Lnk-dependent axis of SCF-cKit signal for osteogenesis in bone fracture healing.
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.
Matsumoto
Tomoyuki
T
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.
Ii
Masaaki
M
Nishimura
Hiromi
H
Shoji
Taro
T
Mifune
Yutaka
Y
Kawamoto
Atsuhiko
A
Kuroda
Ryosuke
R
Fukui
Tomoaki
T
Kawakami
Yohei
Y
Kuroda
Tomoya
T
Kwon
Sang Mo
SM
Iwasaki
Hiroto
H
Horii
Miki
M
Yokoyama
Ayumi
A
Oyamada
Akira
A
Lee
Sang Yang
SY
Hayashi
Shinya
S
Kurosaka
Masahiro
M
Takaki
Satoshi
S
Asahara
Takayuki
T
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
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