Molecular cloning of novel osteoneurotrophins and their application as therapeutic agents for bone and cartilage diseases

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1) Neurotrophin (NT) -3 stimulated the proliferation of osteoblastic cells by increasing binding of TRE and SRE to DNA via trk C.Ascorbic acid stimulated expression of NTs, especially NT-3, in osteoblasts.2) Cultured growth cartilage cells expressed NTs and osteocytes expressed NGF and trkA is culture. Expression of NF,BDNF and NT-3 in mouse periodontal ligament cellsincreased as they became confluent while expression of trks decreased.3) Expression of trkA and trkC and NGF and NT-3 increased 2 days after fracture of mouse long bones.4) hcs-24, which was isolated from the human chondrocytic cell line HCS-2/8 as a chondrocyte- (especially hypertrophic cohondrocyte) specific gene, encoded connective tissue growth factor (CTGF). Purified CTGF and recombinant CTGF stimulated proliferation of glia cells and induced neurite formation of PC12D cells. cTGF also stimulated the proliferation and differentiation of chondrocytes, differentiation of osteoblasts, the proliferation and migration of vascular endothelial cells. These findings indicate that Hcs-24/CTGF is a novel osteochondro-neurotrophin (OCNT).5) Immunohistochemical staining with an anti-CTGF antibody revealed that spinal nerves and trigeminal ganglion were highly positive and nerves in cortex and astroglias in hippocampus were also positive. In situ hybridization revealed that motor neuron and neuron in trigeminal ganglion expressed CTGF mRNA.Carbachol stimulated neurite formation of PC12D cells.6) Two types of specific binding sites of ^<125>I-rCTGF were identified on HCS-2/8 cells. MAP kinase was found to be involved in signal transduction in the cells.7) Transgenic mice of OCNT/CTGF had skeletal disorder.8) Both IGF-I and II,which are known to induce neurite formation, stimulated expression of differentiated phenotype of chondroxytes via their respective receptors.These findings suggest that the soluble factors mentioned above can be used as therapeutic agents for bone and cartilage diseases.