Impairment of the Collagenase-3 Endocytotic Receptor System in Cells from Patients with Osteoarthritis

Walling, H. W., Raggatt, L. J., Irvine, D. W., Barmina, O. Y., Toledano, J. E., Goldring, M. B., Hruska, K. A., Adkisson, H. D., Burdge, R. E., Gatt, C. J. Jr., Harwood, D. A. and Partridge, N. C. (2003) Impairment of the Collagenase-3 Endocytotic Receptor System in Cells from Patients with Osteoarthritis. Osteoarthritis and Cartilage, 11 12: 854-863. doi:10.1016/S1063-4584(03)00170-5

Author Walling, H. W.
Raggatt, L. J.
Irvine, D. W.
Barmina, O. Y.
Toledano, J. E.
Goldring, M. B.
Hruska, K. A.
Adkisson, H. D.
Burdge, R. E.
Gatt, C. J. Jr.
Harwood, D. A.
Partridge, N. C.
Title Impairment of the Collagenase-3 Endocytotic Receptor System in Cells from Patients with Osteoarthritis
Journal name Osteoarthritis and Cartilage   Check publisher's open access policy
ISSN 1063-4584
Publication date 2003-12
Year available 2003
Sub-type Article (original research)
DOI 10.1016/S1063-4584(03)00170-5
Volume 11
Issue 12
Start page 854
End page 863
Total pages 10
Editor S. Lohmander
Place of publication London
Publisher Elsevier Science; Published for the Society by Baillière Tindall
Language eng
Subject 110322 Rheumatology and Arthritis
Formatted abstract
Objective: Collagenase-3, a matrix metalloproteinase (MMP-13) that can degrade collagen II and aggrecan, is produced by osteoarthritic (OA) chondrocytes and may contribute to matrix destruction in this disease. Our laboratory has previously identified a specific endocytotic receptor for collagenase-3 on osteoblastic and fibroblastic cells, which couples with the low-density lipoprotein receptor-related protein (LRP1) to mediate the internalization and degradation of this enzyme. We hypothesized that the activity of this receptor system is reduced in OA chondrocytes which may lead to increased local extracellular levels of collagenase-3 and increased destruction of the cartilage matrix at pericellular sites.

Methods: Human chondrocytes and synoviocytes were obtained from OA knees at the time of joint replacement surgery and from non-arthritic control specimens following autopsy or surgery. Enzyme-linked immunosorbant assay (ELISA) was used to measure collagenase-3 secreted from primary cultures. Iodinated collagenase-3 was used to analyze the cell-surface binding, internalization and intracellular degradation of collagenase-3. Reverse-transcriptase polymerase chain reaction was used to confirm chondrocyte phenotype and the expression of collagenase-3 and LRP1 mRNAs.

: OA chondrocytes and synoviocytes demonstrated significantly reduced (75–77%) binding of recombinant 125I collagenase-3. Internalization and degradation of the ligand was also significantly reduced (64–72%) in OA cells. Collagenase-3 removal was inhibited by the LRP1 receptor-associated protein (RAP).

Conclusion: These results suggest a mechanism whereby impaired receptor-mediated removal of collagenase-3 in OA chondrocytes may lead to enhanced local degradation of the cartilage matrix. This work also implicates an LRP family member in endocytotic receptor-mediated collagenase-3 processing and suggests a novel therapeutic target for OA.
Keyword Osteoarthritis (OA)
articular cartilage
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status Unknown

Document type: Journal Article
Sub-type: Article (original research)
Collections: Excellence in Research Australia (ERA) - Collection
Institute for Molecular Bioscience - Publications
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Citation counts: TR Web of Science Citation Count  Cited 9 times in Thomson Reuters Web of Science Article | Citations
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Created: Wed, 21 Jan 2009, 13:29:54 EST by Ms Karen Naughton on behalf of Institute for Molecular Bioscience