title: Lnk-dependent axis of SCF-cKit signal for osteogenesis in bone fracture healing.
abstract: The therapeutic potential of hematopoietic stem cells/endothelial progenitor cells (HSCs/EPCs) for fracture healing has been demonstrated with evidence for enhanced vasculogenesis/angiogenesis and osteogenesis at the site of fracture. The adaptor protein Lnk has recently been identified as an essential inhibitor of stem cell factor (SCF)-cKit signaling during stem cell self-renewal, and Lnk-deficient mice demonstrate enhanced hematopoietic reconstitution. In this study, we investigated whether the loss of Lnk signaling enhances the regenerative response during fracture healing. Radiological and histological examination showed accelerated fracture healing and remodeling in Lnk-deficient mice compared with wild-type mice. Molecular, physiological, and morphological approaches showed that vasculogenesis/angiogenesis and osteogenesis were promoted in Lnk-deficient mice by the mobilization and recruitment of HSCs/EPCs via activation of the SCF-cKit signaling pathway in the perifracture zone, which established a favorable environment for bone healing and remodeling. In addition, osteoblasts (OBs) from Lnk-deficient mice had a greater potential for terminal differentiation in response to SCF-cKit signaling in vitro. These findings suggest that inhibition of Lnk may have therapeutic potential by promoting an environment conducive to vasculogenesis/angiogenesis and osteogenesis and by facilitating OB terminal differentiation, leading to enhanced fracture healing.
authors.affiliation: Group of Vascular Regeneration Research, Institute of Biomedical Research and Innovation, Department of Orthopedic Surgery, Kobe University Graduate School of Medicine, 565-8686, Osaka, Japan.
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Matsumoto
authors.forename: Masaaki
authors.initials: M
authors.lastname: Ii
authors.forename: Hiromi
authors.initials: H
authors.lastname: Nishimura
authors.forename: Taro
authors.initials: T
authors.lastname: Shoji
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Mifune
authors.forename: Atsuhiko
authors.initials: A
authors.lastname: Kawamoto
authors.forename: Ryosuke
authors.initials: R
authors.lastname: Kuroda
authors.forename: Tomoaki
authors.initials: T
authors.lastname: Fukui
authors.forename: Yohei
authors.initials: Y
authors.lastname: Kawakami
authors.forename: Tomoya
authors.initials: T
authors.lastname: Kuroda
authors.forename: Sang Mo
authors.initials: SM
authors.lastname: Kwon
authors.forename: Hiroto
authors.initials: H
authors.lastname: Iwasaki
authors.forename: Miki
authors.initials: M
authors.lastname: Horii
authors.forename: Ayumi
authors.initials: A
authors.lastname: Yokoyama
authors.forename: Akira
authors.initials: A
authors.lastname: Oyamada
authors.forename: Sang Yang
authors.initials: SY
authors.lastname: Lee
authors.forename: Shinya
authors.initials: S
authors.lastname: Hayashi
authors.forename: Masahiro
authors.initials: M
authors.lastname: Kurosaka
authors.forename: Satoshi
authors.initials: S
authors.lastname: Takaki
authors.forename: Takayuki
authors.initials: T
authors.lastname: Asahara
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D002454:Cell Differentiation; D017102:Fracture Healing; D050723:Fractures, Bone / Q000378:metabolism / Q000503:physiopathology / Q000628:therapy; D006410:Hematopoiesis / Q000235:genetics; D006412:Hematopoietic Stem Cells / Q000378:metabolism / Q000473:pathology; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D051379:Mice; D009389:Neovascularization, Pathologic; D018919:Neovascularization, Physiologic; D010006:Osteoblasts / Q000378:metabolism / Q000473:pathology; D010012:Osteogenesis / Q000235:genetics; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D019009:Proto-Oncogene Proteins c-kit / Q000378:metabolism*; D015398:Signal Transduction; D019089:Stem Cell Factor / Q000378:metabolism*; D013234:Stem Cells / Q000378:metabolism / Q000473:pathology
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D047908:Intracellular Signaling Peptides and Proteins; C490777:Lnk protein, mouse; D008565:Membrane Proteins; D011506:Proteins; D019089:Stem Cell Factor; D019009:Proto-Oncogene Proteins c-kit