The role of sox-9 in condrogenesis

THE ROLE OF SOX9 IN CONDROGENESIS

Human articular cartilage is an avascular structure which has multiple functions in adult organisms such as articulation capacity in joints or elastic and loading capacity in intervertebral discs. Cartilage is the first skeletal tissue to be formed during the endocondral ossification in the embryogenesis leading to the creation of all mature cartilages andbones, with the exception of the flat bones in the skull. [1]

During the development of the vertebrate skeleton, endochondral bone formation is initiated when multipotent mesenchymal cells in the limb bud aggregate to form mesenchymal condensations which prefigure the skeletal elements. Cells within the pre-chondrogenic condensation up-regulate cell adhesion mechanisms and begin to synthesizespecific extracellular matrix molecules, and the condensations expand through a combination of proliferation and recruitment of surrounding mesenchyme. The generation of these condensations creates an environment which is conducive to the differentiation of chondrocytes[2,3,4]
Chondrogenesis is defined as the process through which the MCs differentiate into chondroblasts that subsequently eitherdevelop into adult chondrocytes or undergo hypertrophy and apoptosis.4 [5]. Chondrogenesis is a multi-step cellular event. [6]. First undifferentiated Mesenchymal cells proliferate, aggregate with each other, condense, become immature chondroblasts, transform into prehypertrophic chondrocytes, and differentiate into hypertrophic chondrocytes [5, 7]. Finally the chondrocytes form growth plates andcontribute to the longitudinal skeletal growth [8].
Cartilage matrix genes typify overt the successive stages of proliferation and differentiation that produce all cellular states observed in the growth plate. In immature chondroblasts the products of these genes, which include type II collagen alpha 1 (Col2a1), type XI collagen alpha 2 (Col11a2), and aggrecan 1 (Agc1), form the characteristicextracellular matrix of cartilages. As chondrocytes proceed to terminal maturation in growth plates, they downregulate the expression of these proteins, activate new cartilage matrix genes, like type X collagen alpha 1 (Col10a1), Indian hedgehog (Ihh), osteopontin , and undergo hypertrophy. [5]

In addiction, during the early chondrogenesis (in immature chondroblasts) a critical component ofchondrocyte lineage is the transcription Factor Sox 9 which belongs to the SRY family and contains the high mobility group box (HMG-box) DNA binding domain whit 50% similarity to that of sex-determining region Y (SRY), the testis- determining gene in mammals [9,10].

The influence of Sox 9 on chondrogenesis is via the regulation the expression of a multiple cartilage specific proteins includingCol2a1, which is the major cartilage matrix protein [2, 11]. Colagen II gene has a minimal DNA element in intron 1 which is a direct target for Sox 9, the mutants in this enhancer abolish the activation of collagen II by SOX9[9] .
Heterozygous mutations in the human SOX9 gene cause the skeletal malformation syndrome campomelic dysplasia (CD) [1], a severe skeletal malformation syndrome and acompainedby and XY sex reversal.
Characteristic features in CD patients are severe anomalies in multiple
skeletal elements, including shortened and angulated long bones, hypoplastic scapulae, a small thoracic cage, deformed pelvis and spine, micrognathia, cleft palate, and a flat nasal bridge. [9,12].

The identification of mutations in the SRY-related SOX9 gene in patients with campomelic dysplasia,and multiple analyses in genetically modified mice revealed that Sox9 promotes the early stage, but suppresses the late stage, of chondrogenesis [5,13,14,15].

Sox9 plays a role in controlling the expression of downstream gene of Col 2a1 and is essential for cartilage tissue development. Indeed genetic modification with adenoviral vectors encoding sox9 will be the first step toward obtaining...