OBJECTIVE: Synovial fibrosis is a major contributor to joint stiffness in osteoarthritis (OA). Transforming growth factor β (TGFβ), which is elevated in OA, plays a key role in the onset and persistence of synovial fibrosis. However, blocking of TGFβ in OA as a therapeutic intervention for fibrosis is not an option since TGFβ is crucial for cartilage maintenance and repair. Therefore, we undertook the present study to seek targets downstream of TGFβ 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 TGFβ and were elevated in OA-related fibrosis. We analyzed gene expression in TGFβ-stimulated human OA synovial fibroblasts and in the synovium of mice with TGFβ-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 TGFβ-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 TGFβ in vivo in mice with TGFβ-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.
OBJECTIVE: Synovial fibrosis is a major contributor to joint stiffness in osteoarthritis (OA). Transforming growth factor β (TGFβ), which is elevated in OA, plays a key role in the onset and persistence of synovial fibrosis. However, blocking of TGFβ in OA as a therapeutic intervention for fibrosis is not an option since TGFβ is crucial for cartilage maintenance and repair. Therefore, we undertook the present study to seek targets downstream of TGFβ 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 TGFβ and were elevated in OA-related fibrosis. We analyzed gene expression in TGFβ-stimulated human OA synovial fibroblasts and in the synovium of mice with TGFβ-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 TGFβ-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 TGFβ in vivo in mice with TGFβ-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.
Authors: D R Haudenschild; A K Carlson; D L Zignego; J H N Yik; J K Hilmer; R K June Journal: Osteoarthritis Cartilage Date: 2018-12-18 Impact factor: 6.576
Authors: Nathan M Solbak; Bryan J Heard; Yamini Achari; May Chung; Nigel G Shrive; Cyril B Frank; David A Hart Journal: Inflamm Res Date: 2015-06-20 Impact factor: 4.575
Authors: Theerut Luangmonkong; Su Suriguga; Emilia Bigaeva; Miriam Boersema; Dorenda Oosterhuis; Koert P de Jong; Detlef Schuppan; Henricus A M Mutsaers; Peter Olinga Journal: Br J Pharmacol Date: 2017-08-11 Impact factor: 8.739
Authors: Rutger A F Gjaltema; Miesje M van der Stoel; Miriam Boersema; Ruud A Bank Journal: Proc Natl Acad Sci U S A Date: 2016-06-13 Impact factor: 11.205