Cargando…

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

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...

Descripción completa

Detalles Bibliográficos
Autores principales: Taves, Sarah, Sun, Junjiang, Livingston, Eric W., Chen, Xin, Amiaud, Jerome, Brion, Regis, Hannah, William B., Bateman, Ted A., Heymann, Dominique, Monahan, Paul E.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6783554/
https://www.ncbi.nlm.nih.gov/pubmed/31594977
http://dx.doi.org/10.1038/s41598-019-50787-9
_version_ 1783457581301235712
author Taves, Sarah
Sun, Junjiang
Livingston, Eric W.
Chen, Xin
Amiaud, Jerome
Brion, Regis
Hannah, William B.
Bateman, Ted A.
Heymann, Dominique
Monahan, Paul E.
author_facet Taves, Sarah
Sun, Junjiang
Livingston, Eric W.
Chen, Xin
Amiaud, Jerome
Brion, Regis
Hannah, William B.
Bateman, Ted A.
Heymann, Dominique
Monahan, Paul E.
author_sort Taves, Sarah
collection PubMed
description 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.
format Online
Article
Text
id pubmed-6783554
institution National Center for Biotechnology Information
language English
publishDate 2019
publisher Nature Publishing Group UK
record_format MEDLINE/PubMed
spelling pubmed-67835542019-10-17 Hemophilia A and B mice, but not VWF(−/−)mice, display bone defects in congenital development and remodeling after injury Taves, Sarah Sun, Junjiang Livingston, Eric W. Chen, Xin Amiaud, Jerome Brion, Regis Hannah, William B. Bateman, Ted A. Heymann, Dominique Monahan, Paul E. Sci Rep Article 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. Nature Publishing Group UK 2019-10-08 /pmc/articles/PMC6783554/ /pubmed/31594977 http://dx.doi.org/10.1038/s41598-019-50787-9 Text en © The Author(s) 2019 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Taves, Sarah
Sun, Junjiang
Livingston, Eric W.
Chen, Xin
Amiaud, Jerome
Brion, Regis
Hannah, William B.
Bateman, Ted A.
Heymann, Dominique
Monahan, Paul E.
Hemophilia A and B mice, but not VWF(−/−)mice, display bone defects in congenital development and remodeling after injury
title Hemophilia A and B mice, but not VWF(−/−)mice, display bone defects in congenital development and remodeling after injury
title_full Hemophilia A and B mice, but not VWF(−/−)mice, display bone defects in congenital development and remodeling after injury
title_fullStr Hemophilia A and B mice, but not VWF(−/−)mice, display bone defects in congenital development and remodeling after injury
title_full_unstemmed Hemophilia A and B mice, but not VWF(−/−)mice, display bone defects in congenital development and remodeling after injury
title_short Hemophilia A and B mice, but not VWF(−/−)mice, display bone defects in congenital development and remodeling after injury
title_sort hemophilia a and b mice, but not vwf(−/−)mice, display bone defects in congenital development and remodeling after injury
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6783554/
https://www.ncbi.nlm.nih.gov/pubmed/31594977
http://dx.doi.org/10.1038/s41598-019-50787-9
work_keys_str_mv AT tavessarah hemophiliaaandbmicebutnotvwfmicedisplaybonedefectsincongenitaldevelopmentandremodelingafterinjury
AT sunjunjiang hemophiliaaandbmicebutnotvwfmicedisplaybonedefectsincongenitaldevelopmentandremodelingafterinjury
AT livingstonericw hemophiliaaandbmicebutnotvwfmicedisplaybonedefectsincongenitaldevelopmentandremodelingafterinjury
AT chenxin hemophiliaaandbmicebutnotvwfmicedisplaybonedefectsincongenitaldevelopmentandremodelingafterinjury
AT amiaudjerome hemophiliaaandbmicebutnotvwfmicedisplaybonedefectsincongenitaldevelopmentandremodelingafterinjury
AT brionregis hemophiliaaandbmicebutnotvwfmicedisplaybonedefectsincongenitaldevelopmentandremodelingafterinjury
AT hannahwilliamb hemophiliaaandbmicebutnotvwfmicedisplaybonedefectsincongenitaldevelopmentandremodelingafterinjury
AT batemanteda hemophiliaaandbmicebutnotvwfmicedisplaybonedefectsincongenitaldevelopmentandremodelingafterinjury
AT heymanndominique hemophiliaaandbmicebutnotvwfmicedisplaybonedefectsincongenitaldevelopmentandremodelingafterinjury
AT monahanpaule hemophiliaaandbmicebutnotvwfmicedisplaybonedefectsincongenitaldevelopmentandremodelingafterinjury