Objective. Chondrocytes produce nitric oxide (NO) and undergo apoptosis in response to exogenous NO. This study sought to examine the relationship between NO synthesis, chondrocyte apoptosis, and the development of cartilage degradation during experimental osteoarthritis (OA). Methods. OA was induced in rabbits by anterior cruciate ligament transection (ACLT). Knees were harvested after 4 weeks and assessed for OA severity and chondrocyte apoptosis. Conditioned media from cultured cartilage explants were analyzed for nitrite content. Cartilage sections were analyzed by immunohisto-chemistry for the presence of nitrotyrosine. Results. All ACLT knees demonstrated osteoar-thritic changes. Conditioned media from ACLT cartilage organ cultures contained higher levels of nitrite as compared with cartilage samples from the nonoperated side or from rabbits that had not received ACLT. Cultures of specific areas of cartilage from ACLT knees showed high levels of NO production in the medial femoral and medial tibia1 cartilage. Approximately 28.7% of chondrocytes isolated from ACLT cartilage and 6.7% of chondrocytes from cartilage of the nonoperated side underwent apoptosis. In situ staining demonstrated apoptotic cells in the superficial and middle zones of ACLT cartilage. A high number of apoptotic cells was present at the pannus-cartilage junction. In control cartilage, the superficial zone contained a small number of cells in apoptosis. The prevalence of apoptotic cells Supported by NIH grants AG-07996 and AR-42438.

These results suggest that one of the mechanism of therapeutic effect of HA is down-regulation of MMP-3 and IL-1beta in synovium during early development of OA.

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Hypertrophic chondrocytes in osteophytes express VEGF and this can promote vascular invasion of cartilage. The presence of TUNEL-positive cells shows a similar distribution as nitrotyrosine immunoreactivity during all phases of osteophyte development, suggesting that NO production and chondrocyte death are related events in osteophyte formation.

Objective. To examine the pathologic changes in meniscus tissue during experimental osteoarthritis (OA) and to determine the relationship between nitric oxide (NO) synthesis, apoptosis, and meniscus degradation.Methods. OA was induced in rabbits by anterior cruciate ligament (ACL) transection. Knees were harvested after 9 weeks and assessed for OA severity. Menisci were subjected to histologic, immunohistochemical, and electron microscopic analyses for the presence of nitrotyrosine and apoptosis. Menisci were also cultured for analysis of NO production.Results. All menisci from joints with ACL transection demonstrated degenerative changes. A high number of apoptotic cells was present in the medial part of menisci, which contains chondrocytic cells. Menisci from nonoperated contralateral knees contained only small numbers of cells in apoptosis. Conditioned media from meniscus cultures contained similarly elevated levels of nitrite as cartilage cultures from the same arthritic knees. Nitrotyrosine immunoreactivity, an indicator of in vivo NO production, was prominent in menisci from knees with ACL transection. In addition, menisci from normal knees produced high levels of NO in response to in vitro stimulation with interleukin-1␤ or lipopolysaccharide.Conclusion. These observations suggest that pathologic changes in menisci are a regular feature of experimentally induced OA and are associated with NO production and meniscus cell apoptosis.