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In-vitro differences among nonsteroidal antiinflammatory drugs in their activities related to osteoarthritis pathophysiology
Osteoarthritis and Cartilage (1999) 7, 355–357 1999 OsteoArthritis Research Society International Article No. joca.1998.0197, available online at http://www.idealibrary.com on
1063–4584/99/030355+03 $12.00/0
In-vitro differences among nonsteroidal antiinflammatory drugs in their activities related to osteoarthritis pathophysiology BY Y. HENROTIN AND J-Y. REGINSTER Bone and Cartilage Metabolism Research Unit, CHU Sart-Tilman, University of Lie`ge, Belgium
NONSTEROIDAL anti-inflammatory drugs (NSAIDs) are commonly used for the treatment of osteoarthritis (OA). These drugs are recognized as often relieving the symptoms of OA. Nevertheless, several types of NSAIDs (e.g., sodium salicylate) inhibit the synthesis of proteoglycans (PGs) and collagens by chondrocytes in vitro. Hence, they may diminish the potential of cartilage repair in OA. These in-vitro observations are compatible with in-vivo studies suggesting that some NSAIDs (e.g., aspirin), accelerate the progression of OA. Therefore, it is important to determine the e#ects of a new NSAID on the anabolic functions of chondrocytes. Since there are no validated non-invasive methods for quantifying the anabolic and catabolic activities of cartilage in vivo, much information on the adverse e#ects of NSAIDs on chondrocyte functions can be obtained by in-vitro methods using cartilage tissue or di#erentiated chondrocytes. The aims of in-vitro studies should be the screening of the e#ects of NSAIDs on chondroformation and chondroresorption processes but also on cytokines activity and synthesis and by this way allow the classification of these drugs according their pharmacological in-vitro e#ects. Dingle and collaborators [1] have divided NSAIDs in three categories, with respect to their in-vitro action upon anabolic functions of OA cartilage: (1) those such as aceclofenac, which can stimulate matrix component synthesis; (2) those such as piroxicam, which express a neutral e#ect on cartilage anabolism; (3) those like ibuprofen, naproxen and indomethacin, which significantly inhibit anabolic functions of chondrocytes. However, caution must be taken with regard of these conclusions because they come from short-term organ culture with plasmatic concentration of NSAIDs. Moreover, the results vary on isolated chondrocyte culture systems. Some NSAIDs which show an anabolic e#ect after short-term treatment,
may have adverse e#ects on cartilage integrity when administrated during long term treatment or at higher doses. Some NSAIDs, such as indomethacin, may exert their deleterious e#ects on cartilage matrix synthesis by inhibiting prostaglandin E2 (PGE2) production [2]. PGE2 have been demonstrated to enhance collagen and proteoglycan synthesis by human chondrocytes secondary to the production of insulin-like growth factor (IGF)-1 [3]. Moreover, PGE2 inhibits the synthesis of IL-1. IL-1 is the most important catabolic cytokine in OA, capable of overcoming the stimulating e#ect of IGF-1 on matrix components synthesis [4]. Therefore, the inhibition of PGE2 synthesis by NSAIDs may induce the release of IL-1 and then inhibit cartilage matrix protein synthesis (Fig. 1). Although NSAIDs inhibit PGE2, only some show an inhibitory e#ect on matrix component synthesis. Other deleterious mechanisms include the inhibition of glycosyltransferase activity [5], the uncoupling of mitochondrial oxidative phosphorylation [6], the activation of cAMP-dependent kinase A [7] or the disruption of protein-protein interactions at the cellular membrane level [8]. On the other hand, the stimulatory e#ect of some NSAIDs may be related to their inhibitory e#ect on IL-1 production or IL-1 receptor expression [9] and thus could promote growth factor activity, including IGF-1 and TGF-â. Moreover, a number of NSAIDs, such as tiaprofenic acid, naproxen and indomethacin, inhibit aggrecans degradation in cartilage tissue and suppress cartilage breakdown in animal models of OA. These beneficial actions of NSAIDs seem to be related to their inhibiting e#ect on metalloproteinases synthesis and activity. The metalloproteinase activity may be modulated by NSAIDs stimulating action on the production by chondrocytes of tissue inhibitor of metalloproteases-1 (TIMP-1) or by their inhibiting action on plasminogen activator synthesis [10]. 355
356
Henrotin and Reginster: In-vitro differences among nonsteroidal antiinflammatory drugs
FIG. 1. Mechanisms of action of NSAIDs in cartilage anabolism: interaction between catabolic cytokines, growth factors and prostaglandins. IL-1, Interleukin-1; IGF-1, Insulin-like growth factor-1; IGF-BP, Insulin-like growth factor binding protein; cAMP, Cyclic adenosine monophosphate.
Cartilage injury can also be mediated by active oxygen species (O2 , H2O2, OH) produced by chondrocytes and inflammatory cells present in the synovial membrane. Several NSAIDs, such as nimesulide, have the faculty to scavenge oxygen radicals and/or inhibit their production by NADPH oxidase [11]. Finally, it is interesting to note that NSAIDs e#ects on chondrocyte metabolic activities widely vary as a function of the concentration tested, the age of the donor, the metabolic activity of the chondrocytes and the severity of cartilage lesions. It has been reported that osteoarthritic cartilage is more vulnerable to the influence of NSAIDs than intact cartilage. In conclusion, in-vitro research yields valuable informations on the bioactivity profile of NSAID drugs on chondrocyte metabolism. Nevertheless, extrapolation from in vitro to in vivo must be carried out with caution. References 1. Dingle J et al. The e#ect of NSAIDs on human articular cartilage glycosaminoglycan synthesis. Eur J Rheum Inflam 1996;16:47–52.
2. Dingle J. Prostaglandins in human cartilage metabolism. J Lipid Med 1993;6:310–2. 3. Di Battista J, Dore S, Martel-Pelletier J, Pelletier JP. Prostaglandin E2 stimulates incorporation of proline into collagenase digestible proteins in human articular chondrocytes: identification of an e#ector autocrine loop involving insulin-like growth factor I. Mol Cell Endocrinol 1997;123: 27–35. 4. Kunkel S, Chensue S. Arachidonic acid metabolites regulate interleukin-1 production. Biochem Biophys Res Commun 1985;128:892–7. 5. David M, Vignon E, Peschard M et al. E#ect of non-steroidal anti-inflammatory drugs (NSAIDs) on glycosyltransferase activity from osteoarthritic cartilage. Br J Rheumatol 1992;31 (Suppl 1):13–7. 6. Mahmud T, Rafi S, Scott D et al. Nonsteroidal antiinflammatory drugs and uncoupling of mitochondrial oxidative phosphorylation. Arthritis Rheum 1996;39:1998–2003. 7. Malemud C, Papay R, Hasler P, Kammer G. The e#ect of nonsteroidal anti-inflammatory drugs on cAMP-dependent protein kinase-mediated phosphorylation by human chondrocytes in culture. Clin Exp Rheumatol 1994;12:149–56. 8. Abramson S, Weissmann G. The mechanisms of action of nonsteroidal antiinflammatory drugs. Arthritis Rheum 1989;32:1–9. 9. Pelletier J-P, McCollum R, DiBattista J et al. Regulation of human normal and osteoarthritic
Osteoarthritis and Cartilage Vol. 7 No. 3 chondrocyte interleukin-1 receptor by antirheumatic drugs. Arthritis Rheum 1993;36:1517–27. 10. Yamada H, Kikuchi T, Nemoto O, Obata K, Sato H, Seiki M, Shimnei M. E#ects of indomethacin on the production of matrix metalloproteinase-3 and tissue inhibitor of metalloproteinases-1 by human
357
articular chondrocytes. J Rheumatol 1996;23: 1739–43. 11. Facino M, Carini M, Aldini G. Antioxidant activity of nimesulide and its main metabolites. Drugs 1993;46 (Suppl 1):15–21.
1063–4584/99/030355+03 $12.00/0
In-vitro differences among nonsteroidal antiinflammatory drugs in their activities related to osteoarthritis pathophysiology BY Y. HENROTIN AND J-Y. REGINSTER Bone and Cartilage Metabolism Research Unit, CHU Sart-Tilman, University of Lie`ge, Belgium
NONSTEROIDAL anti-inflammatory drugs (NSAIDs) are commonly used for the treatment of osteoarthritis (OA). These drugs are recognized as often relieving the symptoms of OA. Nevertheless, several types of NSAIDs (e.g., sodium salicylate) inhibit the synthesis of proteoglycans (PGs) and collagens by chondrocytes in vitro. Hence, they may diminish the potential of cartilage repair in OA. These in-vitro observations are compatible with in-vivo studies suggesting that some NSAIDs (e.g., aspirin), accelerate the progression of OA. Therefore, it is important to determine the e#ects of a new NSAID on the anabolic functions of chondrocytes. Since there are no validated non-invasive methods for quantifying the anabolic and catabolic activities of cartilage in vivo, much information on the adverse e#ects of NSAIDs on chondrocyte functions can be obtained by in-vitro methods using cartilage tissue or di#erentiated chondrocytes. The aims of in-vitro studies should be the screening of the e#ects of NSAIDs on chondroformation and chondroresorption processes but also on cytokines activity and synthesis and by this way allow the classification of these drugs according their pharmacological in-vitro e#ects. Dingle and collaborators [1] have divided NSAIDs in three categories, with respect to their in-vitro action upon anabolic functions of OA cartilage: (1) those such as aceclofenac, which can stimulate matrix component synthesis; (2) those such as piroxicam, which express a neutral e#ect on cartilage anabolism; (3) those like ibuprofen, naproxen and indomethacin, which significantly inhibit anabolic functions of chondrocytes. However, caution must be taken with regard of these conclusions because they come from short-term organ culture with plasmatic concentration of NSAIDs. Moreover, the results vary on isolated chondrocyte culture systems. Some NSAIDs which show an anabolic e#ect after short-term treatment,
may have adverse e#ects on cartilage integrity when administrated during long term treatment or at higher doses. Some NSAIDs, such as indomethacin, may exert their deleterious e#ects on cartilage matrix synthesis by inhibiting prostaglandin E2 (PGE2) production [2]. PGE2 have been demonstrated to enhance collagen and proteoglycan synthesis by human chondrocytes secondary to the production of insulin-like growth factor (IGF)-1 [3]. Moreover, PGE2 inhibits the synthesis of IL-1. IL-1 is the most important catabolic cytokine in OA, capable of overcoming the stimulating e#ect of IGF-1 on matrix components synthesis [4]. Therefore, the inhibition of PGE2 synthesis by NSAIDs may induce the release of IL-1 and then inhibit cartilage matrix protein synthesis (Fig. 1). Although NSAIDs inhibit PGE2, only some show an inhibitory e#ect on matrix component synthesis. Other deleterious mechanisms include the inhibition of glycosyltransferase activity [5], the uncoupling of mitochondrial oxidative phosphorylation [6], the activation of cAMP-dependent kinase A [7] or the disruption of protein-protein interactions at the cellular membrane level [8]. On the other hand, the stimulatory e#ect of some NSAIDs may be related to their inhibitory e#ect on IL-1 production or IL-1 receptor expression [9] and thus could promote growth factor activity, including IGF-1 and TGF-â. Moreover, a number of NSAIDs, such as tiaprofenic acid, naproxen and indomethacin, inhibit aggrecans degradation in cartilage tissue and suppress cartilage breakdown in animal models of OA. These beneficial actions of NSAIDs seem to be related to their inhibiting e#ect on metalloproteinases synthesis and activity. The metalloproteinase activity may be modulated by NSAIDs stimulating action on the production by chondrocytes of tissue inhibitor of metalloproteases-1 (TIMP-1) or by their inhibiting action on plasminogen activator synthesis [10]. 355
356
Henrotin and Reginster: In-vitro differences among nonsteroidal antiinflammatory drugs
FIG. 1. Mechanisms of action of NSAIDs in cartilage anabolism: interaction between catabolic cytokines, growth factors and prostaglandins. IL-1, Interleukin-1; IGF-1, Insulin-like growth factor-1; IGF-BP, Insulin-like growth factor binding protein; cAMP, Cyclic adenosine monophosphate.
Cartilage injury can also be mediated by active oxygen species (O2 , H2O2, OH) produced by chondrocytes and inflammatory cells present in the synovial membrane. Several NSAIDs, such as nimesulide, have the faculty to scavenge oxygen radicals and/or inhibit their production by NADPH oxidase [11]. Finally, it is interesting to note that NSAIDs e#ects on chondrocyte metabolic activities widely vary as a function of the concentration tested, the age of the donor, the metabolic activity of the chondrocytes and the severity of cartilage lesions. It has been reported that osteoarthritic cartilage is more vulnerable to the influence of NSAIDs than intact cartilage. In conclusion, in-vitro research yields valuable informations on the bioactivity profile of NSAID drugs on chondrocyte metabolism. Nevertheless, extrapolation from in vitro to in vivo must be carried out with caution. References 1. Dingle J et al. The e#ect of NSAIDs on human articular cartilage glycosaminoglycan synthesis. Eur J Rheum Inflam 1996;16:47–52.
2. Dingle J. Prostaglandins in human cartilage metabolism. J Lipid Med 1993;6:310–2. 3. Di Battista J, Dore S, Martel-Pelletier J, Pelletier JP. Prostaglandin E2 stimulates incorporation of proline into collagenase digestible proteins in human articular chondrocytes: identification of an e#ector autocrine loop involving insulin-like growth factor I. Mol Cell Endocrinol 1997;123: 27–35. 4. Kunkel S, Chensue S. Arachidonic acid metabolites regulate interleukin-1 production. Biochem Biophys Res Commun 1985;128:892–7. 5. David M, Vignon E, Peschard M et al. E#ect of non-steroidal anti-inflammatory drugs (NSAIDs) on glycosyltransferase activity from osteoarthritic cartilage. Br J Rheumatol 1992;31 (Suppl 1):13–7. 6. Mahmud T, Rafi S, Scott D et al. Nonsteroidal antiinflammatory drugs and uncoupling of mitochondrial oxidative phosphorylation. Arthritis Rheum 1996;39:1998–2003. 7. Malemud C, Papay R, Hasler P, Kammer G. The e#ect of nonsteroidal anti-inflammatory drugs on cAMP-dependent protein kinase-mediated phosphorylation by human chondrocytes in culture. Clin Exp Rheumatol 1994;12:149–56. 8. Abramson S, Weissmann G. The mechanisms of action of nonsteroidal antiinflammatory drugs. Arthritis Rheum 1989;32:1–9. 9. Pelletier J-P, McCollum R, DiBattista J et al. Regulation of human normal and osteoarthritic
Osteoarthritis and Cartilage Vol. 7 No. 3 chondrocyte interleukin-1 receptor by antirheumatic drugs. Arthritis Rheum 1993;36:1517–27. 10. Yamada H, Kikuchi T, Nemoto O, Obata K, Sato H, Seiki M, Shimnei M. E#ects of indomethacin on the production of matrix metalloproteinase-3 and tissue inhibitor of metalloproteinases-1 by human
357
articular chondrocytes. J Rheumatol 1996;23: 1739–43. 11. Facino M, Carini M, Aldini G. Antioxidant activity of nimesulide and its main metabolites. Drugs 1993;46 (Suppl 1):15–21.