Strontium ranelate increases cartilage matrix formation

Based on previous studies showing that strontium ranelate (S12911) modulate s bone loss in osteoporosis, it could be hypothesized that this drug also i s effective on cartilage degradation in osteoarthritis (OA). This was inves tigated in vitro on normal and OA human chondrocytes treated or not treated with interleukin-1 beta (IL-1 beta). This model mimics, in vitro, the imba lance between chondroformation and chondroresorption processes observed in vivo in OA cartilage. Chondrocytes were isolated from cartilage by enzymati c digestion and cultured for 24-72 h with 10(-4)-10(-3) M strontium ranelat e, 10(-3) M calcium ranelate, or 2 . 10(-3) M SrCl2 with or without IL-1 be ta or insulin-like growth factor I (IGF-I). Stromelysin activity and strome lysin quantitation were assayed by spectrofluorometry and enzyme amplified sensitivity immunoassay (EASIA), respectively. Proteoglycans (PG) were quan tified using a radioimmunoassay. Newly synthesized glycosaminoglycans (GAGs ) were quantified by labeled sulfate ((Na2SO4)-S-35) incorporation. This me thod allowed the PG size after exclusion chromatography to be determined. S trontium ranelate, calcium ranelate, and SrCl2 did not modify stromelysin s ynthesis even in the presence of IL-1 beta. Calcium ranelate induced strome lysin activation whereas strontium compounds were ineffective. Strontium ra nelate and SrCl2 both strongly stimulated PG production suggesting an ionic effect of strontium independent of the organic moiety. Moreover, 10(-3) M strontium ranelate increased the stimulatory effect of IGF-I (10(-9) M) on PG synthesis but did not reverse the inhibitory effect of IL-1 beta. Stront ium ranelate strongly stimulates human cartilage matrix formation in vitro by a direct ionic effect without stimulating the chondroresorption processe s, This finding provides a preclinical basis for in vivo testing of stronti um ranelate in OA.