Submitted to: Journal of Regenerative Medicine
Publication Type: Peer reviewed journal
Publication Acceptance Date: 8/15/2002
Publication Date: 9/10/2002
Citation: ARONSON, J., LIU, L., GAO, G.G., PERRIEN, D.S., BROWN, E.C., SKINNER, R.A., THOMAS, J.R., MORRIS, K.D., SUVA, L.J., BADGER, T.M., LUMPKIN, C.K. Decreased Endosteal Intramembranous Bone Formation Accompanies Aging in a Mouse Model of Distraction Osteogenesis. Journal of Regenerative Medicine. 2002. v. 3. p. 7-16. Interpretive Summary: The ACNC is studying how diet and nutritional status affects bone development and growth using a procedure known as distraction osteogenesis (DO). This procedure is used in children to lengthen bones that are too short. Usually, this is because one leg or arm grows slower than the other. We also have developed mouse and rat models of OD. This is an excellent model of bone growth, because during DO, bone can grow at the same rate as occurs in fetal or infant development and allows us to study the effects of diet on that process. We have been determining the mechanisms by which this occurs. In this study, we report results from the mouse model and we found that slowing of bone growth, such as occurs in aging, is associated with a deficiency in a particular type of bone, endosteal bone. This model will allow the ACNC to delve much deeper in the mechanisms by which dietary factors alter bone formation early in life.
Technical Abstract: This paper describes a study conducted to test the hypothesis that aging will result in decreased bone formation during distraction osteogenesis (DO). DO is a unique clinical method for the stimulation of new bone formation and subsequent bone lengthening. When applied to other species DO reflects the clinical situation in which older DO patients demonstrate significant delays in mineralization. Given the considerable value of mouse genetics for studying the mechanism(s) of bone formation, we have developed a murine DO model and utilized it to investigate the effect of age on bone formation. Four- and 12-month-old CB57BL/6 male mice (n = 10 per group) underwent DO. External fixators were placed on the left tibiae, and mid-diaphyseal tibial osteotomies were performed immediately following fixator placement. Distraction, which began 6 days after surgery at 0.075 mm twice a day (0.15 mm/day) for 14 days, resulted in a total lengthening of 2.1 mm. Following distraction, the distracted tibiae were removed for high-resolution radiography and histological evaluation. Analysis of radiographs and representative histological sections was performed by video microscopy. Radiographic analysis demonstrated a significant decrease in the mineralized area of distraction gaps of 12- (33.5 ± 4.8%) versus 4-month-old (51.4 ± 5.4%) mice (p < 0.039). Histological analysis of representative specimens confirmed the decrease in bone formation observed in the radiographs (p < 0.001). Endosteal new bone was predominantly intramembranous and appeared highly oriented toward the distraction axis. These results suggest that 12-month-old mice have a relative deficit in endosteal bone formation compared with that in younger mice. The application of this murine DO model to genetically manipulated mice may provide critical insights into the mechanisms of bone formation, repair, and regeneration in a geriatric setting.