Does adult fracture repair recapitulate embryonic skeletal formation?

Bone formation is a continuous process that begins during fetal development and persists throughout Life as a remodeling process. In the event of inju ry, bones heal by generating new bone rather than scar tissue; thus, it can accurately be described as a regenerative process. To elucidate the extent to which fetal skeletal development and skeletal regeneration are similar, we performed a series of detailed expression analyses using a number of ge nes that regulate key stages of endochondral ossification. They included ge nes in the indian hedgehog (ihh) and core binding factor 1 (cbfal) pathways , and genes associated with extracellular matrix remodeling and vascular in vasion including vascular endothelial growth factor (VEGF) and matrix metal loproteinase 13 (mmp13). Our analyses suggested that even at the earliest s tages of mesenchymal cell condensation, chondrocyte (ihh, cbfal and collage n type II-positive) and perichondrial (gli1 and osteocnlcin-positive) cell populations were already specified. As chondrocytes matured, they continued to express cbfal and ihh whereas cbfal, osteocalcin and gli1 persisted in presumptive periosteal cells. Later, VEGF and mmp13 transcripts were abunda nt in chondrocytes as they underwent hypertrophy and terminal differentiati on. Based on these expression patterns and available genetic data, we propo se a model where Ihh and Cbfal, together with Gli1 and Osteocalcin particip ate in establishing reciprocal signal site of injury. The persistence of cb fal and ihh, and their targets osteocnlcin and gli1, in the callus suggests comparable processes of chondrocyte maturation and specification of a neo- perichondrium occur following injury. VEGF and mmp13 are expressed during t he later stages of healing, coincident with the onset of vascularization of the callus and subsequent ossification. Taken together, these data suggest the genetic mechanisms regulating fetal skeletogenesis also regulate adult skeletal regeneration, and point to important regulators of angiogenesis a nd ossification in bone regeneration. (C) 1999 Elsevier Science Ireland Ltd . All rights reserved.