In vitro inhibition of aggrecanase activity by tetracyclines and proteoglycan loss from osteoarthritic human articular cartilage

Tetracyclines were reported to slow down the progression of cartilage damage both in an animal model of osteoarthritis (OA) and in humans. In search for the underlying mechanisms we examined whether tetracyclines possess an inhibitory potential on the activity of aggrecanases and inflammatory mediators and can thus prevent proteoglycan (PG) loss from human articular cartilage. In vitro activity of aggrecanase‐1 and ‐2 was recorded in the presence of 1–100 µM tetracycline, minocycline, or doxycyline. Human knee articular cartilage explants were sorted according to the degree of OA and treated for 10 days with tetracycline derivatives in the presence of interleukin‐1 (IL‐1β). Synthesis and loss of PGs, nitric oxide (NO), and prostaglandin E₂ (PGE₂), as well as the viability were determined. Tetracyclines derivatives dose‐dependently inhibited the activities of both aggrecanases in vitro, whereas no inhibitory effect of tetracyclines on any proteoglycanolytic activities within IL‐1β‐treated human cartilage explants were found. Tetracyclines can significantly modulate NO and PGE₂ levels, but have no effect on PG synthesis and loss within the same human cartilage explant cultures. Altogether, our data show that tetracyclines have no inhibitory potential on any proteoglycanolytic activities within mild or moderately affected human OA cartilage at therapeutic achievable plasma levels.