PB0213 - Recombinant FVIII restore musculoskeletal parameters in a FVIII knockout mice model

Sunday, June 23, 2024

13:45 – 14:45 ICT

Room: Exhibition Hall

Presenting Author(s)

Antoine Babuty, MD

PhD Student
Nantes Université, CNRS UMR6286, US2B, Nantes, France.
Nantes, Pays de la Loire, France

Co-Author(s)

JM

Javier Munoz Garcia

scientist researcher
Nantes Université, CNRS UMR6286, US2B, Nantes, France,Institut de Cancérologie de ‘Ouest, Saint-Herblain, France.
Nantes, Pays de la Loire, France
LF

Laurie Fradet

laboratory technician
Institut de Cancérologie de ‘Ouest, Saint-Herblain, France.
Nantes, Pays de la Loire, France
DC

Denis Cochonneau

scientific engineer
Institut de Cancérologie de ‘Ouest, Saint-Herblain, France.
Nantes, Pays de la Loire, France
MH

Marie-Françoise Heymann

Professor of Medicine
Nantes Université, CNRS UMR6286, US2B, Nantes, France,Institut de Cancérologie de ‘Ouest, Saint-Herblain, France.
Nantes, Pays de la Loire, France
FD

Frank Driessler

MEDICAL AFFAIRS, HEMATOLOGY, Bayer
Bayer Consumer Care AG, Peter Merian Straße 84, CH-4052 BASEL
Basel, Basel-Landschaft, Switzerland
CL

Claudia Lange

MEDICAL AFFAIRS, HEMATOLOGY, Bayer
Bayer Consumer Care AG, Peter Merian Straße 84, CH-4052 BASEL
Basel, Basel-Landschaft, Switzerland
OB

Oleksandr Boychenko

scientist researcher
Bayer Consumer Care AG, Peter Merian Straße 84, CH-4052 BASEL
Basel, Basel-Landschaft, Switzerland
DH

Dominique Heymann

Professor of Medicine
Nantes Université, CNRS UMR6286, US2B, Nantes, France,Institut de Cancérologie de ‘Ouest, Saint-Herblain, France.
Nantes, Pays de la Loire, France

Background:

Background:
Hemophilia patients are subject to recurrent bleeding episodes in joints and related tissues associated with altered angiogenesis, inflammation process, osteopenia and sarcopenia. Recent insights on Factor VIII (FVIII) protein biology suggest that FVIII may contribute to all of these clinical manifestations independently of its canonical hemostatic functions.

Aims:

Aim:
The present work aims to characterize the roles of FVIII on the musculoskeletal development of FVIII knockout (KO) male mice.

Methods:

Methods:
Bone parameters were followed by X-ray micro tomodensitometry, bone vascularization (endomucin, alpha-SMA and NG2 markers), osteoblasts (osterix) and osteoclasts (TRAP) were analyzed by immunohistochemistry. Skeletal muscles were weighed and stained for laminin and myosin subtypes to characterize fiber size and composition. Effects of FVIII were studied by injecting recombinant FVIII (rFVIII) once a week, for 6 weeks. Proteomics and metabolomics data were also performed on bone and muscle tissues.

Results:

Results:
As expected FVIII KO mice exhibit an osteoporotic phenotype (e.g. decrease bone trabecular number in FVIII KO mice, p< 0.001, Mann-Whitney test). Interestingly, this bone loss was associated with reduced bone vascularization as revealed by a decrease of endomucin staining, p< 0.001, Mann Whitney Test) compared to Wild Type (WT) mice. This phenotype was rescued by weekly injection of rFVIII.
Quadriceps and tibialis anterior muscles of young mice were surprisingly heavier in FVIII KO mice and exhibits larger fibers. A shift from type IIx to type IIb fibers was observed in FVIII KO mice. This was not reversed by FVIII treatment.
Proteomics and metabolomics data confirmed strong differentiation between WT and FVIII KO muscles and bones.

Conclusion(s):

Conclusion:
The absence of FVIII in males has a negative impact in blood vessel amount in bone that may contribute to the musculoskeletal phenotype observed in FVIII KO mice. Further analyses are underway to determine whether these effects are specific to FVIII or thrombin.