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...
Autores principales: | , , , , , , , , , |
---|---|
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 |