Abstract
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.
Highlights
Hemophilia A and hemophilia B are X-linked recessive inherited bleeding disorders caused by deficient activity of blood coagulation factors VIII (FVIII) and IX (FIX), respectively, resulting in severely deficient thrombin generation
Unlike FVIII−/− and FIX−/− mice, Von Willebrand factor (VWF)−/− mice showed no difference in whole body bone mineral density (BMD) compared to their wild type (WT) littermates at any time point (Table 1, Fig. 1B)
Bone density is determined by a continuous process of coordinated bone formation by osterix+ osteoblastic cells and bone resorption by Tartrate-resistant acid phosphatase (TRAP)+ osteoclasts associated with a dysregulation between OPG and receptor activator of nuclear factor-kappa B (RANK) ligand (RANKL) levels
Summary
Hemophilia A and hemophilia B are X-linked recessive inherited bleeding disorders caused by deficient activity of blood coagulation factors VIII (FVIII) and IX (FIX), respectively, resulting in severely deficient thrombin generation. Recent studies of hemophilia A mice suggest that increased bone resorption and low bone mineral density may be associated with factor VIII deficiency even in the absence of gross hemarthrosis[9,10]. Utilizing mouse FVIII, FIX, and VWF gene knockout disease models (FVIII−/− FIX−/− VWF−/−, respectively, and their WT littermate controls), we compared congenital bone structure as well as remodeling phenotypes following joint hemorrhage. Despite the close physiologic association of VWF with FVIII, we report that male VWF−/− mice do not display this congenital abnormal bone phenotype Hemarthrosis exacerbated these congenital BMD and structural differences in hemophilia mice. At two weeks post-injury, FVIII−/− and FIX−/− mice exhibited drastic trabecular bone loss and large areas of heterotopic mineralization of the cortical bone surface These observations prompted a time course study of early bone response to joint hemorrhage in FVIII−/− mice. VWF−/− animals did not display the same characteristics, leading to the conclusion that an intact FVIII/VWF complex is not required for bone remodeling post-injury
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