[Show abstract][Hide abstract] ABSTRACT: To further understand the expression regulation of MMP-1 and MMP-13 under physiological and pathological conditions, we investigated the combined effects of hypoxia and pro-inflammatory stimuli on the expression of MMP-1 and MMP-13 in rheumatoid synovial fibroblasts.
Synovial fibroblasts were cultured under either hypoxic or normoxic conditions in the presence of IL-1β stimulation. The culture supernatant was analysed for secreted levels of VEGF, MMP-1 and MMP-13. Their gene expression was quantified with real-time and semi-quantitative PCR. Another group of cells was transfected with small-interfering RNA (siRNA) specific for hypoxia-inducible factor-1 α (HIF-1α). The protein levels of HIF-1α were detected by western blot analysis.
In response to 10 ng/ml of IL-1β under normoxia, the levels of MMP-1 and MMP-13 increased compared with the levels observed under hypoxia. IL-1β stimulation under hypoxia induced a 2-fold increase in the level of MMP-1 and a 2-fold decrease in the level of MMP-13 compared with cells cultured under normoxia. A similar pattern of differential expression for MMP-1 and MMP-13 was observed with 1 and 5 ng/ml IL-1β, but not at 0.1 ng/ml. The differential expression of MMPs under the combined effect of IL-1β and hypoxia was significantly attenuated by silencing HIF-1α with siRNA.
Hypoxia in arthritic joints may differentially affect the IL-1β-stimulated expression of MMP-1 and MMP-13 in rheumatoid synovial fibroblasts. This effect is dependent on HIF-1α expression. This hypoxia-mediated differential effect should be taken into consideration when testing the efficiency of therapies that target HIF-1α.
[Show abstract][Hide abstract] ABSTRACT: Thymosin (Tβ4) may have various biological effects that are relevant to the pathogenesis of rheumatoid arthritis (RA). This study was performed to gain insight into the relevance of Tβ4 in the pathogenesis of inflammatory arthritis.
The level of Tβ4 in synovial fluid from patients with osteoarthritis (OA) or RA was measured by enzyme-linked immunosorbent assay. An association between Tβ4 and matrix metalloproteinase (MMP)-1 and MMP-13 (collagenases), MMP-2 and MMP-9 (gelatinases), MMP-7, adiponectin, lactoferrin, vascular endothelial growth factor (VEGF), urokinase-type plasminogen activator (uPA), interleukin (IL)-6, IL-8 and prostaglandin E2 (PGE(2) ) in synovial joint fluids from OA and RA patients were investigated.
The level of Tβ4 in the synovial joint fluid of patients with OA and RA was (mean ± SD) 145 ± 88 and 1359 ± 1685 ng/mL, respectively. The level of Tβ4 in the synovial joint fluid of RA patients was significantly associated with the levels of MMP-9, MMP-13, VEGF, uPA, IL-6 and IL-8, but not with MMP-1, MMP-2, MMP-7, adiponectin and lactoferrin. In contrast, the level of Tβ4 in the synovial joint fluid of patients with OA was not associated with any of these molecules.
The results suggest that Tβ4 may play an important role in bone degradation and inflammation in RA but not OA, although nothing is known about the molecular mechanisms mediating Tβ4 in arthritic joints. The role of Tβ4 in arthritis should be studied to understand its relevance to the pathogenic processes in arthritis.
International Journal of Rheumatic Diseases 10/2011; 14(4):320-4. DOI:10.1111/j.1756-185X.2011.01652.x · 1.77 Impact Factor