CXCL12 (
stromal cell-derived factor 1) is a unique
biological ligand for the
chemokine receptor CXCR4. We previously reported that treatment with a specific CXCR4 antagonist,
AMD3100, exerts a beneficial effect on the development of
collagen-induced arthritis (CIA) in the highly susceptible IFN-gamma receptor-deficient (
IFN-gammaR KO) mouse. We concluded that CXCL12 plays a central role in the pathogenesis of CIA in
IFN-gammaR KO mice by promoting delayed type
hypersensitivity against the auto-
antigen and by interfering with chemotaxis of CXCR4+ cells to the inflamed joints. Here, we investigated whether
AMD3100 can likewise inhibit CIA in wild-type mice and analysed the underlying mechanism. Parenteral treatment with the
drug at the time of onset of
arthritis reduced disease incidence and modestly inhibited severity in affected mice. This beneficial effect was associated with reduced serum concentrations of
IL-6.
AMD3100 did not affect anti-
collagen type II antibodies and, in contrast with its action in
IFN-gammaR KO mice, did not inhibit the delayed type
hypersensitivity response against
collagen type II, suggesting that the beneficial effect cannot be explained by inhibition of humoral or cellular autoimmune responses.
AMD3100 inhibited the in vitro chemotactic effect of CXCL12 on splenocytes, as well as in vivo leukocyte infiltration in CXCL12-containing subcutaneous air pouches. We also demonstrate that, in addition to its effect on cell infiltration, CXCL12 potentiates
receptor activator of NF-kappaB ligand-induced osteoclast differentiation from splenocytes and increases the
calcium phosphate-resorbing capacity of these osteoclasts, both processes being potently counteracted by
AMD3100. Our observations indicate that CXCL12 acts as a pro-inflammatory factor in the pathogenesis of autoimmune
arthritis by attracting inflammatory cells to joints and by stimulating the differentiation and activation of osteoclasts.