title: Effects of low-dose, noncytotoxic, intraarticular liposomal clodronate on development of erosions and proteoglycan loss in established antigen-induced arthritis in rabbits.
abstract: OBJECTIVE
  To assess the clinical and histologic effects of an intraarticular application of low-dose (non-cytotoxic) liposomal clodronate in established antigen-induced monarthritis (AIA) in rabbits.
  
  
  METHODS
  AIA was monitored by assessments of joint swelling, C-reactive protein levels, and radiographic changes in 17 NZW rabbits for 8 weeks during the course of weekly intraarticular injections of liposomal clodronate (0.145 mg/injection, low dose) or "empty" liposomes. The contralateral knee was injected with liposome buffer alone as the control. End-point analyses included macroscopic joint examination, immuno- and TUNEL staining, Safranin O staining/microspectrophotometry, and tumor necrosis factor alpha (TNFalpha) convertase enzyme (TACE) inhibition assay.
  
  
  RESULTS
  Liposomal clodronate-treated rabbits showed a reduction and delay in joint swelling during the first 3 injections. Expression of matrix-bound (solubilized) TNFalpha, lining cell hyperplasia, and levels of RAM-11+ macrophages were low in the synovium of the liposomal clodronate treatment group, but the proportion of apoptotic lining cells was not affected. The radiologic score was low at the end of weeks 2 and 4, but at 8 weeks, no difference, compared with controls, was found in pannus formation or in the extent of joint erosion; also, joint swelling was higher than before initiation of treatment. Injections of liposomal clodronate prevented cartilage proteoglycan loss, which was significant in the superficial zone only. TACE activity was not inhibited by clodronate.
  
  
  CONCLUSIONS
  Liposomal clodronate had temporary antiinflammatory and antierosive effects on established AIA in rabbits. Over the long-term, the loss of cartilage proteoglycans was halted. This observed treatment effect may be related to the inhibition of TNFalpha production and processing in the synovium.
authors.affiliation: University of Helsinki, Finland.
authors.forename: A
authors.initials: A
authors.lastname: Ceponis
authors.forename: E
authors.initials: E
authors.lastname: Waris
authors.forename: J
authors.initials: J
authors.lastname: Mönkkönen
authors.forename: L
authors.initials: L
authors.lastname: Laasonen
authors.forename: M
authors.initials: M
authors.lastname: Hyttinen
authors.forename: S A
authors.initials: SA
authors.lastname: Solovieva
authors.forename: R
authors.initials: R
authors.lastname: Hanemaaijer
authors.forename: A
authors.initials: A
authors.lastname: Bitsch
authors.forename: Y T
authors.initials: YT
authors.lastname: Konttinen
mesh_terms: D051722:ADAM Proteins; D000072198:ADAM17 Protein; D000818:Animals; D000941:Antigens; D017209:Apoptosis; D001168:Arthritis / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D001835:Body Weight / Q000187:drug effects; D002097:C-Reactive Protein / Q000378:metabolism; D002356:Cartilage / Q000187:drug effects / Q000378:metabolism; D004002:Clodronic Acid / Q000008:administration & dosage / Q000494:pharmacology*; D007270:Injections, Intra-Articular; D008081:Liposomes; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors; D015591:Microspectrophotometry; D010619:Phenazines / Q000737:chemistry; D011509:Proteoglycans / Q000378:metabolism*; D011817:Rabbits; D013583:Synovial Membrane / Q000378:metabolism / Q000473:pathology
chemical_list: D000941:Antigens; D008081:Liposomes; D010619:Phenazines; D011509:Proteoglycans; D004002:Clodronic Acid; D002097:C-Reactive Protein; D051722:ADAM Proteins; D008666:Metalloendopeptidases; D000072198:ADAM17 Protein; C009195:safranine T