title: The Tissue Fibrinolytic System Contributes to the Induction of Macrophage Function and CCL3 during Bone Repair in Mice.
abstract: Macrophages play crucial roles in repair process of various tissues. However, the details in the role of macrophages during bone repair still remains unknown. Herein, we examined the contribution of the tissue fibrinolytic system to the macrophage functions in bone repair after femoral bone defect by using male mice deficient in plasminogen (Plg-/-), urokinase-type plasminogen activator (uPA-/-) or tissue-type plasminogen activator (tPA-/-) genes and their wild-type littermates. Bone repair of the femur was delayed in uPA-/- mice until day 6, compared with wild-type (uPA+/+) mice. Number of Osterix-positive cells and vessel formation were decreased in uPA-/- mice at the bone injury site on day 4, compared with those in uPA+/+ mice. Number of macrophages and their phagocytosis at the bone injury site were reduced in uPA-/- and Plg-/-, but not in tPA-/- mice on day 4. Although uPA or plasminogen deficiency did not affect the levels of cytokines, including TNF-α, IL-1β, IL-6, IL-4 and IFN-γ mRNA in the damaged femur, the elevation in CCL3 mRNA levels was suppressed in uPA-/- and Plg-/-, but not in tPA-/- mice. Neutralization of CCL3 antagonized macrophage recruitment to the site of bone injury and delayed bone repair in uPA+/+, but not in uPA-/- mice. Our results provide novel evidence that the tissue fibrinolytic system contributes to the induction of macrophage recruitment and CCL3 at the bone injury site, thereby, leading to the enhancement of the repair process.
authors.affiliation: Department of Physiology and Regenerative Medicine, Kinki University Faculty of Medicine, Osakasayama, Japan.
authors.forename: Naoyuki
authors.initials: N
authors.lastname: Kawao
authors.affiliation: Department of Physiology and Regenerative Medicine, Kinki University Faculty of Medicine, Osakasayama, Japan.
authors.forename: Yukinori
authors.initials: Y
authors.lastname: Tamura
authors.affiliation: Life Science Research Institute, Kinki University, Osaka, Japan.
authors.forename: Yoshitaka
authors.initials: Y
authors.lastname: Horiuchi
authors.affiliation: Life Science Research Institute, Kinki University, Osaka, Japan.
authors.forename: Katsumi
authors.initials: K
authors.lastname: Okumoto
authors.affiliation: Department of Physiology and Regenerative Medicine, Kinki University Faculty of Medicine, Osakasayama, Japan.
authors.forename: Masato
authors.initials: M
authors.lastname: Yano
authors.affiliation: Department of Physiology and Regenerative Medicine, Kinki University Faculty of Medicine, Osakasayama, Japan.
authors.forename: Kiyotaka
authors.initials: K
authors.lastname: Okada
authors.affiliation: Department of Physiology and Regenerative Medicine, Kinki University Faculty of Medicine, Osakasayama, Japan.
authors.forename: Osamu
authors.initials: O
authors.lastname: Matsuo
authors.affiliation: Department of Physiology and Regenerative Medicine, Kinki University Faculty of Medicine, Osakasayama, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kaji
mesh_terms: D000818:Animals; D057134:Antibodies, Neutralizing / Q000494:pharmacology; D002356:Cartilage / Q000187:drug effects / Q000473:pathology; D002452:Cell Count; D018932:Chemokine CCL2 / Q000235:genetics / Q000378:metabolism; D054405:Chemokine CCL3 / Q000235:genetics / Q000378:metabolism*; D054407:Chemokine CCL4 / Q000235:genetics / Q000378:metabolism; D005269:Femur / Q000098:blood supply / Q000187:drug effects / Q000473:pathology*; D005342:Fibrinolysis / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D051379:Mice; D010006:Osteoblasts / Q000187:drug effects / Q000378:metabolism; D010010:Osteoclasts / Q000187:drug effects / Q000378:metabolism; D010587:Phagocytosis / Q000187:drug effects; D010958:Plasminogen / Q000172:deficiency / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D000076182:Sp7 Transcription Factor; D013997:Time Factors; D010959:Tissue Plasminogen Activator / Q000172:deficiency / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism; D014568:Urokinase-Type Plasminogen Activator / Q000172:deficiency / Q000378:metabolism; D014945:Wound Healing / Q000187:drug effects
chemical_list: D057134:Antibodies, Neutralizing; D018932:Chemokine CCL2; D054405:Chemokine CCL3; D054407:Chemokine CCL4; D012333:RNA, Messenger; D000076182:Sp7 Transcription Factor; C479466:Sp7 protein, mouse; D014157:Transcription Factors; D010958:Plasminogen; D010959:Tissue Plasminogen Activator; D014568:Urokinase-Type Plasminogen Activator