Hemophilia A and B mice, but not VWF−/−mice, display bone defects in congenital development and remodeling after injury

Sarah Taves, Junjiang Sun, Eric W. Livingston, Xin Chen, Jerome Amiaud, Regis Brion, William B. Hannah, Ted A. Bateman, Dominique Heymann, Paul E. Monahan

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13 Scopus citations


While joint damage is the primary co-morbidity of hemophilia, osteoporosis and osteopenia are also observed. Coagulation factor VIII deficient (FVIII−/−) mice develop an osteoporotic phenotype in the absence of induced hemarthrosis that is exacerbated two weeks after an induced joint injury. Here we have compared comprehensively the bone health of clotting factor VIII, factor IX, and Von Willebrand Factor knockout (FVIII−/−, FIX−/−, and VWF−/− respectively) mice both in the absence of joint hemorrhage and following induced joint injury. We found FVIII−/− and FIX−/− mice, but not VWF−/− mice, developmentally have an osteoporotic phenotype. Unilateral induced hemarthrosis causes further bone damage in both FVIII−/− and FIX−/− mice, but has little effect on VWF−/− bone health, indicating that the FVIII.VWF complex is not required for normal bone remodeling in vivo. To further investigate the bone healing following hemarthrosis in hemophilia we examined a two week time course using microCT, serum chemistry, and histological analysis. Elevated ratio of osteoprotegerin (OPG)/receptor activator of nuclear factor-kappa B ligand (RANKL), increased osterix+ osteoblastic cells, and decreased smoothness of the cortical bone surface were evident within several days of injury, indicative of acute heterotopic mineralization along the cortical surface. This was closely followed by increased interleukin-6 (IL-6) levels, increased osteoclast numbers, and significant trabecular bone loss. Uncoupled and disorganized bone formation and resorption continued for the duration of the study resulting in significant deterioration of the joint. Further elucidation of the shared mechanisms underlying abnormal bone homeostasis in the absence of FVIII or FIX is needed to guide evidence-based approaches to the screening and treatment of the prevalent bone defects in hemophilia A and B.

Original languageEnglish (US)
Article number14428
JournalScientific reports
Issue number1
StatePublished - Dec 1 2019
Externally publishedYes

ASJC Scopus subject areas

  • General


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