Diminished callus size and cartilage synthesis in alpha 1 beta 1 integrin-deficient mice during bone fracture healing.
Integrins mediate cell adhesion to extracellular matrix components. Integrin alpha 1 beta 1 is a collagen receptor expressed on many mesenchymal cells, but mice deficient in alpha 1 integrin (alpha1-KO) have no gross structural defects. Here, the regeneration of a fractured long bone was studied in alpha1-KO mice. These mice developed significantly less callus tissue than the wild-type (WT) mice, and safranin staining revealed a defect in cartilage formation. The mRNA levels of nine extracellular matrix genes in calluses were evaluated by Northern blotting. During the first 9 days the mRNA levels of cartilage-related genes, including type II collagen, type IX collagen, and type X collagen, were lower in alpha1-KO mice than in WT mice, consistent with the reduced synthesis of cartilaginous matrix appreciated in tissue sections. Histological observations also suggested a diminished number of chondrocytes in the alpha 1-KO callus. Proliferating cell nuclear antigen staining revealed a reduction of mesenchymal progenitors at the callus site. Although, the number of mesenchymal stem cells (MSCs) obtained from WT and alpha 1-KO whole marrow was equal, in cell culture the proliferation rate of the MSCs of alpha 1-KO mice was slower, recapitulating the in vivo observation of reduced callus cell proliferation. The results demonstrate the importance of proper collagen-integrin interaction in fracture healing and suggest that alpha1 integrin plays an essential role in the regulation of MSC proliferation and cartilage production.
Ekholm
Erika
E
Department of Medical Biochemistry and Molecular Biology, University of Turku, Turku, Finland.
Hankenson
Kurt D
KD
Uusitalo
Hannele
H
Hiltunen
Ari
A
Gardner
Humphrey
H
Heino
Jyrki
J
Penttinen
Risto
R
D053674:Aggrecans; D000818:Animals; D002146:Bony Callus / Q000378:metabolism / Q000503:physiopathology*; D002356:Cartilage / Q000378:metabolism / Q000503:physiopathology*; D002455:Cell Division / Q000502:physiology; D003094:Collagen / Q000235:genetics; D016326:Extracellular Matrix Proteins; D017102:Fracture Healing / Q000502:physiology*; D050723:Fractures, Bone / Q000503:physiopathology*; D005838:Genotype; D039222:Integrin alpha1beta1; D016023:Integrins / Q000172:deficiency* / Q000235:genetics; D037181:Lectins, C-Type; D008648:Mesoderm / Q000166:cytology; D051379:Mice; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D011509:Proteoglycans / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism
C508320:Acan protein, mouse; D053674:Aggrecans; D016326:Extracellular Matrix Proteins; D039222:Integrin alpha1beta1; D016023:Integrins; D037181:Lectins, C-Type; D011509:Proteoglycans; D012333:RNA, Messenger; D003094:Collagen