Related Experiment Videos
Osteoarthritis-related fibrosis is associated with both elevated pyridinoline cross-link formation and lysyl
D F G Remst1, E N Blaney Davidson, E L Vitters
1Rheumatology Research and Advanced Therapeutics, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands. D.Remst@reuma.umcn.nl
Objective:
Fibrosis is a major contributor to joint stiffness in osteoarthritis (OA). We investigated several factors associated with the persistence of transforming growth factor beta (TGF-β)-induced fibrosis and whether these factors also play a role in OA-related fibrosis.
Design:
Mice were injected intra-articularly (i.a.) with an adenovirus encoding either TGF-β or connective tissue growth factor (CTGF). In addition, we induced OA by i.a. injection of bacterial collagenase into the right knee joint of C57BL/6 mice. mRNA was isolated from the synovium for Q-PCR analysis of the gene expression of various extracellular matrix (ECM) components, ECM degraders, growth factors and collagen cross-linking-related enzymes. Sections of murine knee joints injected with Ad-TGF-β or Ad-CTGF or from experimental OA were stained for lysyl hydroxylase 2 (LH2). The number of pyridinoline cross-links per triple helix collagen in synovium biopsies was determined with high-performance liquid chromatography (HPLC).
Results:
Expression of collagen alpha-1(I) chain precursor (Col1a1), tissue inhibitor of metalloproteinases 1 (TIMP1) and especially procollagen-lysine, 2-oxoglutarate 5-dioxygenase 2b (Plod2b) were highly upregulated by TGF-β but not by CTGF. Elevated expression of Plod2b mRNA was associated with high lysyl hydroxylase 2 (LH2) protein staining after TGF-β overexpression and in experimental OA. Furthermore, in experimental OA the number of hydroxypyridinoline cross-links was significant increased compared to control knee joints.
Conclusions:
Our data show that elevated LH2b expression is associated with the persistent nature of TGF-β-induced fibrosis. Also in experimental OA, LH2b expression as well as the number of hydroxypyridinoline cross-link were significantly upregulated. We propose that LH2b, and the subsequent increase in pyridinoline cross-links, is responsible for the persistent fibrosis in experimental OA.
Related Concept Videos
Cirrhosis II: Pathophysiology
Fibril-associated Collagen
For example, the type II collagen fibrils in cartilage have covalently bound type IX fibril-associated collagens at regular intervals. Other types of fibril-associated collagens are...
Proteoglycans
Type IV Collagen of Basal Lamina
A type IV collagen molecule has six alpha chains which can exist in...
Introduction to Fibroblasts
Chronic Inflammation: Introduction