Gene Expression Analysis of Murine and Human Osteoarthritis Synovium Reveals Elevation of Transforming Growth Factor beta-Responsive Genes in Osteoarthritis-Related Fibrosis

D. F. G. Remst, A. B. Blom, E. L. Vitters, R. A. Bank, W. B. van den Berg, E. N. Blaney Davidson, P. M. van der Kraan*

*Corresponding author voor dit werk

OnderzoeksoutputAcademicpeer review

97 Citaten (Scopus)

Samenvatting

Objective. Synovial fibrosis is a major contributor to joint stiffness in osteoarthritis (OA). Transforming growth factor beta (TGF beta), which is elevated in OA, plays a key role in the onset and persistence of synovial fibrosis. However, blocking of TGF beta in OA as a therapeutic intervention for fibrosis is not an option since TGF beta is crucial for cartilage maintenance and repair. Therefore, we undertook the present study to seek targets downstream of TGF beta for preventing OA-related fibrosis without interfering with joint homeostasis.

Methods. Experiments were performed to determine whether genes involved in extracellular matrix turnover were responsive to TGF beta and were elevated in OA-related fibrosis. We analyzed gene expression in TGF beta-stimulated human OA synovial fibroblasts and in the synovium of mice with TGF beta-induced fibrosis, mice with experimental OA, and humans with end-stage OA. Gene expression was determined by microarray, low-density array, or quantitative polymerase chain reaction analysis.

Results. We observed an increase in expression of procollagen genes and genes encoding collagen crosslinking enzymes under all of the OA-related fibrotic conditions investigated. Comparison of gene expression in TGF beta-stimulated human OA synovial fibroblasts, synovium from mice with experimental OA, and synovium from humans with end-stage OA revealed that the genes PLOD2, LOX, COL1A1, COL5A1, and TIMP1 were up-regulated in all of these conditions. Additionally, we confirmed that these genes were up-regulated by TGF beta in vivo in mice with TGF beta-induced synovial fibrosis.

Conclusion. Most of the up-regulated genes identified in this study would be poor targets for therapy development, due to their crucial functions in the joint. However, the highly up-regulated gene PLOD2, responsible for the formation of collagen crosslinks that make collagen less susceptible to enzymatic degradation, is an attractive and promising target for interference in OA-related synovial fibrosis.

Originele taal-2English
Pagina's (van-tot)647-656
Aantal pagina's10
TijdschriftArthritis & Rheumatology
Volume66
Nummer van het tijdschrift3
DOI's
StatusPublished - mrt.-2014

Vingerafdruk

Duik in de onderzoeksthema's van 'Gene Expression Analysis of Murine and Human Osteoarthritis Synovium Reveals Elevation of Transforming Growth Factor beta-Responsive Genes in Osteoarthritis-Related Fibrosis'. Samen vormen ze een unieke vingerafdruk.

Citeer dit