Hyaluronan enhances cartilage repair through low grade tissue remodeling involving cytokines and matrix metalloproteinases.
OBJECTIVE
To determine whether the ability of high molecular weight hyaluronan (HA) to reverse cartilage damage caused by specific catabolic mediators of cartilage damage, fibronectin fragments (Fn-fs), occurs through a low grade of enhanced catabolic events such as enhanced matrix metalloproteinase (MMP) expression or cytokine activities.


METHODS
HA from 6.8-kDa to 2 million daltons was studied.


METHODS
The ability of HA to enhance matrix metalloproteinase-3 (MMP-3) epitopes and cartilage proteoglycan (PG) degradation neoepitopes was tested in bovine cartilage, as well as the ability of recombinant human interleukin-1 receptor antagonist protein (rhIRAP) to reverse PG depletion in cartilage first exposed to Fn-f.


RESULTS
All HA forms enhanced MMP-3 epitopes and PG degradation in normal undamaged cartilage and in the case of HA800, the degradation was not sufficient to decrease steady state levels of cartilage PG. When HA800 was added to Fn-f damaged cartilage, restoration of PG occurred, but this was blocked by rhIRAP.


CONCLUSIONS
These results collectively suggest that some of the repair activity of HA800 is through proteolytic activity which is not sufficient to decrease matrix PG content, but is nonetheless elevated above levels in cartilage not treated with HA800.
Homandberg
G A
GA
Department of Biochemistry and Molecular Biology, University of North Dakota School of Medicine and Health Sciences, Box 9037, Grand Forks, ND 58202, USA. ghomandb@medicine.nodak.edu
Ummadi
V
V
Kang
H
H
D000818:Animals; D015153:Blotting, Western; D002356:Cartilage / Q000187:drug effects* / Q000378:metabolism; D002417:Cattle; D017077:Culture Media, Conditioned / Q000494:pharmacology; D016895:Culture Media, Serum-Free / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism*; D010450:Endopeptidases / Q000737:chemistry; D000939:Epitopes / Q000737:chemistry; D005353:Fibronectins / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D006820:Hyaluronic Acid / Q000737:chemistry* / Q000494:pharmacology*; D007150:Immunohistochemistry; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D053590:Interleukin 1 Receptor Antagonist Protein; D007700:Kinetics; D019278:Matrix Metalloproteinase 3 / Q000737:chemistry; D020782:Matrix Metalloproteinases / Q000378:metabolism*; D009842:Oligopeptides / Q000737:chemistry; D010446:Peptide Fragments / Q000737:chemistry; D011112:Polymyxin B / Q000737:chemistry; D011453:Prostaglandins / Q000378:metabolism; D011994:Recombinant Proteins / Q000737:chemistry; D012795:Sialoglycoproteins / Q000737:chemistry; D013997:Time Factors
D017077:Culture Media, Conditioned; D016895:Culture Media, Serum-Free; D016207:Cytokines; D000939:Epitopes; D005353:Fibronectins; C507763:IL1RN protein, human; D053590:Interleukin 1 Receptor Antagonist Protein; D009842:Oligopeptides; D010446:Peptide Fragments; D011453:Prostaglandins; D011994:Recombinant Proteins; D012795:Sialoglycoproteins; C093378:peptide VDIPEN; D007334:Insulin-Like Growth Factor I; D006820:Hyaluronic Acid; D010450:Endopeptidases; D020782:Matrix Metalloproteinases; D019278:Matrix Metalloproteinase 3; C083641:aggrecanase; D011112:Polymyxin B