Inflamm. res. 57 (2008) 351–361 1023-3830/08/070351-11 DOI 10.1007/s00011-007-7204-1 Inflammation Research © Birkhäuser Verlag, Basel, 2008 Abstract. Osteoarthritis (OA) is a painful and degenerating progressive disease of the joints which affects millions of patients worldwide. The cause of OA is largely unknown. Among the potential therapies for the symptomatic treat- ment of OA, the intra-articular administration of a specific bradykinin (BK) B 2 receptor antagonist has been reported to produce a long lasting analgesic effect in patients affected by knee OA. BK is a vasodilator and inflammatory nonapep- tide which is generated in OA synovium. It contributes to the initiation and maintenance of inflammation, to exciting and sensitizing sensory nerve fibres, thus producing pain, and to activating synoviocytes and chondrocytes which are the main cells involved in the homeostasis of synovial fluid and cartilage, respectively. Moreover, BK synergistically poten- tiates the effects produced by pro-inflammatory cytokines. Biochemical and preclinical evidence supporting the thera- peutic relevance of B 2 receptor blockade in OA pathophysi- ology are reviewed in this publication. Key words: B 2 receptor – Icatibant – Inflammation – Pain – Synovium Introduction Bradykinin (BK, H-Arg-Pro-Pro-Gly-Phe-Ser-Pro-Phe-Arg- OH) is known to have potent pro-inflammatory effects and is one of the most potent endogenous algogenic peptides. BK is formed in plasma and inflamed tissues and, by activating the B 2 receptor present in the membrane of several cell types, in- itiates many processes such as vasodilation, plasma extrava- sation, activation of immune cells, induction of leukocyte chemotaxis, and activation of nociceptive neurons. Compel- ling evidence has shown that BK participates in a number of hyperalgesic and inflammatory preclinical models [1]. The growing knowledge of the biological role of kinins, in particular in pain and inflammation, has sustained the de- velopment of potent and selective bradykinin receptor modu- lators as potential therapeutics [2]. The clinical relevance of the blockade of the bradykinin B 2 receptor has been shown in a Phase II study on patients with symptomatic knee osteoarthritis (OA) in which a sin- gle intra-articular injection of the peptidic BK B 2 receptor antagonist Icatibant (previously known as Hoe 140, [DArg 0 , Hyp 3 , Thi 5 , DTic 7 , Oic 8 ]-BK) [3, 4] reduced knee pain inten- sity more effectively than placebo, while no differences in terms of adverse events between the Icatibant and the pla- cebo treated groups were reported [5, 6]. The purpose of this publication is to review biochemical and preclinical evidence which supports the hypothesis for a role of bradykinin and the clinical relevance of B 2 receptor blockade in knee OA pathophysiology. Pathophysiological features of osteoarthritis OA (also known as osteoarthrosis or degenerative arthritis) is the most common form of articular disorders affecting the diarthrodial joints that permit free bone movement. OA is classified as primary, or idiopathic, which is usually subdi- vided by the site of involvement (e. g. hip, knee, etc.), and secondary, or resulting from conditions which change the microenvironment of the cartilage, comprising trauma and congenital abnormalities [7, 8]. The clinical symptoms of OA are pain and functional impairment that includes joint stiffness and dysfunction. The most evident morphologi- cal sign of OA is the progressive degeneration of articular cartilage with the consequent reduction of its volume and of the joint-space. Changes also occur in the subchondral bone with the formation of osteophytes, subchondral cysts, bone marrow oedema, meniscal tears, and inflammation of the synovial membrane. Swelling of the joint is frequently present, as well as synovial and subchondral angiogenesis which may contribute to OA progression [9–11]. Correspondence to: S. Meini Review Knee osteoarthritis: a role for bradykinin? S. Meini, C. A. Maggi Pharmacology Department, Menarini Ricerche S.p.A., via Rismondo 12A, 50135, Firenze, Italy, Fax: +39-055-5680419, e-mail: smeini@menarini-ricerche.it Received 26 October 2007; returned for revision 18 December 2007; received from final revision 17 January 2008; accepted by J. Di Battista 17 January 2008 Published Online First 25 July 2008