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MMP-mediated collagen breakdown induced by activated protein C in equine cartilage is reduced by corticosteroids.
Abstract: 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.
Publication Date: 2009-09-25 PubMed ID: 19777546DOI: 10.1002/jor.21001Google Scholar: Lookup The Equine Research Bank provides access to a large database of publicly available scientific literature. Inclusion in the Research Bank does not imply endorsement of study methods or findings by Mad Barn.
- Journal Article
Summary
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The study investigates the role of activated protein C (APC), a protease produced during cartilage fibrillation conditions, in degrading equine cartilage, and the mitigating effects of corticosteroids. It is found that APC, while working together with certain cytokines, fosters collagen degradation, but does not enhance the release of glycoaminoglycan (GAG). The corticosteroids tested showed indications of suppressing collagen degradation by reducing an enzyme called matrix metalloproteinases (MMP).
Activated Protein C (APC)
- The research highlights the synthesis of the plasma serine protease APC by human chondrocytes in pathological cartilage fibrillation.
- In situations of osteoarthritis, the APC levels are recorded to rise in the synovial fluid, which lubricates the joints.
- The study establishes that APC, in conjunction with either interleukin-1 (IL-1) or tumor necrosis factor-alpha (TNFalpha), provokes significant degradation of collagen from horse cartilage in as short a period as four days.
- However, the same combination does not provoke glycoaminoglycan (GAG) release, a component important in maintaining cartilage strength and resilience.
Role of Matrix Metalloproteinases (MMP)
- APC was found to activate pro-MMP-2 but not pro-MMP-9, essential enzymes in collagen degradation.
- However, no direct activation of pro-MMP-13, another enzyme associated with cartilage breakdown, was observed due to APC.
Effect of Corticosteroids
- The study then evaluated the therapeutic impact of different concentrations of corticosteroids such as dexamethasone, triamcinolone, and methylprednisolone acetate (MPA) on APC-induced cartilage degradation.
- High concentrations of these corticosteroids significantly increased the release of GAG from IL-1+APC-treated explantations or pieces of tissue grown in a culture medium.
- All corticosteroids concentrations, except for MPA at 10(-10)M, provoked significant decrease in IL-1+APC-induced loss of hydroxyproline, an essential component of collagen.
- The corticosteroids also suppressed expression of MMP-1, -3, and -13, which play a key role in collagen degradation.
In summary, the researchers suggested that the degradation of collagen associated with the synergistic effect of IL-1 and APC and the inhibition of this effect by corticosteroids may involve activation and downregulation of MMP expression, respectively.
Cite This Article
APA
Garvican ER, Vaughan-Thomas A, Redmond C, Gabriel N, Clegg PD.
(2009).
MMP-mediated collagen breakdown induced by activated protein C in equine cartilage is reduced by corticosteroids.
J Orthop Res, 28(3), 370-378.
https://doi.org/10.1002/jor.21001 Publication
Researcher Affiliations
- Musculoskeletal Research Group, University of Liverpool Veterinary Teaching Hospital, Leahurst, Neston, Wirral CH647TE, United Kingdom. e.garvican@knac.com
MeSH Terms
- Adrenal Cortex Hormones / administration & dosage
- Animals
- Cartilage / drug effects
- Cartilage / metabolism
- Collagen / metabolism
- Dexamethasone / administration & dosage
- Dose-Response Relationship, Drug
- Drug Synergism
- Glucocorticoids / administration & dosage
- Glycosaminoglycans / metabolism
- Horses
- Humans
- Hydroxyproline / antagonists & inhibitors
- In Vitro Techniques
- Interleukin-1 / pharmacology
- Matrix Metalloproteinases / genetics
- Matrix Metalloproteinases / metabolism
- Methylprednisolone / administration & dosage
- Methylprednisolone / analogs & derivatives
- Methylprednisolone Acetate
- Protein C / administration & dosage
- Protein C / pharmacology
- RNA, Messenger / antagonists & inhibitors
- Recombinant Proteins / pharmacology
- Serine Proteases / administration & dosage
- Serine Proteases / pharmacology
- Time Factors
- Triamcinolone / administration & dosage
- Triamcinolone / analogs & derivatives
- Tumor Necrosis Factor-alpha / pharmacology
Citations
This article has been cited 13 times.- Barton KI, Chung M, Frank CB, Shrive NG, Hart DA. Methylprednisolone acetate mitigates IL1β induced changes in matrix metalloproteinase gene expression in skeletally immature ovine explant knee tissues. Inflamm Res 2021 Jan;70(1):99-107.
- He T, Zhang C, Vedadghavami A, Mehta S, Clark HA, Porter RM, Bajpayee AG. Multi-arm Avidin nano-construct for intra-cartilage delivery of small molecule drugs. J Control Release 2020 Feb;318:109-123.
- Black R, Grodzinsky AJ. Dexamethasone: chondroprotective corticosteroid or catabolic killer?. Eur Cell Mater 2019 Nov 22;38:246-263.
- Connizzo BK, Grodzinsky AJ. Lose-Dose Administration of Dexamethasone Is Beneficial in Preventing Secondary Tendon Damage in a Stress-Deprived Joint Injury Explant Model. J Orthop Res 2020 Jan;38(1):139-149.
- Sluzalska KD, Liebisch G, Ishaque B, Schmitz G, Rickert M, Steinmeyer J. The Effect of Dexamethasone, Adrenergic and Cholinergic Receptor Agonists on Phospholipid Metabolism in Human Osteoarthritic Synoviocytes. Int J Mol Sci 2019 Jan 15;20(2).
- Barton KI, Heard BJ, Chung M, Sevick JL, Martin CR, Achari Y, Frank CB, Shrive NG, Hart DA. Location and gene-specific effects of methylprednisolone acetate on mitigating IL1β-induced inflammation in mature ovine explant knee tissue. Inflamm Res 2017 Mar;66(3):239-248.
- Du J, Liu W, Jin T, Zhao Z, Bai R, Xue H, Chen J, Sun M, Zhang X, Wang G, Wang J. A single-nucleotide polymorphism in MMP9 is associated with decreased risk of steroid-induced osteonecrosis of the femoral head. Oncotarget 2016 Oct 18;7(42):68434-68441.
- Wang Z, Guo A, Ma L, Yu H, Zhang L, Meng H, Cui Y, Yu F, Yang B. Docosahexenoic acid treatment ameliorates cartilage degeneration via a p38 MAPK-dependent mechanism. Int J Mol Med 2016 Jun;37(6):1542-50.
- Kamleh MA, Snowden SG, Grapov D, Blackburn GJ, Watson DG, Xu N, Ståhle M, Wheelock CE. LC-MS metabolomics of psoriasis patients reveals disease severity-dependent increases in circulating amino acids that are ameliorated by anti-TNFα treatment. J Proteome Res 2015 Jan 2;14(1):557-66.
- Wang J, Zhang H, Su C, Chen J, Zhu B, Zhang H, Xiao H, Zhang J. Dexamethasone ameliorates H₂S-induced acute lung injury by alleviating matrix metalloproteinase-2 and -9 expression. PLoS One 2014;9(4):e94701.
- Chen B, Wang B, Zhang WJ, Zhou G, Cao Y, Liu W. Macromolecular crowding effect on cartilaginous matrix production: a comparison of two-dimensional and three-dimensional models. Tissue Eng Part C Methods 2013 Aug;19(8):586-95.
- Rai MF, Graeve T, Twardziok S, Schmidt MF. Evidence for regulated interleukin-4 expression in chondrocyte-scaffolds under in vitro inflammatory conditions. PLoS One 2011;6(10):e25749.
- Troeberg L, Nagase H. Proteases involved in cartilage matrix degradation in osteoarthritis. Biochim Biophys Acta 2012 Jan;1824(1):133-45.
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