pigs. Arthritis Rheum 52: 479-487. Kwan Tat, S., Pelletier, J.P., Lajeunesse, D., Fahmi, H., Lavigne, M. and Martel-Pelletier, J. ( 2008) The differential expression of osteoprotegerin (OPG) and receptor activator of nuclear factor kappaB ligand (RANKL) in human osteoarthritic subchondral bone osteoblasts is an indicator of the metabolic state of these disease cells. Clin Exp Rheumatol 26: 295-304. Legendre, F., Bogdanowicz, P., Martin, G., Domagala, F., Leclercq, S., Pujol, J.P. et al. (2007) Rhein, a diacerhein-derived metabolite, modulates the expression of matrix degrading enzymes and the cell proliferation of articular chondrocytes by inhibiting ERK and JNK-AP-1 dependent pathways. Clin Exp Rheumatol 25: 546-555. Legendre, F., Heuze, A., Boukerrouche, K., Leclercq, S., Boumediene, K., Galera, P. et al. (2009) Rhein, the metabolite of diacerhein, reduces the proliferation of osteoarthritic chondrocytes and synoviocytes without inducing apoptosis . Scand J Rheumatol 38: 104-111. Martel-Pelletier, J., McCollum, R., Di Battista, J.A., Faure, M.P., Chin, J.A., Fournier, S. et al. (1992) The interleukin-1 receptor in normal and osteoarthritic human articular chondrocytes. Identification as the type I receptor and analysis of binding kinetics and biologic function. Arthritis Rheum 35: 530-540. Martel-Pelletier, J., Mineau, F., Jolicoeur, F.C., Cloutier, J.M. and Pelletier, J.P. ( 1998) In vitro effects of diacerhein and rhein on IL-1 and TNF-alpha systems in human osteoarthritic tissues. J Rheumatol 25: 753-762. Martel-Pelletier, J., Lajeunesse, D. and Pelletier, J.P. ( 2005) Etiopathogenesis of osteoarthritis, In: Koopman, W.J. and Moreland, L.W. (eds), Arthritis & allied conditions. A textbook of rheumatology, Lippincott, Williams & Wilkins: Baltimore, pp. 2199-2226. Martel-Pelletier, J., Lajeunesse, D., Reboul, P. and Pelletier, J.P. ( 2007) The role of subchondral bone in osteoarthritis, In: Sharma, L. and Berenbaum, F. (eds), Osteoarthritis: a companion to rheumatology, MosbyElsevier: Philadelphia, pp. 15-32. Martin, G., Bogdanowicz, P., Domagala, F., Ficheux, H. and Pujol, J.P. ( 2003) Rhein inhibits interleukin-1 beta-induced activation of MEK/ERK pathway and DNA binding of NF-kappa B and AP-1 in chondrocytes cultured in hypoxia: a potential mechanism for its disease-modifying effect in osteoarthritis . Inflammation 27: 233-246. Massicotte, F., Lajeunesse, D., Benderdour, M., Pelletier, J.-P., Hilal, G., Duval, N. et al. (2002) Can altered production of interleukin 1β, interleukin-6, transforming growth factor-β and prostaglandin E2 by isolated human subchondral osteoblasts identify two subgroups of osteoarthritic patients . Osteoarthritis Cartilage 10: 491-500. Mazieres, B., Berdah, L., Thiechart, M. and Viguier, G. ( 1993) Diacetylrhein on a postcontusion model of experimental osteoarthritis in the rabbit. Rev Rhum Ed Fr 60: 77S-81S. Mazieres, B., Blanckaert, A., Thiechart, M. and Viguier, G. ( 1996) Diacetylrhein administrated ‘curatively’ in an experimental model of post-contusion osteoarthritis in rabbits. Rev Prat 46: S42-S45 (abstract). McCollum, R., Martel-Pelletier, J., Di Battista, J.A. and Pelletier, J.P. ( 1991) Regulation of interleukin 1 receptors in human articular chondrocytes. J Rheumatol 18: 85-88. Moldovan, F., Pelletier, J.P., Jolicoeur, F.C., Cloutier, J.M. and Martel-Pelletier, J. ( 2000) Diacerhein and rhein reduce the ICE-induced IL-1beta and IL-18 activation in human osteoarthritic cartilage. Osteoarthritis Cartilage 8: 186-196. Moore, A.R., Greenslade, K.J., Alam, C.A. and Willoughby, D.A. ( 1997) Effects of diacerhein on cytokine determinations in a model of cartilage degradation induced by granuloma in mice. Rev Prat 47: S24-S26 (abstract). Moore, A.R., Greenslade, K.J., Alam, C.A. and Willoughby, D.A. ( 1998) Effects of diacerhein on granuloma induced cartilage breakdown in the mouse. Osteoarthritis Cartilage 6: 19-23. Nicolas, P., Tod, M., Padoin, C. and Petitjean, O. ( 1998) Clinical pharmacokinetics of diacerein. Clin Pharmacokinet 35: 347-359. Petitjean, O., Tod, M. and Louchahi, K. ( 1991) Étude de la pharmacocinétique de l’ART 50® en administration aigüe orale a la dose de 50 mg chez le volontaire sain âgé de 61-70 ans et de plus de 70 ans, et en administration réitérée a la dose de 50 mg x 2/jour chez le volontaire âgé de plus de 70 ans. Latoratoires NEGMA, Study PC/ART 9013N . Study report, April 1991. Pelletier, J.P., Mineau, F., Fernandes, J.C., Duval, N. and Martel-Pelletier, J. ( 1998) Diacerhein and rhein reduce the interleukin 1 beta stimulated inducible nitric oxide synthesis level and activity while stimulating cyclooxygenase-2 synthesis in human osteoarthritic chondrocytes. J Rheumatol 25: 2417-2424. 103 Pelletier, J.P., Lajeunesse, D., Reboul, P., Mineau, F., Fernandes, J.C., Sabouret, P. et al. (2001) Diacerein reduces the excess synthesis of bone remodeling factors by human osteoblast cells from osteoarthritic subchondral bone. J Rheumatol 28: 814-824. Pelletier, J.P., Mineau, F., Boileau, C. and Martel-Pelletier, J. ( 2003) Diacerein reduces the level of cartilage chondrocyte DNA fragmentation and death in experimental dog osteoarthritic cartilage at the same time that it inhibits caspase-3 and inducible nitric oxide synthase. Clin Exp Rheumatol 21: 171-177. Pelletier, J.P., Raynauld, J.P., Berthiaume, M.J., Abram, F., Choquette, D., Haraoui, B. et al. (2007) Risk factors associated with the loss of cartilage volume on weight bearing areas in knee osteoarthritis patients assessed by quantitative MRI: a longitudinal study. Arthritis Res Ther 9: R74. Pelletier, J.-P., Raynauld, J.-P., Abram, F., Haraoui, B., Choquette, D. and Martel-Pelletier, J. ( 2008) A new non-invasive method to assess synovitis severity in relation to symptoms and cartilage volume loss in knee osteoarthritis patients using MRI. Osteoarthritis Cartilage 16: S8-S13. Pomarelli, P., Berti, M., Gatti, M.T. and Mosconi, P. ( 1980) A non-steroidal anti-inflammatory drug that stimulates prostaglandin release. Farmaco 35: 836-842. Pujol, J.P., Felisaz, N., Boumediene, K., Ghayor, C., Herrouin, J.F., Bogdanowicz, P. et al. (2000) Effects of diacerein on biosynthesis activities of chondrocytes in culture. Biorheology 37: 177-184. Raynauld, J.P., Kauffmann, C., Beaudoin, G., Berthiaume, M.J., de Guise, J.A., Bloch, D.A. et al. (2003) Reliability of a quantification imaging system using magnetic resonance images to measure cartilage thickness and volume in human normal and osteoarthritic knees. Osteoarthritis Cartilage 11: 351-360. Raynauld, J.-P., Martel-Pelletier, J., Abram, J. and Pelletier, J.-P. ( 2008a) Use of quantitative magnetic resonance imaging (qMRI) in the cross-sectional and longitudinal evaluation of structural changes in knee osteoarthritis (OA) patients, In: Reid, D.M., Miller, C.G. and Baburaj, K. (eds), Clinical trials in rheumatoid arthritis and osteoarthritis, Springer-Verlag: London. Raynauld, J.-P., Martel-Pelletier, J., Berthiaume, M.-J., Abram, F., Choquette, D., Haraoui, B. et al. (2008b) Correlation between bone lesion changes and cartilage volume loss in patients with osteoarthritis of the knee as assessed by quantitative magnetic resonance imaging over a 24-month period. Ann Rheum Dis 67: 683-688. Raynauld, J.P., Martel-Pelletier, J., Berthiaume, M.J., Beaudoin, G., Choquette, D., Haraoui, B. et al. (2006) Long term evaluation of disease progression through the quantitative magnetic resonance imaging of symptomatic knee osteoarthritis patients: correlation with clinical symptoms and radiographic changes. Arthritis Res Ther 8: R21. Raynauld, J.P., Martel-Pelletier, J., Berthiaume, M.J., Labonté, F., Beaudoin, G., de Guise, J.A. et al. (2004) Quantitative magnetic resonance imaging evaluation of knee osteoarthritis progression over two years and correlation with clinical symptoms and radiologic changes. Arthritis Rheum 50: 476-487. Redini, F., Galera, P., Mauviel, A., Loyau, G. and Pujol, J.P. ( 1988) Transforming growth factor beta stimulates collagen and glycosaminoglycan biosynthesis in cultured rabbit articular chondrocytes. FEBS Lett 234: 172-176. Rintelen, B., Neumann, K. and Leeb, B.F. ( 2006) A meta-analysis of controlled clinical studies with diacerein in the treatment of osteoarthritis. Arch Intern Med 166: 1899-1906. Sadouk, M., Pelletier, J.P., Tardif, G., Kiansa, K., Cloutier, J.M. and Martel-Pelletier, J. ( 1995) Human synovial fibroblasts coexpress interleukin-1 receptor type I and type II mRNA: the increased level of the interleukin-1 receptor in osteoarthritic cells is related to an increased level of the type I receptor . Lab Invest 73: 347-355. Saha, N., Moldovan, F., Tardif, G., Pelletier, J.P., Cloutier, J.M. and Martel-Pelletier, J. ( 1999) Interleukin-1beta-converting enzyme/Caspase-1 in human osteoarthritic tissues: localization and role in the maturation of IL-1beta and IL-18. Arthritis Rheum 42: 1577-1587. Sanchez, C., Mathy-Hartert, M., Deberg, M.A., Ficheux, H., Reginster, J.Y. and Henrotin, Y.E. ( 2003) Effects of rhein on human articular chondrocytes in alginate beads. Biochem Pharmacol 65: 377-388. Segré, G. ( 1988) Étude pilote du passage de la rhéine dans le liquide synovial. Laboratoires NEGMA, Study 4A29. Study report, July 1988. Simonin, M.A., Bordji, K., Boyault, S., Bianchi, A., Gouze, E., Becuwe, P. et al. (2002) PPAR-gamma ligands modulate effects of LPS in stimulated rat synovial fibroblasts. Am J Physiol Cell Physiol 282: C125-C133. Smith Jr, G.N., Myers, S.L., Brandt, K.D., Mickler, E.A. and Albrecht, M. ( 1999) Diacerhein treatment reduces the severity of osteoarthritis in the canine cruciate-deficiency model of osteoarthritis. Arthritis Rheum 42: 545-554. Sokoloff, L. ( 1993) Microcracks in the calcified layer of articular cartilage . Arch Pathol Lab Med 117: 191-195. Spencer, C.M. and Wilde, M.I. ( 1997) Diacerein. Drugs 53: 98-108. Stanton, H., Rogerson, F.M., East, C.J., Golub, S.B., Lawlor, K.E., Meeker, C.T. et al. (2005) ADAMTS5 is the major aggrecanase in mouse cartilage in vivo and in vitro. Nature 434: 648-652. 104 Tamura, T. and Ohmori, K. ( 2001) Rhein, an active metabolite of diacerein, suppresses the interleukin-1alpha-induced proteoglycan degradation in cultured rabbit articular chondrocytes. Jpn J Pharmacol 85: 101-104. Tamura, T., Shirai, T., Kosaka, N., Ohmori, K. and Takafumi, N. ( 2002) Pharmacological studies of diacerein in animal models of inflammation, arthritis and bone resorption. Eur J Pharmacol 448: 81-87. Yaron, M., Shirazi, I. and Yaron, I. ( 1999) Anti-interleukin-1 effects of diacerein and rhein in human osteoarthritic synovial tissue and cartilage cultures. Osteoarthritis Cartilage 7: 272-280.


                Comment on this article