Syndecan-1 Is Involved in Osteoprotegerin-Induced Chemotaxis in Human Peripheral Blood Monocytes

Abstract

Chronic inflammation is characterized by tissue infiltration with monocytes/macrophages, which possess broad proinflammatory, destructive, and remodeling capacities. Elevated levels of osteoprotegerin, an important regulator of differentiation and activation of osteoclasts that also affects different cells of the immune system, were found in the serum of patients with chronic inflammatory diseases. The study of whether osteoprotegerin affects monocyte locomotion in vitro and the possible mechanisms and pathways involved was investigated using Boyden microchemotaxis chambers and Western blot analyses. Osteoprotegerin significantly stimulated monocyte chemotaxis, whereas preincubation of monocytes with osteoprotegerin inhibited monocyte migration toward optimal concentrations of regulated upon activation normal T cell expressed and secreted, monocyte chemotactic protein -1, and procalcitonin. The effects of osteoprotegerin were abolished by pretreating cells with heparinase I and chondroitinase or antibodies against the ectodomain of syndecan-1. Osteoprotegerin signaling was shown to involve protein kinase C, phosphatidylinositol 3-kinase/Akt, and tyrosine kinase. Data suggest that osteoprotegerin affects monocyte mi-gration and protein kinase C and phosphatidylinositol 3-kinase/Akt activation via syndecan-1. Osteoprotegerin-induced deactivation of monocyte chemotaxis toward different chemokines is due to interaction of osteoprotegerin with heparan sulfate and chondroitin sulfate.

Evidence of a Role for Osteoprotegerin in the Pathogenesis of Pulmonary Arterial Hypertension

“…Another proposed binding partner for OPG is syndecan-1, and data suggest that OPG can mediate the migration of monocytes via interaction with syndecan-1. 28 Interestingly, the expression of syndecan-1 has been shown to be increased in a rabbit aortic neointimal model; 29 however, we failed to detect expression of syndecan-1 within the pulmonary artery (control or lesions) despite a detectable level of syndecan-1 mRNA in PA-SMCs in culture (A. Lawrie and M. Southwood, unpublished data). The effect of TRAIL on vascular homeostasis is a debated topic with conflicting reports on endothelial cell apoptosis (reviewed by Zauli and Secchiero 30 ) and data suggesting that TRAIL may be a survival, mitotic, and migratory factor for SMCs.…”

Osteoprotegerin: Multiple partners for multiple functions

“…Moreover, OPG induces osteopontin expression via syndecan-1 and activates phosphoinositol 3-kinase/Akt in human periodontal ligament cells (Yongchaitrakul et al 2009). PGs are also involved in OPG-induced chemotaxis of monocytes (Mosheimer et al 2005). Indeed, OPG can interact with syndecan-1 expressed by monocytes (potential osteoclast precursors) and can stimulate the cell migration.…”

New Perspective in Osteoarthritis: The OPG and RANKL System as a Potential Therapeutic Target?

“…It has been shown that OPG, through its heparin binding domain interacts with some proteoglycans such as syndecan-1 and that OPG binding to cells expressing high levels of membranous syndecan-1 is internalized, then degraded. 51,52 Similarly, with RANKL expressing cells, the binding of OPG to membranous RANKL is also internalized, yet through another process, the clathrin coat formation pathway, which occurs before proteasomal and lysosomal degradation (Fig. 3).…”