Effects of low-dose, noncytotoxic, intraarticular liposomal clodronate on development of erosions and proteoglycan loss in established antigen-induced arthritis in rabbits

Objective. To assess the clinical and histologic effects of an intraarticul ar application of low-dose (noncytotoxic) liposomal clodronate in establish ed antigen-induced monarthritis (AIA) in rabbits. Methods. AIA was monitored by assessments of joint swelling, C-reactive pro tein levels, and radiographic changes in 17 NZW rabbits for 8 weeks during the course of weekly intraarticular injections of liposomal clodronate (0.1 45 mg/injection, low dose) or "empty" liposomes. The contralateral knee was injected with liposome buffer alone as the control. End-point analyses inc luded macroscopic joint examination, immuno- and TUNEL staining, Safranin O staining/microspectrophotometry, and tumor necrosis factor alpha (TNF alph a) 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) TNF alpha, lining cell hyperplasia, and levels of RAM-11+ ma crophages were low in the synovium of the liposomal clodronate treatment gr oup, but the proportion of apoptotic lining cells was not affected. The rad iologic score was low at the end of weeks 2 and 4, but at 8 weeks, no diffe rence, compared with controls, was found in pannus formation or in the exte nt of joint erosion; also, joint swelling was higher than before initiation of treatment. Injections of liposomal clodronate prevented cartilage prote oglycan loss, which was significant in the superficial zone only. TACE acti vity was not inhibited by clodronate. Conclusion. Liposomal clodronate had temporary antiinflammatory and antiero sive 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 TNF alpha production and processing in the syn ovium.