MMP-mediated collagen breakdown induced by activated protein C in equine cartilage is reduced by corticosteroids.
The plasma serine protease activated protein C (APC) is synthesized by human chondrocytes at sites of pathological cartilage fibrillation. APC levels are increased in osteoarthritis (OA) synovial fluid, and in vitro APC has been shown to synergize with interleukin-1beta (IL-1) to promote degradation from ovine cartilage. A model of equine cartilage degradation was established and used to explore corticosteroid activities. Intraarticular corticosteroids are a commonly prescribed treatment for joint disease, however their role in disease modification remains unclear. APC synergized with IL-1 or tumor necrosis factor-alpha (TNFalpha), promoting significant collagen degradation from equine cartilage explants within 4 days, but did not augment glycoaminoglycan (GAG) release. APC activated pro-matrix metalloproteinases (MMP)-2 but not pro-MMP-9, as assessed by gelatin zymography. APC did not directly activate pro-MMP-13. Dexamethasone, triamcinolone, and methylprednisolone acetate (MPA) were evaluated at concentrations between 10(- 5)M and 10(-10)M. High concentrations significantly increased GAG release from IL-1+APC-treated explants. With the exception of MPA at 10(-10)M, all concentrations of corticosteroids caused significant decreases in IL-1+APC-driven hydroxyproline loss. Treatment with corticosteroids suppressed expression of MMP-1, -3, and -13 mRNA. The collagenolysis associated with IL-1+APC synergy, and the inhibition of this effect by corticosteroids may involve gelatinase activation and downregulation of MMP expression, respectively.
Garvican
Elaine R
ER
Musculoskeletal Research Group, University of Liverpool Veterinary Teaching Hospital, Leahurst, Neston, Wirral CH647TE, United Kingdom. e.garvican@knac.com
Vaughan-Thomas
Anne
A
Redmond
Colette
C
Gabriel
Natalie
N
Clegg
Peter D
PD
D000305:Adrenal Cortex Hormones / Q000008:administration & dosage*; D000818:Animals; D002356:Cartilage / Q000187:drug effects / Q000378:metabolism*; D003094:Collagen / Q000378:metabolism*; D003907:Dexamethasone / Q000008:administration & dosage; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D005938:Glucocorticoids / Q000008:administration & dosage; D006025:Glycosaminoglycans / Q000378:metabolism; D006736:Horses; D006801:Humans; D006909:Hydroxyproline / Q000037:antagonists & inhibitors; D066298:In Vitro Techniques; D007375:Interleukin-1 / Q000494:pharmacology; D020782:Matrix Metalloproteinases / Q000235:genetics / Q000378:metabolism*; D008775:Methylprednisolone / Q000008:administration & dosage / Q000031:analogs & derivatives; D000077555:Methylprednisolone Acetate; D011486:Protein C / Q000008:administration & dosage / Q000494:pharmacology*; D012333:RNA, Messenger / Q000037:antagonists & inhibitors; D011994:Recombinant Proteins / Q000494:pharmacology; D057057:Serine Proteases / Q000008:administration & dosage / Q000494:pharmacology*; D013997:Time Factors; D014221:Triamcinolone / Q000008:administration & dosage / Q000031:analogs & derivatives*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D000305:Adrenal Cortex Hormones; D005938:Glucocorticoids; D006025:Glycosaminoglycans; D007375:Interleukin-1; D011486:Protein C; D012333:RNA, Messenger; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D014221:Triamcinolone; D000077555:Methylprednisolone Acetate; D003907:Dexamethasone; D003094:Collagen; D057057:Serine Proteases; D020782:Matrix Metalloproteinases; D006909:Hydroxyproline; D008775:Methylprednisolone