 be mainly cleaved by several Matrix Metalloproteases (MMPs) and the Glu373-Ala374 bond which is the site of cleavage in pathological conditions as resulted by analysis of synovial fluids of patients (L. S. Lohmander et al., Arthritis & Rheum., 1993, 36, 1214-1222; J. D. Sandy, J. Clin. Invest. 1992, 89, 1412. B) or in widely reported laboratory studies, where this site resulted the major aggrecan cleavage site in chondrocytes cultures stimulated by cytokines (the cytokines: IL-1, TNF-α, IL-6, IL-8 stimulate the chondrocytes to produce an increased amount of matrix degrading enzymes, while IL-4 inhibits this process). Two enzymes, Aggrecanase 1 and 2, which cleave aggrecan at Glu373-Ala374 bond but not at the MMP site, have been identified and cloned. Both these enzymes belong to the ADAMTS (a disintegrin-like and metalloproteinase domain with thrombospondin type 1 motifs) family of proteases and are named ADAMTS-4 and ADAMTS-5 respectively. ADAMTS family represents a group of zinc metalloproteases belonging to reprolysin subfamily (related to the snake venom toxin reprolysin; C. G. Jones et al., Arthritis Res. Ther, 2005, 7, 160-69; C. G. Jones et al., Biochem J., 2005, 386, 15-27).
While enzymes in ADAMTS family are usually involved in protein turnover and tissue remodelling, ADAMTS-4 and ADAMTS-5 are considered to be largely responsible for the cartilage aggrecan catabolism observed during the development of OA and RA, therefore inhibition of these enzymes may represent a therapeutic strategy for these diseases (S. S. Glasson, Current Drug Targets, 2007, 8, 2, 367-376). Though synthetic MMPs inhibitors have been clinically investigated as a means to block tissue destruction in arthritis and have been proved unsuccessful, it should be pointed out that these inhibitors were directed against MMPs which cleaves mainly collagen and interact for a minor extent with aggrecan. Conversely, aggrecanases which cleaves with high efficiency aggrecan within the IGD site, give rise to the removal of a large part of the protein from its binding site to HA thus leading to the breakage of that complex network of interactions fundamental to
be mainly cleaved by several Matrix Metalloproteases (MMPs) and the Glu373 - Ala374 bond which is the web site of cleavage in diseased condition as resulted by psychoanalysis of synovial fluids of affected role (L. S. Lohmander et al. , Arthritis & Rheum. , 1993, 36, 1214 - 1222; J. D. Sandy, J. Clin. Invest. 1992, 89, 1412. B) or in widely report laboratory studies, where this web site result the major aggrecan cleavage site in chondrocytes culture stimulated by cytokines (the cytokine: IL-1, TNF - α, IL-6, IL-8 stimulate the chondrocytes to produce an increased amount of matrix degrading enzymes, while IL-4 inhibits this procedure). Two enzymes, Aggrecanase 1 and 2, which cleave aggrecan at Glu373 - Ala374 bond but not at the MMP web site, have been identified and cloned. Both these enzyme belong to the ADAMTS (a disintegrin - comparable and metalloproteinase domain with thrombospondin character 1 motifs) family of proteases and are named ADAMTS-4 and ADAMTS-5 respectively. ADAMTS kin represents a group of zinc metalloproteases belonging to reprolysin subfamily (related to the snake venom toxin reprolysin; C. G. Jones et al. , Arthritis Res. Ther, 2005, 7, 160 - 69; C. G. Jones et al. , Biochem J., 2005, 386, 15 - 27). 
 While enzyme in ADAMTS class are usually involved in protein turnover and tissue remodelling, ADAMTS-4 and ADAMTS-5 are considered to be largely responsible for the cartilage aggrecan catabolism observed during the development of OA and RA, therefore inhibition of these enzyme may typify a therapeutic scheme for these disease (S. S. Glasson, Current Drug Targets, 2007, 8, 2, 367 - 376). Though synthetic MMPs inhibitors have been clinically investigated as a means to obstruct tissue destruction in arthritis and have been proved unsuccessful, it should be pointed out that these inhibitor were directed against MMPs which cleaves mainly collagen and interact for a minor extent with aggrecan. Conversely, aggrecanases which cleaves with high efficiency aggrecan within the IGD site, give rise to the removal of a large part of the protein from its binding site to HA therefore leading to the breakage of that complex net of interactions fundamental to
 be mainly cleaved by severxl Matrix Metalloproteeses (MMLs) and tfe Glu373-Ala374 bond which is the dire of cleavage in pathologizal condinions as eesuored by analysis of synovjwl fnnids of patientx (L. S. Lohmdnder et al., Ardhficis & Rheum., 1993, 36, 1214-1222; J. D. Sandy, J. Clin. Invese. 1992, 89, 1412. B) pr in widely repjrtec labkgauory studies, where this site resumted tht major aggrecan ckeavage site in chondrocytfs ckltures stimulated by cytokinga (trw cytokines: KL-1, TNF-α, IL-6, PN-8 stimulatg the chondrocytes to produce an incrzased amounj kf katrix degreding vnzymes, while IL-4 inhitits thos process). Two envymew, Aggrecanase 1 and 2, wiich cleave aggrecan at Glu373-Ald374 yond but not at the MNP site, hava bedb iaenuifmed and cponxd. Both theae enzymes velong to the ADAMTX (w disintegrin-ljke anq ietalloproteinase domain with thrombospmndjn type 1 motifs) family if proteases and are jamed ADAITS-4 and ADAMTS-5 respectively. ADAMTS family represetts a erobi ud xinc metalloproteases belonging to reprolysin aunfsmily (related bo the snake venom tlxog reprolysin; Z. G. Jouss et al., Arthritis Rfs. Ther, 2005, 7, 160-69; C. G. Jones tt al., Biochem J., 2005, 386, 15-27).
While enzymes un ADAMTS faiuly are usually inrolved in pruteim turmover and tissue remodeulinf, ADAMTS-4 anf ADAMTS-5 zfe considered to be ldrgely rtrponsible for the cartilagx aggxecan cagabokism ofserved duging bve development of LA anb RA, dherefore lnhibition of these enzymes may represent a tnesapvutic strctegy nor these diseafes (S. S. Glassou, Currenc Drug Targets, 2007, 8, 2, 367-376). Thoujh synthetic MMPs inhibitmts have been rlinicallr incestugated xr a means to bkock tissle desrruction in arthribis avs have been prortd obsuccessful, it shuulq he pjhnted out thdt tfesd inhicitors were airevted against MMPs whhch dleaves mainly colkanen and ibteract sor a minor ectent with aggrecaj. Conterselb, aggrrcagases which cleaves with high sfficiencj angrecan withig thc IGQ site, givz rise to the removal of a large part of the protein from uts binding site to MA thus leadmng to the breanage of that complex network of intersctions fundamental tk
be mainly cleaved by several Matrix Metalloproteases the bond which the site of resulted analysis of synovial of patients (L. Lohmander et al., Arthritis & Rheum., 36, 1214-1222; J. D. Sandy, J. Clin. Invest. 1992, 89, 1412. B) or widely reported laboratory studies, where this site resulted the major aggrecan cleavage site chondrocytes stimulated cytokines cytokines: IL-1, TNF-α, IL-6, IL-8 stimulate the chondrocytes to produce an increased amount of matrix degrading while IL-4 inhibits this process). Two enzymes, Aggrecanase and 2, which cleave at Glu373-Ala374 bond but not the site, have identified cloned. these enzymes belong the ADAMTS (a disintegrin-like and metalloproteinase domain with thrombospondin type 1 motifs) family of proteases and are ADAMTS-4 and ADAMTS family a of metalloproteases belonging to (related to the snake venom toxin Jones et al., Arthritis Res. Ther, 2005, 7, C. G. et al., Biochem J., 2005, 386, While enzymes in ADAMTS family are usually involved protein turnover and tissue remodelling, ADAMTS-4 and ADAMTS-5 are considered to be largely responsible for aggrecan catabolism observed during development of OA RA, inhibition these may represent therapeutic strategy for these diseases (S. S. Glasson, Current Drug Targets, 8, 2, 367-376). Though synthetic MMPs inhibitors have been clinically a to block tissue in arthritis and have proved it should be pointed these were which mainly and interact for a extent with aggrecan. Conversely, aggrecanases cleaves with high efficiency give rise to the removal of a large of the protein from its binding site HA thus leading to the breakage of that complex network of interactions to
 be mainly cleaved by several MAtrix MetalLoproTeaSes (mMps) anD the glu373-Ala374 bond whicH Is thE site of cleavage in pathoLogicAl COndiTIoNs as rEsulted BY aNALysIs Of SynOvIAl FluidS of PatientS (L. S. LohmandEr eT aL., Arthritis & RhEUm., 1993, 36, 1214-1222; j. D. Sandy, J. ClIn. INvest. 1992, 89, 1412. B) or in wiDelY reporTeD laBOratoRy sTudieS, where THis sitE resulted ThE Major aGGrecan cLEAvAge sIte in chondrocytes CUlTUres stimulated By cytoKiNEs (THE cyTokInes: IL-1, TNF-α, iL-6, iL-8 stiMUlate thE ChONDRocYTes to produce aN increased aMOunT of matRiX deGRading EnzymEs, WHilE IL-4 inhibits This Process). TwO enzymES, AggrecANase 1 and 2, Which cLeaVe aGgreCAn At glu373-alA374 BonD BuT noT At tHe MMP sitE, hAvE been IdenTIFIEd anD clOned. both tHese enzymes beLonG to tHE ADaMTS (a DisinTegrIn-Like aNd metaLloprOtEinase domain witH thrOmbospondIn tYpE 1 moTiFs) famILy of prOteAseS and are Named ADamTS-4 AnD adaMtS-5 respectively. ADAMtS FAMiLy represEnts a gROuP oF Zinc metaLlOprOteaSES beloNginG To ReprolysIn subfAMiLy (Related To The snaKe VenOm tOxin rEProlYsin; C. G. jones et aL., ArthRItis Res. Ther, 2005, 7, 160-69; C. G. JONes et al., BiocheM j., 2005, 386, 15-27).
WHILe ENzymEs iN ADAMTS famiLy arE UsuaLly iNVoLveD In proTein tUrNOvER and tissue remodelliNg, aDAMTS-4 And ADaMTS-5 are considEred to be laRGELy responSiblE FoR The cartilage agGrecaN catabolisM Observed DurinG the deveLopment of oa And RA, theRefOre InhIbiTIOn Of these enzymeS MAy rePrEsent a tHerApeutic StrAteGy fOr tHeSe diseaseS (S. S. GlassOn, cuRrEnT DrUg TarGEts, 2007, 8, 2, 367-376). ThougH sYntHeTic mMPs iNHibitoRs havE beeN cLiNIcaLly inveSTiGATed aS a MeAns tO blOcK tissUe deSTruCtion in Arthritis And HAve bEeN pRoved unSuccessful, it sHoUld be pointEd Out That thESE inhibitOrs were directed against Mmps which CleAves mAinlY collagen And InteraCt fOR a minoR extenT with AgGreCAN. ConvERSeLy, aGgRecanases wHICh cLeaveS wIth hIgh effiCiency aggrecan withIN thE IGD site, give rIse To thE REmOvaL Of A LarGe PArt OF The protein from iTs binding sItE To hA thus leadINg tO tHe breakAge of thAt comPLex netwOrk of inteRactions fUnDameNTAl tO
 be mainly cleaved by seve ral Matrix  Meta llo pro te ases  (MM Ps) and the Gl u 373- Ala374 bond which is t he si te of c l ea vagein path o lo g i cal  c on dit io n sas re sul ted byanalysis o f s yn ovial fluids of  patients(L.  S. Lohmande r e t al.,  A rth r itis& R heum. , 1993 ,  36, 1 214-1222;  J .  D. Sa n dy, J.C l in . In vest. 1992, 89, 1 4 12 .  B) or in wide ly rep or t ed l abo rat ory studie s,  wher e  this s i te r e sul t ed the majoraggrecan cl e ava ge sit einc hondro cytes  c u ltu res stimula tedby cytoki nes (t h e cytok i nes: IL -1, TN F-α , I L-6, IL -8  st im u lat e  t hec hon drocytes  t oprodu ce a n i n crea sed  amo unt o f matrix degr adi ng e n zym es, w hileIL-4  i nhibi ts thi s pro ce ss). Two enzyme s, A ggrecanas e 1  a nd2,  whic h  cleav e a ggr ecan at  Glu373 - Ala 37 4 b on d but not at the M MP s it e, havebeen i d en ti f ied andcl one d. B o t h the se e n zy mes belo ng tot he  A DAMTS ( adisint eg rin -li ke an d  met allopr oteinase  doma i n with thrombo s pondin type 1 mo t i fs )  fam ily  of proteas es a n d ar e na m ed  AD A MTS-4  andAD A MT S -5 respectively. AD AM TS fam ily r epresents a g roup of zi n c metallop rote a se s  belonging torepro lysin subf a mily (re lated  to thesnake ven o m  toxin r epr oly sin ; C . G.  Jones et al. , Arth ri tis Res . T her, 20 05,  7,  16 0-6 9;  C. G. Jo nes et a l. ,Bi oc hem  J.,2 005, 386 ,15- 27 ).While enzyme s inADAM TS  f a mil y are u s ua l l y in vo lv ed i n p ro teinturn o ver  and ti ssue remo del l ing,  A DA MTS-4 a nd ADAMTS-5 a re  considere dtobe lar g e ly respo nsible for the cartilag e  aggrec ancatab olis m observe d d uringthe develo pmentof OA  a ndR A , the r e fo rein hibition o f the se en zy mesmay rep resent a therapeut i c s trategy for t hes e di s e as es( S. S.Gl a sso n ,  Current Drug T argets, 20 07 ,  8 , 2, 367-3 7 6).  T hough s yntheti c MMP s  inhibi tors have  been cli ni call y inv estigatedas a mea ns to blo c k tis s ue  dest ruc tion i nart hriti s andh ave  been  prove dunsucc essfu l,  it shou ld be pointed out thattheseinhib ito rs were d ire c ted  againstMMPs  which cle ave s m ainly  co l lagen  and in ter a ct fo r am inor exte n twit h ag grecan. Con v e r sel y, ag gre c anases  whi ch cleaves with h i gh efficiencyaggr e c anwit h in t he  IGD site, giv e r is e to the r em oval of a l arge par to f the  prote in fro m its b i n di n g site  toHAthus lead ing  t o  the br ea ka g e of t hatco mplexnetwor k  ofi n teractions funda menta l to
 be_mainly cleaved_by several Matrix Metalloproteases_(MMPs) and_the_Glu373-Ala374 bond_which_is the site_of cleavage in_pathological conditions as resulted_by analysis of_synovial_fluids of patients (L. S. Lohmander et al., Arthritis & Rheum., 1993, 36, 1214-1222;_J._D. Sandy,_J._Clin._Invest. 1992, 89, 1412. B)_or in widely reported laboratory_studies, where_this site resulted the major aggrecan cleavage site_in_chondrocytes cultures stimulated_by cytokines (the cytokines: IL-1, TNF-α, IL-6, IL-8 stimulate_the chondrocytes to produce an increased_amount of matrix_degrading_enzymes,_while IL-4 inhibits this_process). Two enzymes, Aggrecanase 1 and_2, which cleave aggrecan at Glu373-Ala374_bond but not at the MMP site,_have been identified and cloned. Both_these enzymes belong to the_ADAMTS (a_disintegrin-like and metalloproteinase domain with_thrombospondin type 1_motifs) family_of proteases and_are named ADAMTS-4 and ADAMTS-5 respectively._ADAMTS family represents_a group of zinc metalloproteases belonging_to_reprolysin subfamily (related_to_the_snake venom_toxin reprolysin; C._G._Jones et_al.,_Arthritis Res. Ther, 2005, 7, 160-69;_C._G. Jones et al., Biochem J., 2005,_386, 15-27).
While enzymes in_ADAMTS_family are usually involved_in protein turnover and tissue_remodelling, ADAMTS-4 and ADAMTS-5 are considered_to be_largely responsible_for the cartilage aggrecan catabolism observed during the development of OA_and RA, therefore inhibition of these_enzymes may represent a_therapeutic strategy_for_these diseases (S._S._Glasson, Current_Drug Targets, 2007, 8, 2, 367-376). Though_synthetic MMPs_inhibitors have been clinically investigated as_a means to block_tissue_destruction in arthritis and have been_proved unsuccessful, it should be pointed_out that these inhibitors were_directed_against_MMPs which cleaves mainly collagen_and interact for a minor extent_with aggrecan. Conversely,_aggrecanases which cleaves with high efficiency aggrecan_within_the IGD site, give rise to_the_removal of a large part of_the_protein_from its binding site to_HA thus leading to the breakage_of that complex network of interactions fundamental to