CD11c+ macrophages and levels of TNF- and MMP-3 are increased in synovial and adipose tissues of osteoarthritic mice with hyperlipidaemia

To understand more clearly the link between osteoarthritis and hyperlipidaemia, we investigated the inflammatory macrophage subsets and macrophage-regulated matrix metalloprotease-3 (MMP-3) and A disintegrin and metalloprotease with thrombospondin motifs-4 (ADAMTS4) in synovial (ST) and adipose tissues (AT) of osteoarthritic mice with hyperlipidaemia (STR/Ort). CD11c(+)F4/80(+)CD11b(+) macrophage populations in the ST and AT of 9-month-old STR/Ort and C57BL/6J mice were characterized and compared by flow cytometry and real-time polymerase chain reaction (PCR) analyses. Expression of tumour necrosis factor (TNF)-, MMP-3 and ADAMTS4, and the response of these factors to anionic liposomal clodronate induced-macrophage depletion were also evaluated by real-time PCR. Expression of TNF- in CD11c(+) cells, which were isolated by magnetic beads, was compared to CD11c(-) cells. In addition, the effect of TNF- on cultured synovial fibroblasts and adipocytes was investigated. CD11c(+)F4/80(+)CD11b(+) macrophages were increased in ST and AT of STR/Ort mice. The CD11c(+) cell fraction highly expressed TNF-. Expression of TNF- and MMP3 was increased in ST and AT, and was decreased upon macrophage depletion. TNF- treatment of cultured synovial fibroblasts and adipocytes markedly up-regulated MMP-3. CD11c(+)F4/80(+)CD11b(+) macrophages were identified as a common inflammatory subset in the AT and ST of STR/Ort mice with hyperlipidaemia. The induction of inflammation in AT and ST may be part of a common mechanism that regulates MMP3 expression through TNF-. Our findings suggest that increased numbers of CD11c(+) macrophages and elevated levels of TNF- and MMP-3 in AT and ST may explain the relationship between hyperlipidaemia and OA.