Induction of autoimmune arthritis after direct injection of bone marrow cells from arthritis-prone SKG/Jcl mice into bone cavity of normal mice.

ABSTRACT

SKG/Jcl (SKG) mice spontaneously develop T cell-mediated autoimmune arthritis and may be an effective model for studying human rheumatoid arthritis. We sought to confirm that arthritis in SKG mice was caused by stem cell disorders. We induced systemic arthritis in normal C57/BL6 (B6) mice (H-2(b) type) by injecting lineage-negative (lin(-)) immature cells isolated from bone marrow cells (BMCs) of SKG mice (H-2(d) type) directly into bone cavities. Twenty weeks later, we analyzed arthritis scores, hematoxylin-eosin (H-E) staining and tartrate-resistant acid phosphatase (TRAP) staining in ankle joints, H-2 type of hematolymphoid and osteoblast-like cells, serum levels of tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) and percentages of CD4(+) T cells and osteoblast-like cells expressing receptor activator of nuclear factor kappa-B ligand (RANKL) in recipient mice. Donor-derived hematolymphoid cells and osteoblast-like cells had completely replaced donor-derived cells in the recipients (H-2(b) to H-2(d)). All recipients showed severe joint swelling with hyperemia and developed hypertrophic synovitis with lymphocytes accumulated around joints. All recipients also had higher TNF-α and IL-6 levels than untreated B6 controls. Furthermore, the percentages of CD4(+) T cells and osteoblast-like cells expressing RANKL and the number of TRAP(+) cells were greater in treated animals. Donor-derived hematolymphoid cells and osteoblast-like cells persisted in these recipients and promoted autoimmune arthritis and an increase in osteoclasts. Because autoimmune arthritis may be associated with abnormal lin(-) immature cells, patients with intractable autoimmune arthritis may be treated by replacing these cells with direct injection of lin(-) immature cells isolated from normal BMCs.