Factor VIII-von Willebrand Factor Complex Inhibits Osteoclastogenesis and Controls Cell Survival

Abstract

Factor VIII-von Willebrand factor (FVIII⅐vWF) complex, a molecule involved in coagulation, can be physically associated with osteoprotegerin (OPG). OPG is an anti-osteoclastic protein and a soluble receptor for the proapoptotic protein TRAIL (tumor necrosis factor-related apoptosis-inducing ligand), suggesting a potential role of FVIII⅐vWF complex in bone and cancer biology. We, thus, assessed the effects of FVIII⅐vWF complex on osteoclastogenesis and cell survival. We first evidenced that FVIII⅐vWF complex inhibited RANKL-induced osteoclastogenesis and enhanced the inhibitory effect of OPG. Interestingly, we revealed by surface plasmon resonance that FVIII⅐vWF complex bound to RANKL, whereas recombinant FVIII and vWF did not. By modeling, we showed that the OPG binding domain to the A1 domain of vWF was closely located and partially overlapped to its binding site to RANKL. Then, we demonstrated that FVIII⅐vWF complex cancelled the inhibitory activity of OPG on TRAIL-induced apoptosis and characterized interactions between these molecules. The present work evidenced a direct activity of FVIII⅐vWF complex on osteoclasts and on induced cell apoptosis, pointing out its potential involvement in physiological bone remodeling or in bone damages associated with severe hemophilia and cancer development.The molecular triad osteoprotegerin (OPG) 3 /RANK/RANKL is a crucial parameter of bone biology. Receptor activator of nuclear factor B ligand (RANKL), a member of the tumor necrosis factor family, is mainly expressed by osteoblasts in the bone microenvironment and acts as a pro-resorption factor (1, 2); RANKL binds to its receptor RANK expressed at the cell surface of osteoclast precursors and induces osteoclastic differentiation and maturation, leading to bone resorption (3, 4). OPG, also mainly produced by osteoblasts, is a soluble decoy receptor for RANKL, preventing the binding of RANKL to RANK and, thus, inhibiting osteoclastogenesis (5-7). Bone turnover is tightly controlled by the OPG/RANK/RANKL triad, and any change in the balance OPG/RANKL leads to pathological conditions (7). OPG is also a receptor for tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) (8, 9), a cytokine that is able to induce a rapid cancer cell death by apoptosis (9 -11). Interestingly, the binding of OPG to TRAIL completely inhibits TRAIL-induced cytotoxicity (8). OPG possesses antiapoptotic properties and, therefore, could be considered as a pro-tumoral agent.Factor VIII is a plasma glycoprotein mainly synthesized by hepatocytes but also by kidney, sinusoidal endothelial cells, and in small amounts by lymphatic tissues (12). Factor VIII is one of the main coagulation factors and allows the completion of the coagulation process. Factor VIII circulates in plasma in a noncovalent complex with the von Willebrand factor (FVIII⅐vWF complex). The most well known genetic disease associated with Factor VIII is hemophilia A, which shows an X-linked inheritance (13). A second important disease associated with low Factor VIII levels is von ...

Structure and function of von Willebrand factor

“…The liver is an important site of factor VIII synthesis. Factor VIII circulates in complex with VWF, and this interaction appears to prevent premature proteolytic cleavage and clearance of factor VIII [14,25]. High expression of VWF in the lung could promote homeostatic process that would help to protect against bleeding after injury through adhesion of cells at the alveolar capillary level in the lung [26].…”

Crystal Structure of Human RANKL Complexed with Its Decoy Receptor Osteoprotegerin

“…The complex of vWF with factor VIII has also been shown to interact with OPG through the vWF and abolish the inhibitory effect of OPG on TRAIL-induced apoptosis (45). The modeling indicated that the contact surface of OPG for vWF is composed of residues Cys 41 to Tyr 48 and Tyr 61 to Glu 68 (45), which has partial overlap with binding site I at the RANKL/OPG interface.…”

The Presence of Trail–opg Complex in Human Osteosarcoma and Human Salivary Gland Adenocarcinoma

“…[8][9][10] Further, it is likely that the determination of TRAIL by commercially available enzyme-linked immunosorbent assay (ELISA) is interfered with due to a large amount of OPG in the samples. Although reverse-transcription polymerase chain reaction (RT-PCR), Northern blot analysis, immunoprecipitation, Western blotting, and ELISA for TRAIL were performed in several studies, [14][15][16][17] there is no study on the protein level of TRAIL-OPG complex due to the unavailability of an ELISA. For clarification of the role of TRAIL in the mammalian body especially in tumors, a specific, quantitative, and highly sensitive assay for the TRAIL-OPG complex is indispensable.…”