Acute Urate Crystal-Induced Arthritis

the production and release of this factor in vitro. In these studies, colchicine, at nonleukopenic doses, is shown to abrogate the acute arthritis induced by monosodium urate crystals in rabbits, but to have no effect upon the arthritis induced by the injection of the purified cell-derived chemotactic factor. Serum colchicine levels were 0.48-0.58 ,uM at 30 min and 0.12-0.3 AM at 90 min after intravenous injection of 0.2 mg/kg colchicine. Peripheral blood polymorphonuclear leukocytes obtained from colchicine-treated animals migrated normally towards a chemotactic stimulus but failed to produce CCF after phagocytosis of monosodium urate crystals. The dialyzed synovial fluid from rabbits injected with microcrystalline sodium urate contained chemotactic activity that was not present when animals were also given intravenous colchicine or injected intra-articularly with the chemotactic factor formyl-methionyl-leucyl-phenylalanine. Furthermore, the synovial fluid from rabbits injected with microcrystalline sodium urate significantly decreased 1251-CCF binding to neutrophils. The binding of '25I-CCF to its neutrophil receptor was not significantly reduced by the synovial fluid of colchicinetreated rabbits nor by the synovial fluid ofcontrol rabbits injected with the chemotactic factor formyl-methionylleucyl-phenylalanine. Colchicine (10 and 0.1 AM) was shown to have no effect upon the binding of 125I_CCF to its cell receptor. Received for publication 11 December 1978 and in revised form I May 1979. INTRODUCTION Although colchicine has been used for over a century in the treatment and prevention of gouty arthritis, a complete understanding of its site(s) of action has remained elusive. Colchicine is unique among therapeutic agents used in the treatment of acute arthritis in that its usefulness is generally felt to be relatively limited to this rheumatic disease and that it is not a potent general anti-ihflammatory agent (1-3). Experimentally, colchicine has been demonstrated to dramatically abrogate the inflammatory response to urate crystals in humans (4), but to have only weak effects against induced intradermal staphylococcal infection in guinea pig (5). In vitro, colchicine and other anti-microtubule agents have been reported to diminish polymorphonuclear leukocyte (PMN)1 chemotaxis (6, 7) and lysosomal enzyme release (8). However, it seems unlikely that the major in vivo pharmacologic action of colchicine is via either of these mechanisms because neither is unique to urate crystal-induced inflammation, and a drug capable of suppressing such PMN functions would be expected to have more general anti-inflammatory effects than colchicine exhibits. The question therefore remains as to the existence of a relatively unique step in the development of acute urate crystal-induced arthritis which is colchicine-sensitive and of secondary importance in other natural and experimental inflammatory conditions. Evidence suggests that urate crystal-induced arthritis can develop in the absence of complement (9, 10), Hageman factor (11), and kinins (11); we (12, 13), and others (14), have proposed that the initial stimulus in 'Abbreviations used in this paper: BSA, bovine serum albumin; CCF, crystal-induced chemotactic factor; FMLP, formyl-methionyl-leucyl-phenylalanine; MSU, microcrystalline sodium urate; PMN, polymorphonuclear leukocyte(s). J. Clin. Invest. ( The American Society for Clinical Investigation, Inc. * 0021-9738/79/09/0775/06 $1.00 Volume 64 September 1979 775-780 775 the development ofthe acute gouty attack is the phagocytosis of urate crystals by PMN (and possibly by other phagocytic cells) which leads to the production of a glycoprotein (8,400 mol wt) chemotactic for neutrophils and monocytes. The glycoprotein is not detected if cells are pretreated with actinomycin D or cycloheximide (15, 16), or if cells are exposed only to urate in solution (14). As first reported by Tse and Phelps (17), the chemotactic activity does not appear if the cells are exposed to colchicine at therapeutic levels before their incubation with urate crystals. More recent studies (15) corroborate and extend these findings to demonstrate that the chemotactic glycoprotein is not detectable in the media or subcellular fractions of colchicine-treated cells allowed to phagocytose urate crystals. It should be noted that phagocytosis per se was not impaired by the colchicine treatment in these experiments. Recent work (18) has shown that the intra-articular injection of the purified urate crystal-induced chemotactic factor (CCF) in rabbits produces a profound arthritis that is histologically identical with that produced by urate crystal injection. However, PMN accumulation in the synovial fluid occurs even more rapidly than in urate crystalinduced arthritis, a finding consistent with the circumvention of the early stages of the inflammatory process consisting of crystal phagocytosis, factor synthesis, and release. This study presents data indicating that the primary mechanism of colchicine action in ameliorating and preventing the acute gouty attack is by inhibiting the production and(or) release of the cell-derived chemotactic factor which normally mediates the inflammatory response to urate crystals.