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trioglitazone greatly inhibited inflammatorycytokine expression, inhibited proteoglycandegradation, MMP-1, MMP-13 and17, 18interleukin-1β production.To look at the role of PPAR-γ agonists onthe angiogenic response following ACLrupture and its effect on secondary jointstabilizing structures, rabbits were given alow dose of 5 mg/kg /day of rosiglitazonefor four weeks then had their MCLs CD-31and SMA volumes measured. This dose waschosen to see if levels less than 30 mg/kgused in another in vivo osteoarthritic guineapig model study would be an effectivetreatment. 21 No rabbit had any ACL injuryprior to surgery or injections. Quantificationof the vascularity in the MCLs showeda significant 3-fold increase in vascularvolume as identified by the volumetric CD-31 antibody label in the ACL transectedknees versus controls. When looking atthe effects of the rosiglitazone treatment,the vascular volumes of the treated ACLtransected MCL was reduced to nearcontrol MCL levels. Overall, rosiglitazonehas the ability to limit excess vascularendothelium development in the MCL afterACL transection.Quantification of the SMA volumes in theMCLs by volumetric SMA antibody labellingwas also performed. Rosiglitazone causeda reduction in SMA volume over untreatedACL ruptured knees. An unexpected findingin this study compared to other studies wasthe similarity between SMA volumes in ACLruptured MCLs and non-operated controlMCLs. Another unexpected finding was thatthe control MCLs had a much greater SMAvolume than the rosiglitazone treated MCLs,while CD-31 volumes in these groups weresimilar. A possible reason for these findingscould be that the rosiglitazone treatmentmay affect the production of MMP-13 andinterleukin-1β differently. In one study, thePPAR-γ agonist pioglitazone was shownto decrease interleukin-1β and MMP-13. 33Interleukin-1β is an angiogenic initiatoreffecting endothelial cell production. MMP-13 is a factor released from endothelialcells, which plays a role in the degradationof fibrous collagens, facilitating vascularsmooth muscle and adventitial cellmigration and proliferation. If rosiglitazoneaffects MMP-13 more than interleukin-1βthis will lead to decreased smooth muscleproduction. Decreased levels of smoothmuscle may contribute to endothelialdysfunction and decreased responsivenessof MCL vasculature, which has been foundin ACL ruptured osteoarthritis models. 34Future studies with increased subjects pergroup, varying dosages of rosiglitazone andmeasurement of markers for interleukin-1βand MMP-13 need to be conducted to gaina better understanding of the mechanismsthat are occurring.This study has two inherent weaknesses,which can confound the results obtained.First, there are only two subjects per group,which is quite low compared to a numberof other rabbit studies conducted. 10, 34 Inthose cases, there were usually minimumsof 6 rabbits per group. The second limitationwas the use of the contralateral MCL in therosiglitazone treated rabbits. Due to thebudgetary constraints of the study, the costincurred to treat separate control rabbitswith rosiglitazone and increased subjects pergroup would not have been feasible.Based on our results, it seems that therosiglitazone treatment has a significantimpact on decreasing angiogenic activityin the MCL of the ACL ruptured rabbitmodel. Due to the reduced angiogenicactivity, the use of this PPAR-γ agonist couldprove beneficial in reducing the negativeeffects angiogenesis has on the structuraland physiological properties of the MCLin response to an ACL ruptured humanknee. Rosiglitazone may prove beneficial inother secondary stabilizing structures andcomponents in the knee. Further studieslooking at the effects of rosiglitazone onthese structures by using RT-PCR, cartilageand meniscal grading, blood flow imaging ofthe MCL and biomechanical testing of theMCL are thus warranted.Overall, quantification of the vasculature ofthe MCL of ACL ruptured and rosiglitazonetreated knees by confocal microscopy hasshown that rosiglitazone significantlydecreased the angiogenic and physiologicaldegeneration of the MCL. Vascularendothelium volumes returned to nearcontrol levels in rosiglitazone treated MCLsin ACL ruptured knees while vascular smoothmuscle volume was lower in rosiglitazonetreated versus non – treated MCLs.ACKNOWLEDGEMENTSThe authors wish to thank the CanadianInstitute for Health Research (CIHR) forproviding the operating funds for thisproject. The authors also thank Tim Leonardfrom the Human Performance Laboratoryat the University of Calgary for histechnical support provided for the confocalmicroscope.REFERENCES1. 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