RESUMO
Foreign body giant cells (FBGCs) are a hallmark of the foreign body reaction caused by biomaterial implantation and are thought to contribute to biomaterial degradation and the duration of the response. Osteopontin (OPN) is a secreted, acidic matricellular protein with multiple phosphorylation sites that is highly expressed at sites of inflammation. OPN wildtype and knockout mice were implanted with poly(vinyl alcohol) sponges and explanted at 14 days. OPN knockout mice had more foreign body giant cells but fewer macrophages surrounding the implants than their wildtype counterparts. In an in vitro human FBGC assay, addition of soluble OPN was found to reduce macrophage fusion to giant cells. These are the first studies to show a direct inhibitory role of OPN in FBGC formation in response to implantation.
Assuntos
Materiais Biocompatíveis , Células Gigantes de Corpo Estranho/fisiologia , Sialoglicoproteínas/genética , Sialoglicoproteínas/fisiologia , Animais , Adesão Celular , Reação a Corpo Estranho , Células Gigantes de Corpo Estranho/metabolismo , Fator Estimulador de Colônias de Granulócitos e Macrófagos/metabolismo , Heterozigoto , Humanos , Imuno-Histoquímica , Inflamação , Macrófagos/citologia , Macrófagos/metabolismo , Camundongos , Camundongos Knockout , Camundongos Transgênicos , Osteopontina , Fosforilação , Poliuretanos , Próteses e Implantes , Ligação Proteica , Isoformas de Proteínas , Proteínas Recombinantes/química , Sialoglicoproteínas/metabolismo , Propriedades de Superfície , Fatores de TempoRESUMO
The foreign body reaction (FBR) develops in response to the implantation of almost all biomaterials and can be detrimental to their function. The formation of foreign body giant cells (FBGC), which damage the surface of biomaterials, is considered a hallmark of this reaction. FBGC derive from blood-borne monocytes that enter the implantation site after surgery in response to the release of chemotactic signals. In this study, we implanted biomaterials subcutaneous (s.c.) in mice that lack the monocyte chemoattractant CC chemokine ligand 2 (CCL2) and found that biomaterials were encapsulated despite reduced FBGC formation. The latter was due to compromised macrophage fusion rather than migration. Consistent with the reduction in FBGC formation, biodegradable biomaterials sustained reduced damage in CCL2-null mice. Furthermore, blockade of CCL2 function by localized gene delivery in wild-type mice hindered FBGC formation, despite normal monocyte recruitment. The requirement for CCL2 in fusion was confirmed by the ability of both a CCL2 inhibitory peptide and an anti-CCL2 Ab to reduce FBGC formation from peripheral blood monocytes in an in vitro assay. Our findings demonstrate a previously unreported involvement of CCL2 in FBGC formation, and suggest that FBGC are not the primary determinants of capsule formation in the FBR.
