Spontaneous fracture (sfx): A mouse genetic model of defective peripubertal bone formation

A new mouse model of stage-specific hone growth failure and fracture has be en recovered as an autosomal recessive mutation, designated spontaneous fra cture (sfx), The sfx/sfx mice are phenotypically normal until shortly after weaning, when reduced mobility and impaired somatic growth are first noted . By 6 weeks of age, body, spleen, and thymus weights, as well as hematocri ts and serum calcium, inorganic phosphate, total alkaline phosphatase, insu lin-like growth factor-I, and osteocalcin levels are decreased. The sfx/sfx mice also show reduced femoral cortical density and diaphyseal circumferen ce, as well as a paucity of mature osteoblasts on bone surfaces. Histologic al analyses of the femur and tibia in the mutants show subtle reduction of chondrocyte numbers in epiphyseal-plate columns, reduction of matrix, and n ear absence of osteoid below the differentiated chondrocytes. Trabeculae in proximal tibiae, iliacs, and vertebral bodies are sparse and thin. Cortica l bone thickness of mutants is markedly thinned in all sites examined. By 7 -8 weeks, radiographic films routinely show spontaneous impact fractures of the distal femur accompanied by callus formation, whereas complete fractur es are less commonly observed. Volumetric bone mineral density (BMD) of mut ant femurs is similar to +/? littermates in the center of the femoral diaph ysis, but BMD declines as either end of the femoral diaphysis is approached . We have mapped the gene responsible for this phenotype to central Chromos ome 14, Reduced bone mass, impaired bone formation, abnormalities of bone a rchitecture, and a disposition to spontaneous fracture identify sfx/sfx mic e as a useful model for understanding the mechanisms responsible for peripu bertal bone formation. (C) 2000 by Elsevier Science Inc. All rights reserve d.