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Coagulation factor VIII deficient (FVIII<jats:sup>\u2212\/\u2212<\/jats:sup>) 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<jats:sup>\u2212\/\u2212<\/jats:sup>, FIX<jats:sup>\u2212\/\u2212<\/jats:sup>, and VWF<jats:sup>\u2212\/\u2212<\/jats:sup> respectively) mice both in the absence of joint hemorrhage and following induced joint injury. We found FVIII<jats:sup>\u2212\/\u2212<\/jats:sup> and FIX<jats:sup>\u2212\/\u2212<\/jats:sup> mice, but not VWF<jats:sup>\u2212\/\u2212<\/jats:sup> mice, developmentally have an osteoporotic phenotype. Unilateral induced hemarthrosis causes further bone damage in both FVIII<jats:sup>\u2212\/\u2212<\/jats:sup> and FIX<jats:sup>\u2212\/\u2212<\/jats:sup> mice, but has little effect on VWF<jats:sup>\u2212\/\u2212<\/jats:sup> bone health, indicating that the FVIII.VWF complex is not required for normal bone remodeling <jats:italic>in vivo<\/jats:italic>. 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<jats:sup>+<\/jats:sup> 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.<\/jats:p>","DOI":"10.1038\/s41598-019-50787-9","type":"journal-article","created":{"date-parts":[[2019,10,8]],"date-time":"2019-10-08T10:25:35Z","timestamp":1570530335000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":24,"title":["Hemophilia A and B mice, but not VWF\u2212\/\u2212mice, display bone defects in congenital development and remodeling after injury"],"prefix":"10.1038","volume":"9","author":[{"given":"Sarah","family":"Taves","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junjiang","family":"Sun","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eric W.","family":"Livingston","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xin","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jerome","family":"Amiaud","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Regis","family":"Brion","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William B.","family":"Hannah","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ted A.","family":"Bateman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dominique","family":"Heymann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul E.","family":"Monahan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2019,10,8]]},"reference":[{"key":"50787_CR1","doi-asserted-by":"publisher","first-page":"S18","DOI":"10.1053\/j.seminhematol.2005.11.026","volume":"43","author":"WK Hoots","year":"2006","unstructured":"Hoots, W. 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Monahan during the conduct of these studies received research support through the University of North Carolina from Baxter Healthcare, Asklepios BioPharmaceutical and Novo Nordisk. He has received research support in the past from Baxter Healthcare, Novo Nordisk, and Pfizer. He holds patents licensed to Asklepios, for which he receives royalties. He has received payment for consultation, services, and for speaking for Asklepios, Chatham LLC, Baxter Healthcare and Pfizer and has additionally consulted for Bayer, Novo Nordisk, and Biogen. Following the completion of these studies but during a portion of the time of manuscript preparation he was an employee of Baxalta (now a part of Shire). He is now an employee of Spark Therapeutics.\u201d Dr T.A. Bateman has received compensation for consulting and speaker work for Baxter Health Care Corporation and research support from Novo Nordisk. Prof. D. Heymann has received research support from Baxter\/Baxalta (now a part of Shire). Dr Sarah Taves was an employee of Novo Nordisk (during the conduct of these studies) via the STAR Fellowship mechanism. J. Sun, EW Livingston, X Chen, J Amiaud, R Brion, WB Hannah have no relevant disclosures or conflicts of interest to declare.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing Interests"}}],"article-number":"14428"}}