1(II) collagen chain gene (Col2a1), aggrecan (Acan) and the 2(XI) collagen chain gene (Col11a2); it sustains the survival of proliferative chondrocytes during development (Ikegami et al., 2011); SOX9 overexpression in proliferative chondrocytes suppresses their hypertrophy (Akiyama
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چکیده
INTRODUCTION Vertebrate bones develop through membranous or endochondral ossification. Except for craniofacial bones and the clavicle, all bones are established through the latter process (Olsen et al., 2000; Karsenty et al., 2009). At the onset of endochondral bone formation, mesenchymal cells first undergo condensation, followed by differentiation of cells within these condensations into chondrocytes. Chondrocytes then proliferate and produce extracellular matrix to form the primordial cartilage that prefigures the future skeletal elements. Shortly after the formation of the primordial cartilage, proliferating chondrocytes in the central region of the cartilage exit the cell cycle and differentiate into prehypertrophic, and subsequently hypertrophic, chondrocytes. The proliferating chondrocytes closest to the prehypertrophic chondrocytes flatten out and form orderly columns of flat chondrocytes that continue to proliferate. Finally, hypertrophic chondrocytes progress to terminal maturation, following which they express matrix metalloproteinase 13 (MMP13). The terminally matured chondrocytes undergo apoptosis. Blood vessels, along with osteoblasts, osteoclasts and hematopoietic cells, then invade this region and form primary ossification centers. Within these centers, the hypertrophic cartilage matrix is degraded, the hypertrophic chondrocytes die, and bone replaces the disappearing cartilage. Recent molecular and genetic studies coupled with classical histological approaches have revealed many of the factors that are involved in endochondral bone formation (Lefebvre and Smits, 2005). For example, SOX9 is expressed in mesenchymal progenitor cells and in chondrocytes, but its expression ceases in prehypertrophic chondrocytes (Ng et al., 1997; Zhao et al., 1997). SOX9 has a variety of functions in chondrogenesis: its expression in mesenchymal progenitor cells is essential for cartilage formation (Akiyama et al., 2002); it directly regulates cartilage-specific matrix genes such as the 1(II) collagen chain gene (Col2a1), aggrecan (Acan) and the 2(XI) collagen chain gene (Col11a2); it sustains the survival of proliferative chondrocytes during development (Ikegami et al., 2011); SOX9 overexpression in proliferative chondrocytes suppresses their hypertrophy (Akiyama et al., 2004); and it negatively regulates the transcription of the gene that encodes vascular endothelial growth factor (VEGF), which is expressed by hypertrophic chondrocytes (Hattori et al., 2010). Regarding the hypertrophic differentiation of chondrocytes, several crucial transcriptional regulators have been identified. Histone deacetylase 4 (HDAC4), a class II HDAC, represses the expression of multiple genes through chromatin remodeling, thereby regulating cell fate. To elucidate the specific role of HDAC4, Hdac4-null mice have been generated and were noted to display dwarfism and inappropriate chondrocyte hypertrophy, Development 139, 1153-1163 (2012) doi:10.1242/dev.072652 © 2012. Published by The Company of Biologists Ltd
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