Mesenchymal stem cells (MSCs) can differentiate into osteoblasts and lead to bone formation in the body. Osteoblast differentiation and bone development are regulated by a network of molecular signals and transcription factors induced by several proteins, including BMP2, osterix, and Runx2. We recently observed that the growth-arrest-specific 7 gene (Gas7) is upregulated during differentiation of human MSCs into osteoblasts. Downregulation of Gas7 using short-hairpin RNA decreased the expression of Runx2, a master regulator of osteogenesis, and its target genes (alkaline phosphatase, type I collagen, osteocalcin, and osteopontin). In addition, knockdown of Gas7 decreased the mineralization of dexamethasone-treated MSCs in culture. Conversely, ectopic expression of Gas7 induced Runx2-dependent transcriptional activity and gene expression leading to osteoblast differentiation and matrix mineralization. Genetic mutations of the Gas7 gene increased body fat levels and decreased bone density in mice. These results showed that Gas7 plays a role in regulating the pathways which are essential for osteoblast differentiation and bone development. In this review, we summarize the involvement of Gas7 in MSC-based osteogenesis and osteoporosis and describe the possible mechanisms responsible for the maintenance of cellular homeostasis in MSCs and osteoblasts. 1. Gas7: A Pombe Cdc15 Homology Protein The Gas7 protein is part of the Pombe Cdc 15 homology (PCH) family which belongs to the proline, serine, threonine-rich phosphatase interacting protein (PSTPIP) subfamily [1, 2]. Gas7 was initially identified as an upregulated gene in NIH3T3 cells cultured without serum, and the structure of the encoded protein showed homology to Oct2 and synapsins, proteins involved, respectively, in neuron development, and neurotransmitter release [3, 4]. Gas7 is selectively expressed in mature cerebellar neurons, cerebral cortical neurons, and hippocampal neurons [4, 5]. The human Gas7 gene is located on chromosome 17p12 (based on information provided by Ensembl and UDB/GeneLoc). Open reading frame analysis of the 412 amino acid-coding Gas7 gene predicted the production of a 47,266-Da protein. Gas7a and Gas7b protein isoforms, which are obtained by alternative splicing, have also been described [6]. Several studies have been performed to examine the physiological functions of Gas7 in humans and rodents [3, 7]. These studies have shown that Gas7 is mainly expressed in the brain and is involved in morphological differentiation and neuritogenesis [3, 5–7]. These observations are
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