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ND: | ME10640399
PMID: | 10640399
LR: | 20061115
CED: | 20000218
DCO: | 20000218
Autoren: | Patwari P; Kurz B; Sandy JD; Grodzinsky AJ
Titel: | Mannosamine inhibits aggrecanase-mediated changes in the physical properties and biochemical composition of articular cartilage.
Quelle: | Archives of biochemistry and biophysics; VOL: 374 (1); p. 79-85 /20000201/
PM: | Print
SU: | IM
Sprache: | English
CY: | UNITED STATES
JID: | 0372430
ISSN: | 0003-9861
CO: | ABBIA4
Institution: | Continuum Electromechanics Laboratory, Center for Biomedical Engineering, Department of EECS, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA. pkp@mit.edu
DT: | In Vitro; Journal Article; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, P.H.S.
NG: | AR33236 AR NIAMS
Schlagwörter
CT: | AGGRECANS; ANIMALS; BIOMECHANICS; CARTILAGE, ARTICULAR/chemistry; CARTILAGE, ARTICULAR/*drug effects; CARTILAGE, ARTICULAR/physiopathology; CATTLE; DOSE-RESPONSE RELATIONSHIP, DRUG; ENDOPEPTIDASES/*metabolism; EXTRACELLULAR MATRIX PROTEINS/*; GLYCOSAMINOGLYCANS/metabolism; HEXOSAMINES/*pharmacology; INTERLEUKIN-1/pharmacology; LECTINS, C-TYPE; PROTEOGLYCANS/drug effects; PROTEOGLYCANS/metabolism; TIME FACTORS
CTG: | AGGREKANE; TIER; BIOMECHANIK; KNORPEL, GELENK-/Chemie; KNORPEL, GELENK-/*Arzneimittelwirkungen; KNORPEL, GELENK-/Pathophysiologie; RINDER; DOSIS-WIRKUNGSBEZIEHUNG, ARZNEIMITTEL-; ENDOPEPTIDASEN/*Stoffwechsel; EXTRAZELLULÄRE MATRIXPROTEINE/*; GLYCOSAMINO-GLYCANE/Stoffwechsel; HEXOSAMINE/*Pharmakologie; INTERLEUKIN-1/Pharmakologie; LECTINE, C-TYP-; PROTEOGLYCANE/Arzneimittelwirkungen; PROTEOGLYCANE/Stoffwechsel; ZEITFAKTOREN
TE: | Aggrecans; Extracellular Matrix Proteins; Glycosaminoglycans; Hexosamines; Interleukin-1; Lectins, C-Type; Proteoglycans; mannosamine/2636-92-2; Endopeptidases/E.C. 3.4.-; aggrecanase/E.C. 3.4.99.-
CR: | 2636-92-2; E.C. 3.4.-; E.C. 3.4.99.-
AB: | The enzymatic processes underlying the degradation of aggrecan in cartilage and the corresponding changes in the biomechanical properties of the tissue are an important part of the pathophysiology of osteoarthritis. Recent studies have demonstrated that the hexosamines glucosamine (GlcN) and mannosamine (ManN) can inhibit aggrecanase-mediated cleavage of aggrecan in IL-1-treated cartilage cultures. The term aggrecanase describes two or more members of the ADAMTS family of metalloproteinases whose glutamyl endopeptidase activity is known to be responsible for much of the aggrecan degradation seen in human arthritides. In this study we examined the effect of ManN and GlcN on aggrecanase-mediated degradation of aggrecan induced by IL-1alpha and the corresponding tissue mechanical properties in newborn bovine articular cartilage. After 6 days of culture in 10 ng/ml IL-1 plus ManN, mechanical testing of explants in confined compression demonstrated that ManN inhibited the IL-1alpha-induced degradation in tissue equilibrium modulus, dynamic stiffness, streaming potential, and hydraulic permeability, in a dose-dependent fashion, with peak inhibition ( approximately 75-100% inhibition) reached by a concentration of 1.35 mM. Aggrecan from explants cultured in IL-1 was found by Western analysis to be almost entirely processed down to the G1-NITEGE(373) end product. Addition of ManN or GlcN was found to produce 75-90% inhibition of this cleavage, but the proportion of aggrecan remaining in the tissue which was cleaved at aggrecanase sites in the chondroitin sulfate (CS)-rich region (Glu(1501) and Glu(1687)) was higher than with IL-1 alone. This result suggests that the preservation of mechanical properties by hexosamines in explants is primarily due to inhibition of cleavage at the Glu(373) site in the interglobular domain. While the precise mechanism by which hexosamines function in this system is unclear, the present analysis suggests that the mechanical properties examined may be predominantly a function of electrostatic repulsion due to the charged CS chains in the tightly packed repetitive sequences of the CS-1 region. - CNOTE: Copyright 2000 Academic Press.

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