Arg-Gly-Asp-Ser peptide analogs suppress cartilage chondrolytic activities of integrin-binding and nonbinding fibronectin fragments.
We have reported that Fn fragments (Fn-f), which have been detected in synovial fluids of osteoarthritis and rheumatoid arthritis patients, can potently cause cartilage chondrolysis and depress proteoglycan (PG) synthesis in cartilage tissue cultured as explants. Amino-terminal 29-kDa, gelatin-binding 50-kDa, and integrin-binding 140-kDa Fn-f are active. In order to investigate the mode of action and devise means of blocking the damage mediated by all Fn-f, we have tested the effects of various analogs resembling the integrin binding sequence, Arg-Gly-Asp-Ser, on blocking Fn-f-mediated chondrolysis. The analog peptides, Gly-Arg-Ala-Asp-Ser-Pro-Lys and Arg-Phe-Asp-Ser, at concentrations as low as 1 microM, blocked the effects of all three Fn-f on cartilage degradation, while the native sequence peptide, Arg-Gly-Asp-Ser, had very low Fn-f-blocking activity and by itself caused cartilage damage. Random sequence peptides dissimilar to the analog sequences were inactive as inhibitors as well as was a sequence analog, Phe-Asp-Arg-Ser, related to the Arg-Phe-Asp-Ser inhibitor. The analog inhibitory peptides decreased rates of Fn-f-mediated PG degradation and release from cartilage and decreased Fn-f-mediated PG synthesis depression. The analog inhibitory peptides alone had no detectable effect on cartilage PG degradation or PG synthesis rates. These data show that the chondrolytic activities of integrin-binding and nonbinding Fn-f can be blocked by synthetic peptide analogs of the Arg-Gly-Asp-Ser sequence and suggest that these peptides may be useful for blocking other activities of Fn-f.
Homandberg
G A
GA
Department of Biochemistry, Rush Medical College, Rush-Presbyterian-St. Luke's Medical Center, Chicago, Illinois 60612-3864.
Hui
F
F
D000595:Amino Acid Sequence; D000818:Animals; D002356:Cartilage / Q000187:drug effects* / Q000378:metabolism; D002417:Cattle; D016895:Culture Media, Serum-Free; D005353:Fibronectins / Q000494:pharmacology*; D066298:In Vitro Techniques; D016023:Integrins / Q000378:metabolism; D008969:Molecular Sequence Data; D009842:Oligopeptides / Q000737:chemistry*; D010446:Peptide Fragments / Q000494:pharmacology*; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology*; D011509:Proteoglycans / Q000378:metabolism; D013431:Sulfates / Q000378:metabolism
D016895:Culture Media, Serum-Free; D005353:Fibronectins; D016023:Integrins; D009842:Oligopeptides; D010446:Peptide Fragments; D010975:Platelet Aggregation Inhibitors; D011509:Proteoglycans; D013431:Sulfates; C046617:arginyl-glycyl-aspartyl-serine