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-1γ), 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 immunochemically evaluated, respectively. The knee joints were histologically assessed for manifestations of OA. MIP-1γ levels and nuclear factor-κB (NF-κB) 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-1γ expression were examined using immunohistochemistry. Results: The number of CD4⁺ T cells and the expression of interferon-γ (IFN-γ) 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-1γ and NF-κB. The expression of MIP-1γ can be detected in synovium which CD4⁺ T cells were infiltrated. The increased MIP-1γ 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-1γ 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-1γ expression and subsequent osteoclast formation.