Bone is a dynamic tissue that undergoes constant adaption to maintain skeletal size, shape and structure integrity. Bone modelling is a process that is responsible for bone growth and adaption that require both formation and bone removal (resorption). Two types of cells are involved in bone modelling, osteoblasts for bone formation and osteoclasts for bone resorption.
The bone matrix is produced by bone-forming cells osteoblasts, which are derived from bone marrow mesenchymal stem cells. Osteoblasts are differentiated from mesenchymal progenitor cells into proliferating pre-osteoblasts, then mature bone-matrix producing osteoblasts. The master activator of osteoblast differentiation is Runx2 (runt-related transcription factor 2). In Runx2-deficient mice, osteoblasts fail to differentiate and the formation and mineralization of bone are completely absent. In addition, mice lacking only one allele of Runx2 display hypoplastic clavicles and delayed closure of the fontanelles, a phenotype that mimics the human disease cleidocranial dysplasia (CCD). Genetic analysis of CCD patients revealed heterozygous mutations of Runx2 gene, thus demonstrating the critical role of Runx2 in human osteoblast differentiation. Osterix (Osx) is a zinc finger-containing transcription factor expressed in osteoblasts and is also an obligatory factor for normal osteoblast differentiation. Osx-deficient mice are perinatal lethal due to arrested osteoblast maturation, and lack mineralized bone, similar to Runx2- deficient mice but less severe. The finding that Runx2 is expressed in Osxdeficient mice but Osx is not expressed in Runx2-deficient mice is an indication that Osx acts downstream of Runx2 in the transcriptional cascades of osteoblast differentiation.
Various growth factors also modulate osteoblast proliferation, differentiation and maturation including bone morphogenetic proteins (BMPs), fibroblast growth factors (FGFs), insulin-like growth factors (IGFs), parathyroid hormone (PTH). The fully differentiated osteoblasts are characterized by ex