High mobility group box-1 (HMGB-1) in osteoarthritic cartilage.

OBJECTIVES:Nucleosomal high mobility group box-1 (HMGB-1) is translocated and released from necrotic and activated cells as an endogenous danger signal (alarmin) and cytokine. It was hypothesised that it plays a role in osteoarthritis (OA). characterised by cellular activation, inflammation and enchondral bone formation. METHODS:Bovine knee joint samples, collected from culled animals, were scored using histologic/histochemical grading to intact looking, mild, moderate or severe and immunohistochemically stained for HMGB-1. Chondrocyte pellets, produced from human bone marrow-derived mesenchymal stem cells and stimulated with tumour necrosis factor-a (TNF-alpha), were similarly stained. RESULTS:In healthy looking OA cartilage chondrocyte nuclei were usually HMGB-1 negative and in mild OA staining was restricted to nuclei. In moderate OA lesions HMGB-1 was also seen in the cytoplasm and occasionally pericellular matrix and in severe OA lesions often also in intra- and inter-territorial matrix. The tidemark in healthy cartilage did not contain HMGB-1, which however was seen at this interface as linear deposits even in intact-looking and mild OA lesions, as multiple wave-like deposits in moderate and as heavy granular deposits in severe lesions. TNF-alpha stimulation of chondrocytes caused translocation of HMGB-1 from the nucleus to the cytoplasm. CONCLUSIONS:In resting chondrocytes tight nucleosomal HMGB-1 binding might cause steric hindrance of immunostaining. TNF-alpha- or OA-mediated activation leads to nuclear staining and cytoplasmic translocation. Advancing OA leads to increasingly intense extra-/pericellular deposition of HMGB-1 alarmin, indicating local chondrocyte activation and/or necrosis. In particular, HMGB-1 at the tidemark might play a role in the pathological thickening of subchondral bone plate/osteophyte formation.

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