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

Overview

Journal J Biol Chem

Specialty Biochemistry

Date 2009 Sep 18

PMID 19758994

Citations 26

Authors

Marc Baudhuin

Laurence Duplomb

Stephane Teletchea

Celine Charrier

Mike Maillasson

Marc Fouassier

Dominique Heymann

Affiliations

Soon will be listed here.

Abstract

Factor VIII-von Willebrand factor (FVIII.vWF) 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 FVIII.vWF complex in bone and cancer biology. We, thus, assessed the effects of FVIII.vWF complex on osteoclastogenesis and cell survival. We first evidenced that FVIII.vWF complex inhibited RANKL-induced osteoclastogenesis and enhanced the inhibitory effect of OPG. Interestingly, we revealed by surface plasmon resonance that FVIII.vWF 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 FVIII.vWF 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 FVIII.vWF 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.

Citing Articles

Bone and Hemophilia: The Role of Factor VIII-Systematic Review.

Berni M, Forlino A, Caliogna L, Felice L, Di Minno M, Jannelli E Int J Mol Sci. 2025; 26(5).

PMID: 40076794 PMC: 11900269. DOI: 10.3390/ijms26052172.

Could PTH/Ca Ratio Serve as a New Marker for Evaluating Bone Metabolism in Hemophilia Patients?.

Ersal T, Hunutlu F, Gursoy V, Elgun E, Yavuz S, Dal Akkus I Diagnostics (Basel). 2025; 15(5).

PMID: 40075885 PMC: 11899577. DOI: 10.3390/diagnostics15050638.

von Willebrand disease and angiodysplasia: a wider view of pathogenesis in pursuit of therapy.

Crossette-Thambiah C, Randi A, Laffan M Haematologica. 2024; 110(3):588-595.

PMID: 39506901 PMC: 11873708. DOI: 10.3324/haematol.2024.285244.

Effects of coagulation factors on bone cells and consequences of their absence in haemophilia a patients.

Battafarano G, Lancellotti S, Sacco M, Rossi M, Terreri S, Di Gregorio J Sci Rep. 2024; 14(1):25001.

PMID: 39443571 PMC: 11499919. DOI: 10.1038/s41598-024-75747-w.

Novel functions for von Willebrand factor.

Atiq F, ODonnell J Blood. 2024; 144(12):1247-1256.

PMID: 38728426 PMC: 11561537. DOI: 10.1182/blood.2023021915.

References

Duplomb L, Baudhuin M, Charrier C, Berreur M, Trichet V, Blanchard F . Interleukin-6 inhibits receptor activator of nuclear factor kappaB ligand-induced osteoclastogenesis by diverting cells into the macrophage lineage: key role of Serine727 phosphorylation of signal transducer and activator of transcription 3. Endocrinology. 2008; 149(7):3688-97. DOI: 10.1210/en.2007-1719. View

Pitti R, Marsters S, Ruppert S, Donahue C, Moore A, Ashkenazi A . Induction of apoptosis by Apo-2 ligand, a new member of the tumor necrosis factor cytokine family. J Biol Chem. 1996; 271(22):12687-90. DOI: 10.1074/jbc.271.22.12687. View

Baudhuin M, Lamoureux F, Duplomb L, Redini F, Heymann D . RANKL, RANK, osteoprotegerin: key partners of osteoimmunology and vascular diseases. Cell Mol Life Sci. 2007; 64(18):2334-50. PMC: 11149428. DOI: 10.1007/s00018-007-7104-0. View

DE PALMA A, COTLER J . Hemophilic arthropathy. AMA Arch Surg. 1956; 72(2):247-50. DOI: 10.1001/archsurg.1956.01270200063011. View

Nichols W, Hultin M, James A, Manco-Johnson M, Montgomery R, Ortel T . von Willebrand disease (VWD): evidence-based diagnosis and management guidelines, the National Heart, Lung, and Blood Institute (NHLBI) Expert Panel report (USA). Haemophilia. 2008; 14(2):171-232. DOI: 10.1111/j.1365-2516.2007.01643.x. View

Fukuda K, Doggett T, Bankston L, Cruz M, Diacovo T, Liddington R . Structural basis of von Willebrand factor activation by the snake toxin botrocetin. Structure. 2002; 10(7):943-50. DOI: 10.1016/s0969-2126(02)00787-6. View

Kovacs C . Hemophilia, low bone mass, and osteopenia/osteoporosis. Transfus Apher Sci. 2008; 38(1):33-40. DOI: 10.1016/j.transci.2007.12.003. View

Johnstone R, Frew A, Smyth M . The TRAIL apoptotic pathway in cancer onset, progression and therapy. Nat Rev Cancer. 2008; 8(10):782-98. DOI: 10.1038/nrc2465. View

Burgess T, Qian Y, Kaufman S, Ring B, Van G, Capparelli C . The ligand for osteoprotegerin (OPGL) directly activates mature osteoclasts. J Cell Biol. 1999; 145(3):527-38. PMC: 2185088. DOI: 10.1083/jcb.145.3.527. View

10.

Franchini M, Targher G, Manzato F, Lippi G . Acquired factor VIII inhibitors in oncohematology: a systematic review. Crit Rev Oncol Hematol. 2008; 66(3):194-9. DOI: 10.1016/j.critrevonc.2007.12.004. View

11.

Wiley S, Schooley K, Smolak P, Din W, Huang C, Nicholl J . Identification and characterization of a new member of the TNF family that induces apoptosis. Immunity. 1995; 3(6):673-82. DOI: 10.1016/1074-7613(95)90057-8. View

12.

Degli-Esposti M . To die or not to die--the quest of the TRAIL receptors. J Leukoc Biol. 1999; 65(5):535-42. DOI: 10.1002/jlb.65.5.535. View

13.

Kong Y, Yoshida H, Sarosi I, Tan H, Timms E, Capparelli C . OPGL is a key regulator of osteoclastogenesis, lymphocyte development and lymph-node organogenesis. Nature. 1999; 397(6717):315-23. DOI: 10.1038/16852. View

14.

Bucay N, Sarosi I, Dunstan C, Morony S, Tarpley J, Capparelli C . osteoprotegerin-deficient mice develop early onset osteoporosis and arterial calcification. Genes Dev. 1998; 12(9):1260-8. PMC: 316769. DOI: 10.1101/gad.12.9.1260. View

15.

Simonet W, Lacey D, Dunstan C, Kelley M, Chang M, Luthy R . Osteoprotegerin: a novel secreted protein involved in the regulation of bone density. Cell. 1997; 89(2):309-19. DOI: 10.1016/s0092-8674(00)80209-3. View

16.

LARKIN M, Blackshields G, Brown N, Chenna R, McGettigan P, McWilliam H . Clustal W and Clustal X version 2.0. Bioinformatics. 2007; 23(21):2947-8. DOI: 10.1093/bioinformatics/btm404. View

17.

Emery J, McDonnell P, Burke M, Deen K, Lyn S, SILVERMAN C . Osteoprotegerin is a receptor for the cytotoxic ligand TRAIL. J Biol Chem. 1998; 273(23):14363-7. DOI: 10.1074/jbc.273.23.14363. View

18.

Manco-Johnson M, Abshire T, Shapiro A, Riske B, Hacker M, Kilcoyne R . Prophylaxis versus episodic treatment to prevent joint disease in boys with severe hemophilia. N Engl J Med. 2007; 357(6):535-44. DOI: 10.1056/NEJMoa067659. View

19.

Ito S, Wakabayashi K, Ubukata O, Hayashi S, Okada F, Hata T . Crystal structure of the extracellular domain of mouse RANK ligand at 2.2-A resolution. J Biol Chem. 2001; 277(8):6631-6. DOI: 10.1074/jbc.M106525200. View

20.

Pan G, Ni J, Wei Y, Yu G, Gentz R, Dixit V . An antagonist decoy receptor and a death domain-containing receptor for TRAIL. Science. 1997; 277(5327):815-8. DOI: 10.1126/science.277.5327.815. View