“We think that we have identified one of the early steps in developing OA.”—Frank Echtermeyer, PhD
Syndecan-4 controls the activation of aggrecan cleavage by a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 5 (ADAMTS-5), which is crucial for the breakdown of cartilage matrix during OA. Syndecan-4 interacts with the protease and through regulating mitogen-activated protein kinase (MAPK)-dependent synthesis of matrix metalloproteinase-3 (MMP-3), the researchers explain.Syndecan-4 Plays Key Role in OA Cartilage Damage
“Our study shows a central role for the cell surface receptor syndecan-4 in 2 fundamental processes leading to cartilage destruction; first syndecan-4 controls the expression of metalloprotease (MMP-3) that is critically involved in the activation of ADAMTS-5, another protease that causes the cleavage of the cartilage compound aggrecan and secondly, syndecan-4 anchors ADAMTS-5 on the chondrocyte surface to allow cartilage degradation in close proximity of chondrocytes and prevents ADAMTS-5 from being washed out the cartilage,” says Frank Echtermeyer, PhD, of Medical University Hannover in Hannover, Germany. “We think that we have indentified one of the early steps in developing OA.”
The new research used mouse, rat and human models to analyze the effects of syndecan-4, and the effects of syndecan-4 deficiency on the development and progression of OA-like cartilage destruction in mice.
They found that syndecan-4 is specifically induced in type X collagen-producing chondrocytes both in human osteoarthritis and in mouse models of OA. The intra-articular injections of syndecan-4-specific antibodies into wild-type mice protect from proteoglycan loss and thereby prevent osteoarthritic cartilage damage in a surgically-induced model of OA. The occurrence of less severe OA-like cartilage destruction in both syndecan-4-deficient mice and syndecan-4-specific antibody-treated wild-type mice results from a marked decrease in ADAMTS-5 activity.
Translating research into practice: Blocking syndecan-4 and OA cartilage repair
“Our data suggest that strategies aimed at the inhibition of syndecan-4 will be of great value for the treatment of cartilage damage in osteoarthritis,” said co-study author Thomas Pap, MD, of the University in Muenster in Germany said. “We have followed the strategy of blocking syndecan-4 with specific antibodies in our animal model and we think that this could also be used in patients,” he said. Now “we are trying to convince some companies to produce and test our syndecan-4 antibody in clinical trials.”
Reference
1. Echtermeyer F, Bertrand J, Dreier R, et al. Syndecan-4 regulates ADAMTS-5 activation and cartilage breakdown in osteoarthritis. Nature Medicine. [epub ahead of print Aug. 16, 2009].
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