Role of nitric oxide in the inhibition of BMP-2-mediated stimulation of proteoglycan synthesis in articular cartilage

Objective: Bone morphogenetic protein-2 (BMP-2)-mediated stimulation of art icular cartilage proteoglycan (PG) synthesis is suppressed in arthritic mur ine knee joints and by interleukin-1 (IL-7). The goal of this study was to investigate whether the gaseous mediator nitric oxide (NO) plays a crucial role in the inhibition of BMP-2 effects by IL-l. Methods: Bone morphogenetic protein-2 alone or in combination with IL-l was injected into the right knee joint of wild-type and NOS2 deficient C57Bl/6 x129/Sv mice. Proteoglycan synthesis was measured ex vivo by incorporation of S-35-sulfate on day 1, 2 and 3 after injection. To study the role of NO in the inhibition BMP-2-mediated stimulation of PG synthesis in arthritic j oints, BMP-2 was injected intra-articularly in the joints of wild-type and NOS2 deficient mice with zymosan-induced arthritis. To check for NOS2 defic iency, NO production was measured in conditioned medium after challenge of patellae with surrounding tissue with IL-1. Results: BMP-2 potently stimulated proteoglycan synthesis in articular cart ilage of normal knees (up to 4-fold) but not in arthritic knees. Go-injecti on of BMP-P with tumor necrosis factor a had no effect on BMP-2-mediated st imulation of PG synthesis but co-injection with IL-1 a resulted in a nearly total inhibition of BMP-2-mediated stimulation. In contrast, in NOS2 defic ient mice IL-1 had no effect on BMP-2-mediated stimulation of PG synthesis. However. injection of BMP-2 into arthritic knee joints of NOS2 knock out m ice did not result in significant stimulation of PG synthesis. Conclusions: In this study we show that NO plays a role in the inhibition o f BMP-2-mediated stimulation of PG synthesis by IL-l. However, NO, or at le ast NOS2, plays no dominant role in the inhibition of BMP-2 effects in arth ritic knee joints. (C) 2000 OsteoArthritis Research Society international.