NOTCHing the bone: insights into multi-functionality

Abstract

Evolutionarily conserved Notch signaling plays a critical role during embryonic and postnatal life. The importance of Notch signaling in the determination of cell fate, and the spatio-temporal regulation of proliferation, differentiation and apoptosis has been demonstrated in various different organ systems. However, how Notch signaling affects the bone development was unknown until now. The in vivo effects of Notch signaling in lineage commitment, bone formation and bone resorption were demonstrated in recent studies. In addition to regulation of osteoblastogenesis, osteoblast directed osteoclastogenesis by Notch signaling revealed a dimorphic effect for this signaling pathway providing another example of such in bone development. Moreover, identification of the cross talk between the hematopoietic stem cell niche and osteoblasts through Notch signaling also suggested another important role for Notch signaling, i.e., the coupling of cellular components of the bone microenvironment. The association between the gain and loss of function of Notch activity in bone pathology highlights Notch as a potentially novel therapeutic target for the treatment of metabolic bone disease and bone cancer. In this review, we will focus primarily on the regulation of bone cells, i.e., osteoblasts and osteoclasts by Notch signaling. We will also review the importance of Notch in specifying bone-hematopoietic stem cell niche interactions within the bone microenvironment. Finally, we will discuss potential clinical implications and future directions for this field.

Figure 1. Canonical Notch signaling in mammals

Upon binding of Notch ligand (Delta-like or Jagged) to Notch receptor (1-4) on an adjacent cell, a series of proteolytic cleavages occurs (TACE, γ-secretase), resulting in the release of the Notch intracellular domain (Notch ICD). Notch ICD subsequently translocates into the nucleus. In the absence of nuclear Notch ICD, the transcription factor Rbp-Jκ is bound to co-repressors (Co-R) and represses transcription. When Notch signaling is activated, nuclear Notch ICD binds to Rbp-Jκ and recruits the nuclear protein Mastermind Like (MAML) to form a ternary complex that functions as a transcriptional activator activating the transcription of Notch target genes including those belonging to the Hes and Hey families.

Figure 2. Function of Notch in bone homeostasis

Prior to the commitment to osteoblastic lineage, Notch maintains mesenchymal stem cells in an undifferentiated stage by repressing Runx2. In established osteoblastic lineages, pathological gain of Notch function activates expansion of the immature osteoblastic pool by increasing transcription of Osx, Cyclin D, and Cyclin E and by repressing the function of Runx2 via direct interaction and inhibition of its binding. Physiologically, it inhibits osteoclastogenesis by increasing Opg production over Rankl production.

Figure 3. Multiple roles of Notch in bone marrow environment

Osteoblasts act as signal sending cells and activate Notch signaling in HSCs leading to increased expansion of these cells. If osteoclasts or other cell types of bone marrow micro-environment also trigger a Notch dependent response remain to be elucidated.