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

Abstract

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 (LTB 4 ) and platelet-activating factor (PAF) were also involved in neutrophil adherence to OBs, as shown by the blocking effect of selective LTB 4 and PAF receptor antagonists, and a cytosolic phospholipase A 2a (cPLA 2a ) inhibitor. Blockade of CD49d/CS1 and inhibition of the cPLA 2a 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 b 1 integrin CD29/CD49d-fibronectin peptide CS1 receptors and cPLA 2a -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;

NLRP3 promotes autophagy of urate crystals phagocytized by human osteoblasts

“…In addition, OBs stimulated by MSU reduce their proliferation rate without change of their viability, and MSU crystals remain intact inside OBs. Together with the bone matrix irregularly calcified and the reduced number of OBs present on the osteoid close to MSU deposits [29], the present results indicate that MSU microcrystals, when phagocytized by the nonprofessional phagocyte OBs, activate NLRP3, which in turn upregulates a nonproductive macroautophagy that fails to clear MSU. Reduced anabolic functions and increased catabolic functions of OBs subsequent to MSU phagocytosis also suggest that MSU-activated OBs can be responsible for reduction of calcified bone matrix and increase of matrix degradation.…”

“…None of the volunteers had metabolic bone disorders or malignancy. Explants and subsequent conditions of culture were as previously described [22,29,45,46]. In brief, OBs were grown in α-MEM supplemented with 10% FBS.…”

“…However, signaling pathways activated by MSU internalization in OBs remain unknown. It is also relevant that the bone matrix close to MSU deposits was shown to be irregularly calcified, that MSU microcrystals were abundant in new bone matrix, and that these events are associated with a low density of OBs dispersed on the osteoid [29]. As a corollary, MSU crystals in the extracellular milieu could lead to different sequences of cell activation, such as initial nonspecific contact with cell membrane, and/or opportunistic occupancy of various receptors with subsequent activation of intracellular signals that lead to their phagocytosis.…”

Cytokine-Mediated Bone Destruction in Rheumatoid Arthritis

“…Thus, the effect of RANKL in activated neutrophils is predominantly mediated by the membrane-bound form, in contrast to activated T cells, where RANKL signaling is mediated by both cell surface and soluble RANKL [106, 107]. In addition, neutrophils affect the function of osteoblasts in children on chronic glucocorticoid therapy and in patients with tophaceous gout, resulting in altered bone remodeling [108, 109]. …”

No impact of serum uric acid on the outcome of recent-onset arthritis

“…In RA, higher levels of SUA have been associated with a higher prevalence of CV disease 4. At the joint level, monosodium urate crystals can negatively influence local bone remodelling by excessive osteoclast formation and reduced osteoblast differentiation 5–7. Taking these data into account, we hypothesised that SUA levels in recent-onset arthritis are associated with a higher inflammatory state and thus might contribute to a more severe outcome, expressed by joint destruction and CV death rates in patients with RA and development of RA in patients with undifferentiated arthritis (UA).…”