Diminished Callus Size and Cartilage Synthesis in α1β1 Integrin-Deficient Mice during Bone Fracture Healing

Abstract

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.

The integrin–collagen connection – a glue for tissue repair?

“…As mentioned above, integrin α1β1 is expressed in chondrocytes and osteogenic cells. Reduced callus size and reduced cartilage production have been observed in bone fracture healing experiments, and it has been suggested that these effects correlate with a proliferation defect within mesenchymal precursor cells that occurs in the absence of α1β1 (Ekholm et al, 2002). Independent experiments have later demonstrated that osteoarthritis is accelerated in the absence of α1 (Zemmyo et al, 2003).…”

Comparison of the healing of open tibial fractures covered with either muscle or fasciocutaneous tissue in a murine model

“…[24][25][26][27][28][29][30][31][32] Open techniques have been used to create murine femoral fractures secured both by external [33][34][35] and internal fixation. 36 Despite the small size, the healing of fractures of the murine tibia stabilized using an external fixator has been studied.…”

Altered fracture repair in the absence of MMP9

“…An inflammatory reaction exerts a substantial effect on adult skeletal repair (Simon et al, 2002), whereas the immune system has no known role in fetal skeletogenesis. Likewise, skeletal progenitor cells abound in the fetus, whereas they may be limited in number in the adult (Bruder et al, 1994;Ekholm et al, 2002).…”