Mediation of nonerosive arthritis in a mouse model of lupus by interferon-alpha-stimulated monocyte differentiation that is nonpermissive of osteoclastogenesis.

Inflammatory arthritis is one of the most common clinical features in autoimmune disorders (1), and radiologic evidence of joint damage (erosions and joint space narrowing), is observed in almost all patients with rheumatoid arthritis (RA) followed for more than five years (2, 3). Pro-inflammatory mediators in RA joints stimulate the production of monocyte/macrophage osteoclast precursors (OCP), which migrate to the bone-pannus interface, and differentiate in response to elevated levels of receptor activator of nuclear factor κB-ligand (RANKL) to become bone-resorbing osteoclasts (OCs) that mediate focal erosions (4–7). Despite the presence of joint deformities on physical examination, not all forms of inflammatory arthritis involve degradation of cartilage and bone resorption. For example, patients with systemic lupus erythematosus (SLE) often complain of musculoskeletal symptoms, with 50% of patients reporting articular pain on presentation (8, 9). Additionally, these patients often develop RA-like deformities (ulnar deviation, tendonopathies and subluxation), but only 4–6% of patients display erosive changes on plain radiographs, and histological assessment of their joint tissue shows mild to moderate synovial hyperplasia, microvascular changes and perivascular inflammation with mononuclear cellular infiltrate (10, 11). The joint disease in these SLE patients, commonly referred to as Jaccoud arthritis (JA), is characterized by an absence of radiographic erosive changes, and has a relatively benign prognosis (12). Thus, elucidating the mechanism of non-erosive arthritis in JA could have significant implications for the unmet needs of individuals that suffer from destructive RA. Interferon-alpha (IFN-α) has emerged as the dominant cytokine that is dysregulated in SLE. IFN-α is mainly expressed by plasmacytoid dendritic cells (pDC), and simulates the differentiation and activation of myeloid dendritic cells (mDC) to present autoantigens (13, 14). Increased serum IFN-α correlates with both lupus disease activity and severity (15–17), and PBMC isolated from these patients express a unique gene expression pattern known as the IFN-α transcriptome (18, 19). Intriguingly, this transcriptome reverts to a pattern similar to that expressed in healthy controls following effective steroid therapy (18), which simultaneously causes glucocorticoid-induced osteoporosis (20), thus explaining why this non-erosive SLE phenotype in many patients is broadly overlooked. Convincing preclinical evidence for an IFN-α model of autoimmunity has also been generated using the New Zealand black (NZB)×New Zealand white (NZW) F1 mouse model of lupus (21, 22). These mice develop severe immune complex-mediated glomerulonephritis associated with high serum levels of antinuclear autoantibodies evident at 5 months of age. Moreover, IFNAR1−/− mice have severe osteopenia due to increased circulating OCP and uncontrolled bone resorption (23). Interestingly, the genetic component of the NZB lupus-susceptibility locus on distal chromosome 1 is known to contain the interferon-inducible gene Ifi202 (24), the up-regulation of which is correlated with disease in these mice and is now used as a surrogate reporter of the IFN-α gene expression profile. We reasoned that the increased mDC differentiation seen in human SLE and NZBxNZW F1 mice must occur at the expense of osteoclastogenesis, as these cells are derived from the same myelomonocyte precursor (25). Based on this information, we proposed an IFN-α-biased myelopoiesis model to explain the non-erosive nature of JA. In this model, concomitant inflammatory arthritis and lupus stimulate the production and release of myelomonocyte precursors from the bone marrow, which are irreversibly committed toward CD11b+CD11c+ mDC differentiation. Furthermore, we postulated that the mDC precursors have lost all osteoclastogenic potential as a direct result of exposure to elevated systemic IFN-α (25). As such, these cells fail to respond to RANKL in inflamed joints, and focal erosion becomes impossible due to the lack of mature OCs. Here we directly test this hypothesis with serum-induced arthritis (SIA) experiments in NZBxNZW F1 mice, and by injecting Ad-IFN-α into NZW non-SLE mice followed by administration of arthritogenic K/BxN serum. The results demonstrate that IFN-α is sufficient to induce the non-erosive phenotype observed in JA by prevention of osteoclastogenesis due to myeloid differentiation towards mDC.