Signaling networks that control the lineage commitment and differentiation of bone cells

Abstract

Osteoblasts and osteoclasts are the two major bone cells involved in the bone remodeling process. Osteoblasts are responsible for bone formation while osteoclasts are the bone-resorbing cells. The major event that triggers osteogenesis and bone remodeling is the transition of mesenchymal stem cells into differentiating osteoblast cells and monocyte/macrophage precursors into differentiating osteoclasts. Imbalance in differentiation and function of these two cell types will result in skeletal diseases such as osteoporosis, Paget's disease, rheumatoid arthritis, osteopetrosis, periodontal disease, and bone cancer metastases. Osteoblast and osteoclast commitment and differentiation are controlled by complex activities involving signal transduction and transcriptional regulation of gene expression. Recent advances in molecular and genetic studies using gene targeting in mice enable a better understanding of the multiple factors and signaling networks that control the differentiation process at a molecular level. This review summarizes recent advances in studies of signaling transduction pathways and transcriptional regulation of osteoblast and osteoclast cell lineage commitment and differentiation. Understanding the signaling networks that control the commitment and differentiation of bone cells will not only expand our basic understanding of the molecular mechanisms of skeletal development but will also aid our ability to develop therapeutic means of intervention in skeletal diseases.

FIGURE 1

Transcription factors and signaling involved in the osteoblast differentiation pathway. Osteoblasts and chondrocytes are derived from common mesenchymal stem cell precursors. Runx2 stimulates terminal differentiation. A number of transcription factors are involved in Runx2 regulation and function, either upstream of Runx2 or as coactivators or corepressors. Runx2 functions upstream of Osx, which is required after Runx2 for osteoblast differentiation. Ihh and Wnt/β-catenin are key signaling molecules in osteoblastogenesis.

FIGURE 2

Stages of osteoclast differentiation from hematopoietic lineage cells. M-CSF and RANKL are essential external stimuli for osteoclastogenesis. PU.1, Mitf, NF-κB, AP-1, and NFATc1 are required for differentiation of mature osteoclasts.

FIGURE 3

Seven important signaling networks of osteoblast differentiation. Binding of Wnt to the FZD receptor induces β-catenin accumulation, which translocates to the nucleus to activate target gene transcription. Several transcription factors have been found crucial for osteoblast differentiation downstream of this signaling pathway, such as Runx2, Osterix, and ATF4. They are essential for differentiation of mesenchymal stem cells into differentiated osteoblasts and also function in the transcription of osteoblast-specific genes.

FIGURE 4

RANK signaling network of osteoclast differentiation. Binding of RANKL to its receptor RANK induces various intracellular signaling cascades through TRAF-6, such as MAP (ERK, p38, JNK), NF-κB, Src, and NFATc1. Several transcription factors have been found crucial for osteoclast differentiation downstream of RANKL/RANK signaling such as NF-κB, NFATc1, c-Fos, c-Jun, and Mitf. RGS10 functions downstream of RANKL to regulate calcium oscillations and NFATc1 expression. These transcription factors are essential for differentiation of mononuclear precursors into multinucleated osteoclasts and are essential for the transcription of osteoclast-specific genes.