Knee osteoarthritis: a role for bradykinin?

Meini, Stefania; Maggi, Carlo Alberto

doi:10.1007/s00011-007-7204-1

Cited by 60 publications

(50 citation statements)

References 125 publications

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“…Intraarticular injections of hyaluronate have generally been effective for treatment of moderate to severe knee pain in OA subjects and bradykinin has been reported to have a role in this knee pain (45). Since hyaluronate can reduce bradykinin-induced pain (46), bradykinin-induced pain models might be useful for evaluating the effects of these compounds (ROCK inhibitors) on OA pain.…”

Section: Discussionmentioning

confidence: 99%

Alleviating Effects of AS1892802, a Rho Kinase Inhibitor, on Osteoarthritic Disorders in Rodents

et al. 2011

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Abstract. The effects of AS1892802, a selective Rho-associated coiled coil kinase (ROCK) inhibitor, on knee cartilage damage and pain behavior were examined in a rat model of osteoarthritis (OA). Monoiodoacetate (MIA) was intraarticularly injected into the right knee joints of rats. ROCK I and II mRNA levels increased in knee joints of MIA-injected rats. Our newly synthesized ROCK inhibitor, AS1892802, was injected into the ipsilateral knee or administered p.o. for 3 weeks. The compound dose-dependently and significantly inhibited of cartilage damage in the tibial plateau in a dose-dependent manner and decreased the weight distribution deficit associated with MIA injection. In addition, the compound also inhibited bradykinin induced pain responses in normal rats. In vitro, the compound could induce chondrocyte differentiation in a chondrogenic cell line and significantly inhibited IL-1β-or bradykinin-induced prostaglandin E 2 production in a synovial cell line. AS1892802 prevents cartilage damage induced by MIA and has analgesic effects in rat pain models, suggesting that AS1892802 may be clinically useful for the treatment of OA.[Supplementary Figure: available only at http://dx

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Section: Discussionmentioning

confidence: 99%

Alleviating Effects of AS1892802, a Rho Kinase Inhibitor, on Osteoarthritic Disorders in Rodents

et al. 2011

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“…By stimulating the constitutively expressed kinin B 2 receptors, it mediates many processes such as vasodilation, plasma extravasation (Green et al, 1994;Lo et al, 1999), inflammatory cell recruitment, and activation and sensitization of nociceptive afferent nerve terminals (Kanaka et al, 1985;Dray andPerkins, 1988, 1993;Steranka et al, 1988;Dray, 1997). A pathogenetic role for bradykinin in osteoarthritis has been hypothesized (Meini and Maggi, 2008), and there is evidence that, when injected in the rat knee joint, BK causes a progressive incapacitation that was inhibited by the selective B 2 receptor antagonist icatibant (Tonussi and Ferreira, 1997). Icatibant, in a model of adjuvant-induced arthritis in the rat, showed anti-inflammatory effects on knee joint swelling and reduction of tissue kallikrein levels in synovial tissue (Sharma and Wirth, 1996).…”

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confidence: 99%

Effect of Intra-articular 4-(S)-Amino-5-(4-{4-[2,4-dichloro-3-(2,4-dimethyl-8-quinolyloxymethyl)phenylsulfonamido]-tetrahydro-2H-4-pyranylcarbonyl} piperazino)-5-oxopentyl](trimethyl)ammonium chloride hydrochloride (MEN16132), a Kinin B₂ Receptor Antagonist, on Nociceptive Response in Monosodium Iodoacetate-Induced Experimental Osteoarthritis in Rats

Cialdai

Giuliani²,

Valenti³

et al. 2009

J Pharmacol Exp Ther

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The present study was designed to investigate the role of bradykinin (BK) in the knee joint osteoarthritis induced by intraarticular (i.ar.) administration of monosodium iodoacetate (MIA) in the rat, and to determine the efficacy of the kinin B 2 receptor antagonists, 4-(S)-amino-5-(4-{4-[2,4-dichloro-3-(2,4-dimethyl-8-quinolyloxymethyl)phenylsulfonamido]-tetrahydro-2H-4-pyranylcarbonyl} piperazino)-5-oxopentyl](trimethyl)ammonium chloride hydrochloride (MEN16132) and icatibant, in reducing pain. Rats received MIA (1 mg/25 l i.ar.) in the right knee. MEN16132, icatibant (1, 3, and 10 g/25 l i.ar.), or saline were administered 7 days after MIA treatment, and their antinociceptive effect was observed for 2 weeks. MEN16132 induced a marked and sustained reduction of incapacitation produced by MIA, approximately 56% inhibition of pain at 3 g/knee. MEN16132 analgesia was more potent and longer lasting, up to 10 days, than icatibant. MEN16132 (3 g/knee), at different time points from MIA treatment in separate groups of animals, produced comparable maximal antinociceptive effects, whereas the pain response induced by MIA was unaffected if MEN16132 (10 g/knee) was administered in the contralateral knee. Indomethacin at high doses (100 -625 g/knee) inhibited by approximately 40% but with a short duration the MIAinduced pain. MIA treatment produced a significant increase of BK and prostaglandin E 2 (PGE 2 ) metabolite levels in synovial fluid up to 21 days, and PGE 2 metabolite levels were reduced almost to basal values by MEN16132. In conclusion the potent and long-lasting analgesic effect of MEN16132 in MIA-induced osteoarthritis indicates an important role for BK in osteoarthritic pain, and suggests that MEN16132 can be a candidate for the treatment of this chronic disease.Osteoarthritis (OA) is a degenerative joint disease that affects most of the elderly population causing chronic pain and joint disability. In particular, the OA of the knee is characterized by histological changes of the joint involving degeneration of articular cartilage with fibrillation and erosion, synovitis, remodeling of subchondral bone with osteophytes formation at the joint margins, and sclerosis of subchondral bone (Goldring and Goldring, 2007). The pathophysiology behind these modifications is complex and involves a combination of mechanical, cellular, and biochemical processes that are not yet completely understood. Inflammation contributes to increase structural degeneration by releasing catabolic and proinflammatory mediators including cytokines, nitric oxide, and matrix metalloproteinases that may activate chondrocytes and synovial fibroblasts leading to cartilage destruction (Goldenberg et al., 1982;Yasuda, 2006;Sutton et al., 2009). No drug modifying OA progression is currently available, and treatment options are focused on symptomatic relief of pain and inflammation to improve the joint function. Nonsteroidal anti-inflammatory drugs (NSAIDs), corticosteroids, and opiates are widely used, but Article, publication date, and c...

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“…14,31 BDKRB2 is involved in the initiation and maintenance of inflammation, producing pain, and activating synoviocytes and chondrocytes: the main cells involved in the homeostasis of synovial fluid and cartilage, respectively. 13,32 BDKRB2 signaling leading to NO production via eNOS has been well studied. 33 Given the known association of the BDKRB2 with OA and its association with NO production, we found positive correlation between the BDKRB2 levels in synovial tissue and NO production in serum from patients with OA.…”

Section: Discussionmentioning

confidence: 99%

BDKRB2 +9/−9 bp polymorphisms influence BDKRB2 expression levels and NO production in knee osteoarthritis

Chen

Zhang

et al. 2016

Exp Biol Med (Maywood)

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The bradykinin B2 receptor (BDKRB2) plays a key role in the inflammation process of osteoarthritis. Nitric oxide has also long been considered to be a catabolic factor that contributes to inflammatory response and the osteoarthritis disease pathology. Several studies have reported that the BDKRB2 þ9/À9 bp polymorphisms are associated with transcription of the receptor. However, the roles of BDKRB2 polymorphisms in inflammation in osteoarthritis remain unclear. This study enrolled 156 subjects with primary knee osteoarthritis and 58 healthy volunteers. BDKRB2 polymorphisms were genotyped, and the mRNA and protein levels of BDKRB2 in synovial tissues from osteoarthritis patients were measured by quantitative real-time polymerase chain reaction and western blot analysis, respectively. Nitric oxide production in serum from patients with osteoarthritis was measured using a nitric oxide assay kit. We found that the mean BDKRB2 mRNA levels were significantly higher in Kallgren-Lawrence grade-4 osteoarthritis patients than patients with lower grade osteoarthritis. The þ9/À9 bp polymorphisms significantly affected the BDKRB2 mRNA and protein expression levels in synovial tissues from osteoarthritis subjects. Osteoarthritis patients with þ9/À9 and À9/À9 genotypes had higher BDKRB2 expression levels in synovial tissue and nitric oxide production in serum. Moreover, positive correlation was found between the BDKRB2 levels in synovial tissue and nitric oxide production. Compared with health controls, significant increases of nitric oxide production in osteoarthritis were detected which were associated with increasing severity of osteoarthritis. Multiple linear regression analysis (adjusted for gender and age) showed serum nitric oxide level was positively associated with BDKRB2 polymorphism and Kallgren-Lawrence grade and was inversely associated with obesity. Our findings showed that the BDKRB2 þ9/À9 bp polymorphisms affected the gene expression and nitric oxide production, which were associated with radiographic severity of osteoarthritis, suggesting that the BDKRB2 þ9/À9 bp polymorphisms may act as a genetic modulator of osteoarthritis, and play an essential role in inflammatory process in osteoarthritis.

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Knee osteoarthritis: a role for bradykinin?

Cited by 60 publications

References 125 publications

Alleviating Effects of AS1892802, a Rho Kinase Inhibitor, on Osteoarthritic Disorders in Rodents

Alleviating Effects of AS1892802, a Rho Kinase Inhibitor, on Osteoarthritic Disorders in Rodents

BDKRB2 +9/−9 bp polymorphisms influence BDKRB2 expression levels and NO production in knee osteoarthritis

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