PB0145 - Extra-hemostatic roles of FVIII in musculoskeletal system in a FVIII knockout mice model

Sunday, June 25, 2023

18:30 – 19:30 ET

Room: Exhibition

Presenting Author(s)

Babuty Antoine, MD (he/him/his)

PhD Student
Nantes University Hospital, Nantes, France, 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

GLOBAL MEDICAL AFFAIRS DIRECTOR HEMATOLOGY, Bayer
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. Institut de Cancérologie de ‘Ouest, Saint-Herblain, France.
Nantes, Pays de la Loire, France

Background: Hemophilia patients are subject to recurrent bleeding episodes in joints and associated tissues associated with altered angiogenesis, inflammation processes, osteopenia and sarcopenia. Since decades, these bone and muscle disorders has been interpreted as result of the prolonged sedentary lifestyle of affected patients. Recent insights on FVIII protein biology suggest that FVIII may contribute to all of these clinical manifestations independently of its canonical hemostatic functions.

Aims: The present work aims to characterize musculoskeletal tissues in a FVIII knockout (KO) murine model.

Methods: Previous work from our lab showed that FVIII KO mice also exhibit an osteoporotic phenotype as has described in HA patients. Moreover, bone growth and remodeling processes were associated with specific vascular subsets related to subpopulations of endothelial cells. In this context, we have analyzed the vascular networks associated to bone remodeling in tibia bone of WT and FVIII KO mice by immunohistochemistry.

Results: Three different vascular markers (endomucin, alpha-SMA and NG2) were combined to analyze the venous endothelium, arteries and perivascular cells, respectively. Interestingly, our data showed that male FVIII KO mice exhibit a significant decrease of intra-bone blood vessels and perivascular-associated cells compared to WT.In terms of muscle tissue, the weight (Quadriceps) of the skeletal muscles was significantly higher in WT male mice compared to FVIII KO mice. These data reveal, for the first time, an altered skeletal muscle phenotype in male FVIII KO mice corresponding to a sarcopenia. Based on this observation, we characterized the fiber composition of the muscles by immunohistochemistry. FVIII KO mice showed differential composition of muscle fibers more specifically in I and IIb fibers.

Conclusion(s): The absence of FVIII in males has a negative impact in blood vessel amount in bone and fiber muscle composition that may contribute to the osteoporosis and loss of muscle mass observed in FVIII KO mice.