T helper cells promote disease progression of osteoarthritis by inducing macrophage inflammatory protein-1γ

Objective: Immune cells are involved in the pathogenesis of osteoarthritis (OA). We examined the effects of T helper (Th) cells, which induce the expression of macrophage inflammatory protein (MIP-1 gamma), on the progression of OA. Design: Using anterior cruciate ligament-transection (ACLT), we induced OA in one hind-leg knee joint of B6 mice. The CD4(+) T cells from splenocytes and synovium were flow-cytometrically and immuno-chemically evaluated, respectively. The knee joints were histologically assessed for manifestations of OA. MIP-1 gamma levels and nuclear factor-kappa B (NF-kappa B) in the knee joints were measured using enzyme-linked immunosorbent and immunoblotting assays, respectively; osteoclastogenesis was detected by tartrate-resistant acid phosphatase (TRAP) staining. The inflammatory responses and MIP-1 gamma expression were examined using immunohistochemistry. Results: The number of CD4(+) T cells and the expression of interferon-gamma (IFN-gamma) increased during OA onset (30 days after ACLT) and then decreased at a later stage of OA (90 days after ACLT). Tissue damage induced by CD4(+) T cells was evident at the later stage. The activation of CD4(+) T cells induced the expression of MIP-1 gamma and NF-kappa B. The expression of MIP-1 gamma can be detected in synovium which CD4(+) T cells were infiltrated. The increased MIP-1 gamma expression caused an increase in the number of osteoclasts in joints. The regulation of CD4(+) T cells was accompanied by increased macrophage infiltration and matrix metalloproteinase (MMP)-9 expression. Histopathological examinations revealed that CD4(+) T cell knockout (CD4(-/-)) mice had less expression of MIP-1 gamma and slower cartilage degeneration than control mice had. Conclusions: CD4(+) T cells were activated during the onset of OA, but cartilage damage was more prominent at a later stage. CD4(+) T cells were involved in the pathogenesis of OA: they induced MIP-1 gamma expression and subsequent osteoclast formation. (C) 2011 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.