Osteoblast Differentiation at a Glance

Abstract

Ossification is a tightly regulated process, performed by specialized cells called osteoblasts. Dysregulation of this process may cause inadequate or excessive mineralization of bones or ectopic calcification, all of which have grave consequences for human health. Understanding osteoblast biology may help to treat diseases such as osteogenesis imperfecta, calcific heart valve disease, osteoporosis, and many others. Osteoblasts are bone-building cells of mesenchymal origin; they differentiate from mesenchymal progenitors, either directly or via an osteochondroprogenitor. The direct pathway is typical for intramembranous ossification of the skull and clavicles, while the latter is a hallmark of endochondral ossification of the axial skeleton and limbs. The pathways merge at the level of preosteoblasts, which progress through 3 stages: proliferation, matrix maturation, and mineralization. Osteoblasts can also differentiate into osteocytes, which are stellate cells populating narrow interconnecting passages within the bone matrix. The key molecular switch in the commitment of mesenchymal progenitors to osteoblast lineage is the transcription factor cbfa/runx2, which has multiple upstream regulators and a wide variety of targets. Upstream is the Wnt/Notch system, Sox9, Msx2, and hedgehog signaling. Cofactors of Runx2 include Osx, Atf4, and others. A few paracrine and endocrine factors serve as coactivators, in particular, bone morphogenetic proteins and parathyroid hormone. The process is further fine-tuned by vitamin D and histone deacetylases. Osteoblast differentiation is subject to regulation by physical stimuli to ensure the formation of bone adequate for structural and dynamic support of the body. Here, we provide a brief description of the various stimuli that influence osteogenesis: shear stress, compression, stretch, micro- and macrogravity, and ultrasound. A complex understanding of factors necessary for osteoblast differentiation paves a way to introduction of artificial bone matrices.

Figure 1

A flowchart depicting the biogenesis of osteoblasts. Mesenchymal stem cells can give rise to 4 lineages (top left) by expressing corresponding transcriptional regulators: PPARγ for adipogenic, MyoD for myogenic, Runx2 for osteoblastic, and Sox9 for chondrocytic lineages. In intramembranous ossification (osteogenesis in the scull and clavicles), preosteoblasts stem directly from mesenchymal stem cells, while in endochondral (osteogenesis of the axial skeleton and the limbs) a common osteo-chondro progenitor gives rise to both cell types. Hypertrophic chondrocytes in a paracrine manner (gray arrow) regulate transformation of perichondral cells into preosteoblasts, or might itself transform into one. The process of maturation of preosteoblasts is shown in the enlargement on the right.

Figure 2

Major regulatory pathways involved in the regulation of Runx2, a chief transcriptional regulator of osteogenesis. Four pathways are elaborated. The Wnt pathway is central in activation of Runx2 via the stabilization of β-catenin. This process in cells other than osteoblasts is inhibited by Dickopf (DKK1/2). This inhibition is removed by BMP signaling via SMADs and Interleukin-11. BMP has other, direct actions on Runx2. TGF-β and Notch signaling is anti-calcific. TGF signal is transmitted into the cell by SMADs (other subsets than BMPs), while Notch relies on the cleavage of its intracellular domain upon activation. Arrows show activation and stump-ends show inhibition.

Figure 3

A short summary of factors activated in osteoblasts by 3 modalities of mechanical stress. The activated and inhibited factors are shown in red. An arrow symbolizes activation and stump-ends show inhibition.