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.
Musculoskeletal Research Group, University of Liverpool Veterinary Teaching Hospital, Leahurst, Neston, Wirral CH647TE, United Kingdom. e.garvican@knac.com
Elaine R
ER
Garvican
Anne
A
Vaughan-Thomas
Colette
C
Redmond
Natalie
N
Gabriel
Peter D
PD
Clegg
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