Osteoblast retraction induced by adherent neutrophils promotes osteoclast bone resorption: implication for altered bone remodeling in chronic gout

Bone destruction in chronic gout is correlated with deposits of monosodium urate (MSU) crystals. Bone with MSU tophi were histopathologically shown to have altered remodeling and cellular distribution. We investigated the impact of neutrophils in bone remodeling associated with MSU and demonstrated that neutrophils, through elastase localized at their surface, induced retraction of confluent osteoblasts (OBs) previously layered on calcified matrix. This OB retraction allowed osteoclasts to resorb cell-free areas of the matrix. This neutrophil effect was concentration dependent and time dependent and required direct contact with OBs. Exposure of OBs to MSU greatly promoted neutrophil adherence to OBs. Neutrophil membrane at the contact zone with OBs showed concentrated fluorescence of dye PKH-67, indicating a cellular contact. Neutrophil-OB interaction increased the survival of neutrophils, reduced their release of lactoferrin in presence of MSU and did not change OB-mediated mineralization. The adhesion of neutrophils to OBs was heterotypic through neutrophil CD29/CD49d and OB-fibronectin peptide CS1. Leukotriene B-4 (LTB4) and platelet-activating factor (PAF) were also involved in neutrophil adherence to OBs, as shown by the blocking effect of selective LTB4 and PAF receptor antagonists, and a cytosolic phospholipase A(2 alpha) (cPLA(2 alpha)) inhibitor. Blockade of CD49d/CS1 and inhibition of the cPLA(2 alpha) had subadditive effects, reducing by 60% the adherence of neutrophils to OBs. Taken together, these data showed that neutrophil adhesion to MSU-activated OBs was mediated by the beta(1) integrin CD29/CD49d-fibronectin peptide CS1 receptors and cPLA(2 alpha)-derived metabolites and impacts on OB and osteoclast functions. These interactions could be involved in the local bone remodeling process of gout. Laboratory Investigation (2011) 91, 905-920; doi:10.1038/labinvest.2011.46; published online 14 March 2011