FSTL1 promotes arthritis in mice by enhancing inflammatory cytokine/chemokine expression

Follistatin-like protein-1 (FSTL-1), a glycoprotein originally cloned from a mouse osteoblastic cell line as a transforming growth factor β (TGFβ)-inducible gene (1). FSTL-1 is encoded on chromosome 3 in humans and chromosome 16 in mice. The human and mouse FSTL-1 proteins share 92% amino acid homology. Based on sequence homology, FSTL-1 belongs to a family of secreted proteins rich in cysteines (SPARC/BM-40/osteonectin) sharing a characteristic structural module (the follistatin-like domain) and a pair of EF hands (2). However, the EF hand calcium binding domains of FSTL-1 are non-functional (2) and, in contrast to follistatin, FSTL-1 does not bind activin (3) suggesting that FSTL-1 exhibits unique and distinctive properties. The function of FSTL-1 is poorly understood. Various, seemingly contradictory, effects have been reported on cell growth and survival. FSTL-1 has been reported to inhibit apoptosis in cardiac myocytes (4), to promote endothelial cell function and blood vessel growth through the activating phosphorylation of Akt and eNOS (5), and to enhance metastatic potential in prostate tumors (6). In contrast, FSTL-1 had a tumor suppressor effect in ovarian and endometrial tumors (7) inhibited invasion in rat fibroblasts transformed by FBR-v-fos (8), and inhibited vascular smooth muscle cell proliferation and migration (9). In the past decade, a number of reports have been published suggesting a role for FSTL-1 in the pathogenesis of rheumatoid arthritis (RA). In 1998, Tanaka et al. cloned FSTL-1 from RA synovial tissue and found FSTL-1 autoantibodies in the serum and synovial fluid of RA patients and suggested that it may be an autoantigen (10). Ameliorative effects of human FSTL-1 on joint inflammation in a mouse model of antibody-induced arthritis have also been reported (3). Our own studies have demonstrated that FSTL-1 expression was increased in RA synovial tissue (11) and in the joints of mice with collagen-induced arthritis (CIA) (12). Over-expression of FSTL-1 exacerbated CIA, while its neutralization with specific antibody ameliorated CIA (11, 13). More recently, we have shown that serum levels of FSTL-1 correlate with active disease in children with a systemic juvenile idiopathic arthritis (JIA) (14). In vitro, over-expression of FSTL-1 increased interferon-γ (IFNγ) secretion from T cells and increased IL-1β, TNF-α and IL-6 secretion from macrophages and fibroblasts (13). FSTL-1 is produced by endotheliocytes (5), myocytes (5) and various cells of the mesenchymal lineage, including osteocytes, chondrocytes, adipocytes, and fibroblasts (14). In contrast to other proinflammatory mediators, it is not produced by cells of the hematopoetic lineage, such as monocytes and lymphocytes (14). Its expression can be induced by innate immune signals, including Toll-like receptor 4 (TLR4) agonists and the arthritogenic cytokines, IL-1β, TNF-α and IL-6 (11, 14). Taken together, these data imply that FSTL-1 plays an important role in the complex network of inflammatory mediators present in the rheumatoid synovium. The current study was designed to further explore the mechanism by which FSTL-1 exerts its proinflammatory effect.