We developed a rat model of limb lengthening to study the basic mechanism of distraction osteogenesis, using a small monolateral external fixator. In 11-week-old male rats we performed a subperiosteal osteotomy in the midshaft of the femur with distraction at 0.25 mm every 12 hours from seven days after operation.Radiological and histological examinations showed a growth zone of constant thickness in the middle of the lengthened segment, with formation of new bone at its proximal and distal ends.Osteogenic cells were arranged longitudinally along the tension vector showing the origin and the fate of individual cells in a single section. Typical endochondral bone formation was prominent in the early stage of distraction, but intramembraneous bone formation became the predominant mechanism of ossification at later stages. We also showed a third mechanism of ossification, 'transchondroid bone formation'. Chondroid bone, a tissue intermediate between bone and cartilage, was formed directly by chondrocyte-like cells, with transition from fibrous tissue to bone occurring gradually and consecutively without capillary invasion.In situ hybridisation using digoxigenin-11-UTPlabelled complementary RNAs showed that the chondroid bone cells temporarily expressed type-II collagen mRNA. They did not show the classical morphological characteristics of chondrocytes, but were assumed to be young chondrocytes undergoing further differentiation into bone-forming cells.We found at least three different modes of ossification during bone lengthening by distraction osteogenesis. We believe that this is the first report of such a rat model, and have shown the validity of in situ hybridisation techniques for the study of the cellular and molecular mechanisms involved in distraction osteogenesis. J Bone Joint Surg [Br] 1997;79-B:824-30. Received 18 November 1996; Accepted after revision 21 March 1997The common principles of current techniques of limb lengthening are osteotomy and slow progressive distraction by an external fixation device.1,2 The type of osteotomy, the timing and rate of distraction, and the apparatus have varied considerably. 3-8 It has been established that slow distraction does not break the bony callus, but actually stimulates osteogenesis and the growth of surrounding soft tissues. The principle has been termed the 'law of tension-stress', 4,5 but the exact mechanism is not understood. We have previously reported the histological findings in lengthened segments in rabbits and concluded that new bone was formed predominantly by endochondral (indirect) ossification.9 Other reports of canine or ovine experiments have established that intramembranous (direct) bone formation is the main mechanism of ossification during distraction osteogenesis. 4,5,10,11 Factors such as the stability of fixation, the timing and rate of distraction, and speciesrelated differences may determine the relative share of endochondral and direct bone formation. Kossmann, Giebel and Glombitza 12 recently described a rat model of tibial lengthening...

R ecent studies of the fibroblast growth factor receptor 3 (FGFR3) gene have established that achondroplasia and hypochondroplasia are allelic disorders of different mutations.To determine whether the genotype could be distinguished on the basis of the phenotype, we analysed height, arm span, and skeletal radiographs from 23 patients with achondroplasia and the G380R mutation of FGFR3 and eight with hypochondroplasia and the N540K mutation. Both conditions share the classical pathological features of micromelic short stature, reduced or unchanged interpedicular distances in the lumbar spine, disproportionately long fibulae, and squared and shortened pelvic ilia. These were significantly more severe in the G380R patients than in the N540K patients.Our About 60% of patients with HCH have been reported to have an asparagine-to-lysine substitution at residue 540 (N540K) of FGFR3. 10,11 Although the genotypic background of the remaining cases of HCH has not been clarified, the N540K substitution seems to be responsible for a significant proportion of cases of this condition. 12-14In spite of a long history of observations suggesting allelism between ACH and HCH, 15 it has been claimed that the clinical and radiological features of ACH and HCH overlap. 16,17 We have compared the phenotype of genotyped populations to clarify whether or not each of these two genotypes has a distinctive phenotype. Patients and MethodsBlood samples were collected from patients clinically diagnosed as having ACH and HCH, and the FGFR3 genotype was determined as previously described. 18 There were 23 patients with ACH and the G380R substitution, 11 boys and 12 girls with a mean age of 10.0 years (5 to 18). Of the eight HCH patients with the N540K substitution, there were five boys and three girls with a mean age of 11.6 years (7 to 18), all of whom had sporadic mutations. We also assessed 30 genetically normal individuals as a control group. There were 17 boys and 13 girls with a mean age of 11.1 years (3 to 17). We analysed height, arm span and skeletal radiographs. Height was evaluated by the height standard deviation score which was obtained from standard growth curves for the Japanese population. Arm span was examined by calculating the span to height ratio percentage.We studied three of the pathological features of ACH and HCH. [19][20][21] We assessed the ratio of the interpedicular distances at the first and fourth lumbar vertebrae (L1/L4 ratio, Fig. 1a) irrespective of whether they were reduced or not.We also determined the ratio of the length of the fibula to that of the tibia (F/T ratio, Fig. 1b) to ascertain whether the