Activating transcription factor-2 (ATF-2) is a basic region leucine zipper protein whose DNA target sequence is the widely distributed cAMP response element (CRE). We report here that mice carrying a germline mutation in ATF-2 demonstrated unique actions of ATF-2 not duplicated by other ATF/CREB family members. Mutant mice had decreased postnatal viability and growth, with a defect in endochondral ossification at epiphyseal plates similar to human hypochondroplasia. The animals had ataxic gait, hyperactivity and decreased hearing. In the brain, there were reduced numbers of cerebellar Purkinje cells, atrophic vestibular sense organs and enlarged ventricles. Unlike CREB alpha/delta-deficient mice whose main defect is in long-term potentiation, the widespread abnormalities in ATF-2 mutant mice demonstrate its absolute requirement for skeletal and central nervous system development, and for maximal induction of select genes with CRE sites, such as E-selectin.

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The effects of low-intensity pulsed ultrasound (US) on the proliferation and chondroitin sulfate synthesis of cultured chondrocytes embedded in Atelocollagen gel in vitro were examined. Articular cartilage was harvested from the hip, knee, and shoulder joints of 10-week-old Japanese white rabbits. Chondrocytes isolated by collagenase digestion were embedded in type I collagen gel, Atelocollagen gel, and were cultured in Dulbecco's modified eagle's medium for 3 weeks. The US apparatus, SAFHS, was used to deliver an ultrasound signal with spatial and temporal average intensities of 30 mW/cm(2) (US group). The frequency was 1.5 MHz with a 200-microsecond tone burst repeated at 1.0 kHz. US treatments were administered for 20 min per day under culture dishes, with the medium replaced twice a week. Another group of cells was exposed to sham ultrasound as a control. Cell number, histological findings, synthesis of isomers of chondroitin sulfate, and stiffness of the chondrocyte-collagen gel composites were analyzed. US exposure promoted synthesis of chondroitin sulfate, especially chondroitin 6-sulfate, although it did not significantly enhance cell number and stiffness. In this three-dimensional culture model, these results suggest that US exposure may be clinically useful in improving the quality of chondrocyte-Atelocollagen implants for transplantation into articular cartilage defects.

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