title: Abnormal joint and bone wound healing in hemophilia mice is improved by extending factor IX activity after hemarthrosis.
abstract: Wound healing requires interactions between coagulation, inflammation, angiogenesis, cellular migration, and proliferation. Healing in dermal wounds of hemophilia B mice is delayed when compared with hemostatically normal wild-type (WT) mice, with abnormal persistence of iron deposition, inflammation, and neovascularity. We observed healing following induced joint hemorrhage in WT and factor IX (FIX) knockout (FIX-/-) mice, examining also parameters previously studied in an excisional skin wound model. Hemostatically normal mice tolerated this joint bleeding challenge, cleared blood from the joint, and healed with minimal pathology, even if additional autologous blood was injected intra-articularly at the time of wounding. Following hemarthrosis, joint wound healing in hemophilia B mice was impaired and demonstrated similar abnormal histologic features as previously described in hemophilic dermal wounds. Therefore, studies of pathophysiology and therapy of hemophilic joint bleeding performed in hemostatically normal animals are not likely to accurately reflect the healing defect of hemophilia. We additionally explored the hypothesis that the use of a FIX replacement protein with extended circulating FIX activity could improve synovial and osteochondral wound healing in hemophilic mice, when compared with treatment with unmodified recombinant FIX (rFIX) in the established joint bleeding model. Significantly improved synovial wound healing and preservation of normal osteochondral architecture are achieved by extending FIX activity after hemarthrosis using glycoPEGylated FIX when compared with an equivalent dose of rFIX. These results suggest that treating joint bleeding only until hemostasis is achieved may not result in optimal joint healing, which is improved by extending factor activity.
authors.affiliation: Gene Therapy Center, University of North Carolina, Chapel Hill, NC.
authors.forename: Junjiang
authors.initials: J
authors.lastname: Sun
authors.affiliation: Department of Hematology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
authors.forename: Baolai
authors.initials: B
authors.lastname: Hua
authors.affiliation: Department of Biomedical Engineering, University of North Carolina, Chapel Hill, NC.
authors.forename: Eric W
authors.initials: EW
authors.lastname: Livingston
authors.affiliation: Department of Biomedical Engineering, University of North Carolina, Chapel Hill, NC.|Global Research, Novo Nordisk A/S, Maløv, Denmark.
authors.forename: Sarah
authors.identifier: 0000-0003-2110-0740
authors.initials: S
authors.lastname: Taves
authors.affiliation: Global Research, Novo Nordisk A/S, Maløv, Denmark.
authors.forename: Peter B
authors.initials: PB
authors.lastname: Johansen
authors.affiliation: Department of Pathology, Duke University and Durham Veterans Affairs Medical Centers, Durham, NC.
authors.forename: Maureane
authors.initials: M
authors.lastname: Hoffman
authors.affiliation: Global Research, Novo Nordisk A/S, Maløv, Denmark.
authors.forename: Mirella
authors.initials: M
authors.lastname: Ezban
authors.affiliation: Division of Hematology/Oncology, Department of Medicine.
authors.forename: Dougald M
authors.initials: DM
authors.lastname: Monroe
authors.affiliation: Department of Biomedical Engineering, University of North Carolina, Chapel Hill, NC.|Department of Radiation Oncology, and.
authors.forename: Ted A
authors.initials: TA
authors.lastname: Bateman
authors.affiliation: Gene Therapy Center, University of North Carolina, Chapel Hill, NC.|Harold R. Roberts Comprehensive Hemophilia Diagnosis and Treatment Center, University of North Carolina, Chapel Hill, NC; and.|Shire Plc, Cambridge, MA.
authors.forename: Paul E
authors.identifier: 0000-0001-6759-9888
authors.initials: PE
authors.lastname: Monahan
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D005164:Factor IX / Q000235:genetics / Q000494:pharmacology; D006395:Hemarthrosis / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D002836:Hemophilia B / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D007596:Joints / Q000293:injuries / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D012867:Skin / Q000293:injuries / Q000378:metabolism; D014945:Wound Healing / Q000187:drug effects / Q000235:genetics
chemical_list: D005164:Factor IX