Together with our earlier studies, the data presented here support the conclusion that FSTL-1 is a major mediator of the inflammatory cascade that underlies arthritis. For instance, we have demonstrated that over-expression of FSTL-1 in mouse paws by gene transfer resulted in severe paw swelling and arthritis (15
), while neutralization of FSTL-1 suppressed arthritis (11
). Also, transfection of FSTL-1 into macrophages and fibroblasts lead to up-regulation of proinflammatory cytokines with central roles in chronic arthritis, including IL-1-β and TNF-α (11
While expression of FSTL-1 in osteoblasts and fibroblasts has been previously reported, the finding that FSTL-1 can be produced by other mesenchymal cells, including adipoctyes and chondrocytes, is novel. These results, along with the observation that synovial fluid levels are 2–3 fold higher than serum levels, support the conclusion that the joint is a primary source of FSTL-1. Furthermore, it supports the concept that the joint matrix, including bone, cartilage, and adipose tissue, is not merely a passive target of destruction by blood-derived immune cells in arthritis; rather, this joint matrix plays an active role in perpetuating and amplifying the inflammatory response by releasing pro-inflammatory mediators, such as FSTL-1.
The present study suggests that systemic-onset JRA is characterized by elevated concentrations of serum and synovial fluid FSTL-1 that are not observed in other forms of JRA. Elevation of serum FSTL-1 correlated closely with markers of disease activity in systemic-onset JRA, including elevated ESR and platelet count, but we did not observe this correlation in oligoarthritis or polyarthritis. These data suggest that FSTL-1 might be useful as a biomarker of disease activity in this JRA subtype. An important caveat is that, although the results are statistically-significant, the number of systemic onset samples available to us was small. It will be important to validate these findings in a larger cohort of patients. Also, because we used banked samples, we had limited clinical data other than ESR and platelet counts. It will be of interest to compare FSTL-1 levels to additional measures of clinical activity.
The specificity for systemic JRA is interesting in light of our finding that FSTL-1 secretion from human fibroblast-like synoviocytes was significantly greater following incubation with IL-1β than with TNF-α. Systemic-onset JRA has recently been shown to have a strong IL-1β gene expression signature (17
). Many patients with systemic-onset JRA respond well to the IL-1 receptor antagonist, Anakinra, (17
) but less well to anti-TNF therapy (4
). However, it is as yet unclear why patients with polyarticular and oligoarticular arthritis did not have elevated FSTL-1 titers, since TNF-α also induced FSTL-1 secretion from fibroblast-like synoviocytes, albeit to a lesser degree, and TNF-α is a central cytokine in polyarticular disease (2
). It is possible that the preferential induction of FSTL-1 by IL-1β is more pronounced in vivo than in vitro, although this is speculative and requires further study.
These findings suggest the possibility that FSTL-1 might be a useful biomarker in other disorders driven by IL-1β, such as the autoinflammatory syndromes, including Muckle-Wells and neonatal-onset multisystem inflammatory disease (NOMID) (19
). We are currently investigating this possibility. None of the samples we evaluated were from subjects with macrophage activation syndrome (MAS), which is a serious complication of systemic-onset JRA that can lead to rapid deterioration and death if not treated aggressively. Whether FSTL-1 titers might be useful to screen for MAS is currently under investigation.
In conclusion, in this study FSTL-1 was found to be a biomarker of active disease in systemic JIA. Further studies are needed to confirm these observations in a larger cohort and to determine whether FSTL-1 might also be useful as a biomarker in other autoimmune and autoinflammatory conditions, particularly those with a strong IL-1β component. FSTL-1 may also represent a therapeutic target in certain forms of arthritis and other inflammatory diseases.