Genetic and transcriptional control of bone formation

Abstract

An exquisite interplay of developmental cues, transcription factors, and coregulatory and signaling proteins support formation of skeletal elements of the jaw during embryogenesis and dynamic remodeling of alveolar bone in postnatal life. These molecules promote initial condensation of the mesenchyme, commitment of the mesenchymal progenitor to osteogenic lineage cells, and differentiation of committed osteoblasts to mature osteocytes within mineralized bone. Parallel regulatory networks promote formation of the functional osteoclast from mononuclear cells to support continuous bone remodeling within the alveolar bone. With an ever expanding list of new regulatory factors, the complexities of the molecular mechanisms that control gene expression in skeletal cells are being further appreciated. This article examines the multifunctional roles of prominent nuclear proteins, cytokines, hormones, and paracrine factors that control osteogenesis.

Figure 1. Ontogeny of osteoblast and regulatory control of osteoblast lineage progression and phenotypic features

Sequence and stages of the osteoblast lineage from a self-renewing, pluripotent mesenchymal stem cell to terminally differentiated osteocyte is diagrammatically illustrated. The characteristic feature of each developmental stage is indicated below the cell morphology. Next row summarizes the key transcription factor and co-regulatory protein involved in genetic control of osteoblast differentiation. Factors that negatively regulate Runx2 activity and osteoblast differentiation are indicated in red. Several physiologic mediators influencing osteoblast development, including transforming growth factor β (TGFβ), the bone morphogenetic proteins (BMPs), and fibroblast growth factors (FGFs), Wnt/β-catenin signaling and hormones are also indicated. Secretory molecules, receptor and signal transducer that inhibit osteoblast maturation are highlighted in red. Last row summarize phenotypic marker genes expressed at different developmental stages of osteoblast differentiation.