Molecular mechanisms controlling bone formation during fracture healing and distraction osteogenesis

Abstract

Fracture healing and distraction osteogenesis have important applications in orthopedic, maxillofacial, and periodontal treatment. In this review, the cellular and molecular mechanisms that regulate fracture repair are contrasted with bone regeneration that occurs during distraction osteogenesis. While both processes have many common features, unique differences are observed in the temporal appearance and expression of specific molecular factors that regulate each. The relative importance of inflammatory cytokines in normal and diabetic healing, the transforming growth factor beta superfamily of bone morphogenetic mediators, and the process of angiogenesis are discussed as they relate to bone repair. A complete summary of biological activities and functions of various bioactive factors may be found at COPE (Cytokines & Cells Online Pathfinder Encyclopedia), http://www.copewithcytokines.de/cope.cgi.

Figure 1

Comparisons of the tissue histology and mineralized tissue structure of fracture callus and distraction gap tissues. Murine femur fracture calluses and tibia distraction gap tissue were prepared from specimens obtained 21 days post-fracture or at 21 days post-surgery. (Panel A) Representative longitudinal sections of fracture and distraction osteogenesis were stained with Safranin-O/fast green. Original magnification 25×. (Panel B) Representative longitudinal microCT images at a resolution of 12 microns. Arrows indicate the extent of new bone formation. Both sets of images are presented with the distal and proximal orientations, left to right. The various zones in distraction osteogenesis are indicated. The central fibrous zone, histologically called the fibrous interzone (FIZ), is rich in chondrocyte-like cells, fibroblasts, and oval cells that are morphologically intermediate between fibroblasts and chondrocytes. The fibrous interzone contains differentiating osteoblasts that deposit osteoid along collagen bundles. When these collagen bundles mineralize, they form a zone called the zone of microcolumn formation (MCF). In between the fibrous interzone and the zone of microcolumn formation is a zone of high cell density called the primary matrix or mineralization front (PMF). Separate scale bars for both the histological and microCT images are presented below each image (1 mm).

Figure 2

Comparison of the progression of healing in fractures and distraction osteogenesis. Murine femur fracture calluses and tibia distraction gap tissues were prepared at the indicated time-points. The different stages of healing and bone formation are given for each. Representative histologic specimens are stained with Safranin-O/fast green, which stains cartilage bright red. The scale bar in the lower right indicates 1 mm for all panels.