IL-17A gene transfer induces bone loss and epidermal hyperplasia associated with psoriatic arthritis.

BACKGROUND: Psoriatic arthritis (PsA) is a chronic inflammatory disease characterised by clinical features that include bone loss and epidermal hyperplasia. Aberrant cytokine expression has been linked to joint and skin pathology; however, it is unclear which cytokines are critical for disease initiation. Interleukin 17A (IL-17A) participates in many pathological immune responses; however, its role in PsA has not been fully elucidated. OBJECTIVE: To determine the role of IL-17A in epidermal hyperplasia and bone destruction associated with psoriatic arthritis. DESIGN: An in vivo gene transfer approach was used to investigate the role of IL-17A in animal models of inflammatory (collagen-induced arthritis) and non-inflammatory (receptor activator of NF-κB ligand (RANKL)-gene transfer) bone loss. RESULTS: IL-17A gene transfer induced the expansion of IL-17RA(+)CD11b(+)Gr1(low) osteoclast precursors and a concomitant elevation of biomarkers indicative of bone resorption. This occurred at a time preceding noticeable joint inflammation, suggesting that IL-17A is critical for the induction of pathological bone resorption through direct activation of osteoclast precursors. Moreover, IL-17A induced a second myeloid population CD11b(+)Gr1(high) neutrophil-like cells, which was associated with cutaneous pathology including epidermal hyperplasia, parakeratosis and Munro's microabscesses formation. CONCLUSIONS: Collectively, these data support that IL-17A can play a key role in the pathogenesis of inflammation-associated arthritis and/or skin disease, as observed in PsA.

Anti-IL-17A therapy protects against bone erosion in experimental models of rheumatoid arthritis.

Interleukin-17A (IL-17A) is a pro-inflammatory cytokine secreted by a subset of memory T cells and other innate immune cells. It is associated with rheumatoid arthritis (RA) due to IL-17A expression in RA synovial fluid. The severe bone erosive rat adjuvant-induced arthritis (rAIA) and mouse collagen-induced arthritis (mCIA) models were used to address the therapeutic efficacy of anti-IL-17A treatment with a focused investigation on bone protection. In the rAIA model, treatment with anti-IL-17A completely alleviated arthritis, lowered the level of receptor activator of NFκB ligand (RANKL), and inhibited structural damage to the bones. In the mCIA model, IL-17A neutralization coincident with arthritis development or in mice with established arthritis diminished joint swelling by inhibiting disease initiation and progression. Intriguingly, even the few joints that became outwardly severely inflamed in the presence of an anti-IL-17A antagonist had diminished joint histopathology scores compared to severely inflamed, control-treated mice. The bone-preserving property correlated with decreased RANKL message in severely inflamed paws of arthritic mice. These data identify IL-17A as a key factor in inflammation-mediated bone destruction and support anti-IL-17A therapy for the treatment of inflammatory bone diseases such as RA.

Structural, cellular, and molecular evaluation of bone erosion in experimental models of rheumatoid arthritis: assessment by µCT, histology, and serum biomarkers.

Bone erosion is a clinical endpoint for various diseases including rheumatoid arthritis. In this paper, we used rodent arthritis models with severe bone erosion to examine the structural, cellular, and molecular aspects of the inflammation-driven bone resorption process. Our data show that bone loss is observed only in chronically, severely inflamed joints. The most severely affected anatomic sites were the metatarsal phalangeal joint and tarsal bones of the paw. The magnitude of the inflammation-driven bone erosion was dependent on both the duration of inflammatory response and the severity of the joint swelling response. The application of micro-computed tomography well demonstrated the therapeutic benefit of anti-IL-17A in protection of bones from erosion. Alterations in the cellular profile of the joint occurred prior to any major structural deterioration of the bone. Receptor activator for nuclear factor κB ligand, a potent inducer of osteoclast differentiation and bone resorption, was elevated in animals coincident with severe arthritis initiation. The experimental approaches and concepts outlined in this paper provide a valuable process to evaluate and quantify therapies that modulate rodent arthritis-associated bone-erosion models.