Apoptosis is coordinately regulated with osteoblast formation during bone healing.

The ultimate fate of the expanded pool of osteoblasts formed following a typical bone injury is unclear. Since necrosis has not been described in the latter stages of bone healing, there must be some other mechanism by which obsolete osteoblasts are cleared from an injury site. We therefore evaluated the possibility that their removal is pre-programmed, by investigating the occurrence of apoptosis in rats that received a standardized bone injury. Histological evidence identical to that found in tissues known to exhibit apoptosis was obtained, thereby showing that programmed cell death was a normal concomitant of fracture healing. The concentration of apoptotic bodies reached its maximum after the differentiative response had peaked, suggesting that the two processes were coordinated. The same result was found in a second group of rats that received the same bone injury plus a simultaneous standardized soft-tissue injury. The combined injuries resulted in more osteoblasts and more apoptotic bodies, but an identical temporal relationship between the peak responses in the two parameters. The results suggested that osteoblasts were removed from the injury site via apoptosis, and that the process was coordinately regulated with differentiation. Since the number of apoptotic bodies per osteoblast varied during healing, it is likely that apoptosis was associated with healing and not merely with osteoblast concentration.