**9. Acknowledgment**

We are grateful to Dr Tony Merry from Manchester University for his critical reading of the manuscript before submission.

### **10. References**

Bartholomew, BA.; (1972). Synovial fluid glycosidase activity. *Scand J Rheumatol*, 1, 69-74.


Although many publications (Shinmei et al. 1992; Lohmander et al. 1995; Saxne & Heinegard 1995; Myers 1999; Ortutay et al. 2003) have described increased release of markers of cartilage, bone, and synovial metabolism into joint fluid, serum, and urine in rheumatoid arthritis, the significance of several of these markers remains elusive. Up to now, no markers have yet been formally validated to monitor rheumatoid diseases of the joints. We hypothesize that determining HEX activity in the synovial fluid of patients with suspected idiopatic juvenile arthritis has diagnostic value. Elevation of HEX activity in synovial fluid

Despite its huge public health impact, the conservative treatment of joint diseases, particularly of OA, is limited to a few types of medication which provide primarily symptomatic relief. Inhibition of hexosaminidase activity may represent a potentially novel strategy for treating RA and OA. Liu et al. (2001) have synthesized and investigated a series of iminocyclitols designed as transition-state analogue inhibitors of extracellular human hexosaminidase. Our team (Olszewski et al. 2010) is focusing on pyrimethamine which

We are grateful to Dr Tony Merry from Manchester University for his critical reading of the

Bartholomew, BA.; (1972). Synovial fluid glycosidase activity. *Scand J Rheumatol*, 1, 69-74. Berenbaum, F.; Le Gars, L.; Toussirot, E.; Sanon, A.; Bories, C.; Kaplan, G. & Loiseau, PM.

Czartoryska, B. (1977). Lysosomal glycosidases in heteropolysaccharide catabolism. *Post* 

Chikanza, IC.; Jawed, S.; Naughton, D. & Blade, DR. (1998). Why do we need new treatments for rheumatoid arthritis ? *J Pharm Pharmacol*, 50, 357–369. Dieppe, P. (2000). The management of osteoarthritis in the third millennium. *Scand J* 

Ganguly, NK.; Kinghan, JG.; Lioyd, RS.; Price, CP.; Triger, DR. & Wright, R. (1978). Acid

Giannini, EH.; Ilowite, NT.; Lovell, DJ.; Wallace, CA.; Rabinovich, CE.; Reiff, A.; Higgins, G.

Ikonne, IU.; Rattazzi, MC. & Desnik, RJ. (1975). Characterization of HEX S, the major

Inerot, S.; Heinegard, D.; Audell, L. & Olsson, S.-E. (1978). Articular-cartilage proteoglycans

hydrolases in monocytes from patients with inflammatory bowel disease, chronic

& Gottlieb, B. (2010). Effects of long-term etanercept treatment on growth in children with selected categories of juvenile idiopathic arthritis. Arthritis Rheum,

residual β-hexosaminidase activity in type O Gm2 gangliosidosis (Sandhoff-

(2000). Marked elevation of serum N-acetyl-β-D-hexosaminidase activity in

to greater than 10 µkat/kg of protein, suggests rheumatoid disease.

contributes to the regulation of HEX gene expression in synovial cells.

rheumatoid arthritis*. Clin Exp Rheumatol*, 18, 63–66.

liver disease and rheumatoid arthritis. *Lancet,* 1, 1073-1075.

Jatzkiewitz disease). *Am J Hum Genet*, 27, 639-650.

in aging and osteoarthritis*. Biochem J,* 169, 143–156.

**8. Conclusions** 

**9. Acknowledgment** 

**10. References** 

manuscript before submission.

*Bioch,* 23, 229-266.

62, 11, 3250–3264.

*Rheumatol,* 29, 279-281.


**7** 

*Spain* 

**Innate Mechanisms of Synovitis –** 

*1Jiménez Díaz Foundation University Hospital, Madrid,* 

Olga Sánchez-Pernaute1 et al.\*

**Fibrin Deposits Contribute to Invasion** 

The studies approaching pathogenesis of rheumatoid arthritis shifted over the years to show that non-immune factors could precede activation of immune cells and were therefore targetable (Firestein & Zvaifler, 1990). In opposition to the classic model, in which an initial challenge to the immune system would over time lead to the autoimmune attack of joints, it was suggested that early mechanisms of disease induction were to be found inside joints. It was observed in vitro, that cells from the joints of patients with rheumatoid arthritis spontaneously produced several cytokines (Brennan et al., 1989a). Further studies would confirm the role of tumour necrosis factor alpha (TNF) as a master cytokine, since its inhibition led to a drop in levels of the other soluble mediators (Brennan et al., 1989b), as well as reduction in the expression of HLA-DR molecules (Haworth et al., 1991). Interestingly, TNF was not lymphocyte restricted, but rather pleiotropic. Moreover, it was shown that its principal sources in the arthritic joint were resident macrophages and fibroblast-like cells. This new paradigm was followed by the successful introduction of anti-

Indeed, the rheumatoid lesion at joints is quite unique, and probably sufficient to define the disease. It is characterized by the development of synovitis, a tumour-like transformation of the synovial tissue (Arend, 1997). On one hand, synovitis leads to joint destruction and disability, and on the other it provides a stronghold for spreading the inflammatory process.

There is not a uniform theory to explain how synovitis develops. However, one of the major features of synovitis is the acquisition of invasiveness of synovial fibroblasts. It could be said that rheumatoid synovial fibroblasts exhibit features of transformed cells, but unlike these, they do not show genetic aberrations. Rather, it seems that different activation processes are not correctly balanced by regulatory mechanisms in these cells. In this regard, it is typical of rheumatoid synovial fibroblasts to constitutively express growth factors, adhesion

\* Antonio Gabucio1, Astrid Jüngel2, Michel Neidhart2, María Comazzi2, Gabriel Herrero-Beaumont1,

cytokine therapies, which have totally changed the clinical picture of RA.

**1. Introduction** 

**1.1 Synovitis and the chicken or the egg dilemma** 

**1.2 Role of synovial fibroblasts in synovitis 1.2.1 Invasive features of synovial fibroblasts** 

Renate E. Gay2 and Steffen Gay2

*2Zürich University Hospital, Zürich, Switzerland*

