This study describes specific molecular mechanisms by which supplementation with n-3 fatty acids (i.e. those present in fish oils) can modulate the expression and activity of degradative and inflammatory factors that cause cartilage destruction during arthritis. Our data show that incorporation of n-3 fatty acids (but not other polyunsaturated or saturated fatty acids) into articular cartilage chondrocyte membranes results in a dose-dependent reduction in: (i) the expression and activity of proteoglycan degrading enzymes (aggrecanases) and (ii) the expression of inflammation-inducible cytokines (interleukin (IL)-1␣ and tumor necrosis factor (TNF)-␣) and cyclooxygenase (COX-2), but not the constitutively expressed cyclooxygenase COX-1. These findings provide evidence that n-3 fatty acid supplementation can specifically affect regulatory mechanisms involved in chondrocyte gene transcription and thus further advocate a beneficial role for dietary fish oil supplementation in alleviation of several of the physiological parameters that cause and propogate arthritic disease.
HL-K6-3512) as well as by grants (HL-02212 and HL-16346) from the National Institutes of Health. A Fulbright Travelling Fellowship to C. G. C. is gratefully acknowledged.
Objective. To determine if n-3 polyunsaturated fatty acid (PUFA) supplementation (versus treatment with n-6 polyunsaturated or other fatty acid supplements) affects the metabolism of osteoarthritic (OA) cartilage.Methods. The metabolic profile of human OA cartilage was determined at the time of harvest and after 24-hour exposure to n-3 PUFAs or other classes of Conclusion. These studies show that the pathologic indicators manifested in human OA cartilage can be significantly altered by exposure of the cartilage to n-3 PUFA, but not to other classes of fatty acids.
Fibrinogen displays a regulation of considerable physiological significance by lowering the Ca2+ requirement for the conversion of the fibrin-stabilizing factor (Factor XIII) zymogen to the range of concentrations of this ion found in plasma. Fibrinogen modulates both Ca2+-dependent steps in the complex process of zymogen activation, involving the heterologous dissociation of subunits of the thrombin-modified zymogen (Factor XIII') species (a'2 a'2) and the unmasking b2 of iodoacetamide titratable sites during generation of transamidating activity (a'2 --a*2). It is interesting that a thrombinindependent pathway of zymogen activation (a2b2 X a -A), b2 which we found to operate at Ca2+ concentrations above 50 mM, is not affected by the presence of fibrinogen. Regulation by fibrinogen thus appears to be specific for controlling only the physiological pathway of zymogen conversion.Fibrinogen has always been characterized as the plasma protein that serves as the precursor for the fibrin network formed during the clotting of blood. Accordingly, only the reaction of fibrinogen with thrombin (1-3) and that of fibrin with fibrinoligase (coagulation Factor XIIIa; refs. 4-6) were thought to be of physiological importance. Our recent work reveals that the fibrinogen molecule displays a hitherto unrecognized regulatory property of considerable physiological significance. It will be shown in the present paper that fibrinogen greatly enhances the generation of fibrinoligase activity and lowers the Ca2+ requirement for this process. As such, modulation by fibrinogen is somewhat reminiscent of the biochemical functions of troponin C in muscle (7) and of the various Ca2+-dependent regulatory proteins in other tissues (see refs. 7-11).Fibrinoligase, a transamidase that is responsible for the covalent fusion of fibrin molecules by 'y-glutamyl-elysine bridges The fibrin-stabilizing factor zymogen (Factor XIII) and the pure b subunits were isolated from outdated human plasma by published procedures (24). These purified materials were stored at 40 in 50 mM Tris1HCl, pH 7.5/1 mM EDTA. Concentrations of the zymogen and the b protein were calculated on the basis of E "m = 13.8 at 280 nm (25). The functional molarity of Factor XIII was measured by titration with iodoacetamide as described by Curtis et al. (14). The molarity of thrombin was determined from pre-steadystate kinetics for the hydrolysis of p-nitrophenylguanidobenzoate (26).Factor XIII zymogen was hydrolytically converted from the a2b2 native state to the a'2b2 one (Factor XIII') at 25°, pH 7.5, in solutions of 0.15 ml containing 10MM zymogen and 0.17,gM thrombin, as well as 50 mM Tris-HCl and 0.5 mM EDTA. After a reaction time of 30 min, sufficient amount of hirudin (Sigma, lot 27B-2330) was added to provide a 2-fold excess of hirudin over the clotting units of thrombin, in terms of the thrombinneutralizing potency of the hirudin preparation as specified by the supplier. Total conversion of the a subunits to a' was verified by sodium dodecyl sulfate disc gel polyacryl...
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