Gene Expression Pattern of Cells From Inflamed and Normal Areas of Osteoarthritis Synovial Membrane

Abstract

ObjectiveTo compare the gene expression patterns of synovial cells from inflamed or normal/reactive areas of synovial membrane obtained from the same patient with osteoarthritis (OA).MethodsAt the time of total knee replacement, synovial tissues were obtained from 12 patients with knee OA. The inflammation status of the synovial membrane was characterized according to macroscopic criteria and classified as normal/reactive or inflamed. Biopsy samples were cultured separately for 7 days. Microarray gene expression profiling was performed on normal/reactive and inflamed areas. Western blot and immunohistochemistry were used to confirm the identified genes that were differentially expressed.ResultsWe identified 896 genes that were differentially expressed between normal/reactive and inflamed areas. The key pathways were related to inflammation, cartilage metabolism, Wnt signaling, and angiogenesis. In the inflammation network, the genes TREM1 and S100A9 were strongly up-regulated. The genes MMP3, MMP9, CTSH (cathepsin H), and CTSS (cathepsin S) were significantly up-regulated in the cartilage catabolism pathway, while the most up-regulated anabolism enzyme gene was HAS1. In the Wnt signaling pathway, the genes for Wnt-5a and low-density lipoprotein receptor–related protein 5 were up-regulated, while the gene FZD2 and the gene for Dkk-3 were down-regulated. Finally, STC1, which codes for a protein involved in angiogenesis, was identified as the most up-regulated gene in inflamed compared with normal/reactive areas.ConclusionThis study is the first to identify different expression patterns between 2 areas of the synovial membrane from the same patient. These differences concern several key pathways involved in OA pathogenesis. This analysis also provides information regarding new genes and proteins as potential targets of treatment.

A mechanistic target of rapamycin complex 1/2 (mTORC1)/V-Akt murine thymoma viral oncogene homolog 1 (AKT1)/cathepsin H axis controls filaggrin expression and processing in skin, a novel mechanism for skin barrier disruption in patients with atopic dermatitis

“…CTSH overexpression typically correlates to macrophage infiltration and a proinflammatory environment in a number of tissues 58, 59. Therefore it is likely that the loss of Ctsh leads to an increase in levels of other cathepsins, such as our observation of increased levels of cathepsin B, which might have a proinflammatory role and is known to play an important role in processing of mast cell proteases 60, 61.…”

Emerging targets in osteoarthritis therapy

“…VEGF is expressed by chondrocytes in proximity to the angiogenesis, suggesting that it is involved in recruiting vascular elements. Gene expression profiling identified STC1, a gene encoding stanniocalcin-1, which regulates angiogenic sprouting via the VEGF/VEGF receptor 2 pathway, as the most highly up-regulated gene in inflamed synovial membrane compared to non-inflamed synovium from the same OA patients [123]. A recent study shows that VEGF blockade with bevacizumab inhibits post-traumatic OA in a rabbit model with pain relief possibly associated with prevention of both synovitis and angiogenesis [124].…”

TRPV4 as a therapeutic target for joint diseases

“…PAR-2 can be proteolytically activated by thrombin, granzyme-B, cathepsin-S, and possibly other proteases. These three proteases have been implicated in the pathogenesis of joint diseases, such as rheumatoid arthritis and possibly osteoarthritis (Kummer et al, 1994, Morris et al, 1994, Cella et al, 1997, Dery et al, 1998, Hashimoto et al, 2001, Ronday et al, 2001, Goldbach-Mansky et al, 2005, Weidauer et al, 2007, Hasegawa et al, 2009, Hasegawa et al, 2011, Clark et al, 2012, Tindell et al, 2012, Lambert et al, 2014), and PAR-2 is expressed by synoviocytes, chondrocytes, and innervating sensory neurons (Steinhoff et al, 1999, Steinhoff et al, 2000, Kawabata, 2002, Coelho et al, 2003, Moffatt, 2004, Kanke et al, 2005, Bushell, 2007, Helyes et al, 2010, Denadai-Souza et al, 2012, Russell et al, 2012). …”