TGF-β and BMP signaling in osteoblast differentiation and bone formation

Abstract

Transforming growth factor-beta (TGF-β)/bone morphogenic protein (BMP) signaling is involved in a vast majority of cellular processes and is fundamentally important throughout life. TGF-β/BMPs have widely recognized roles in bone formation during mammalian development and exhibit versatile regulatory functions in the body. Signaling transduction by TGF-β/BMPs is specifically through both canonical Smad-dependent pathways (TGF-β/BMP ligands, receptors and Smads) and non-canonical Smad-independent signaling pathway (e.g. p38 mitogen-activated protein kinase pathway, MAPK). Following TGF-β/BMP induction, both the Smad and p38 MAPK pathways converge at the Runx2 gene to control mesenchymal precursor cell differentiation. The coordinated activity of Runx2 and TGF-β/BMP-activated Smads is critical for formation of the skeleton. Recent advances in molecular and genetic studies using gene targeting in mice enable a better understanding of TGF-β/BMP signaling in bone and in the signaling networks underlying osteoblast differentiation and bone formation. This review summarizes the recent advances in our understanding of TGF-β/BMP signaling in bone from studies of genetic mouse models and human diseases caused by the disruption of TGF-β/BMP signaling. This review also highlights the different modes of cross-talk between TGF-β/BMP signaling and the signaling pathways of MAPK, Wnt, Hedgehog, Notch, and FGF in osteoblast differentiation and bone formation.

Keywords: BMP signaling; Bone; Osteoblasts; Runx2; Smad; TGF signaling.

Figure 1

TGF-β signaling and negative regulation in bone formation. Canonical Smad-dependent TGF-β signaling first binds to receptor type II (R-II) and receptor type I (R-I), and then signaling transduces to their Smads. Activated Smads form a complex with Smad4 and then translocate into the nucleus where they interact with other transcription factors to trigger target gene expression. Smad7 disrupts the activated Smad2/3 to form a complex with Smad4. The non-Smad-dependent TAK1 signaling pathway also regulates bone formation. PTH binding activates PTH1R to stimulate several downstream effectors. PTH binding also drives internalization of PTH1R-TGFβRII complex, which attenuates both TGF-β and PTH signaling on bone development. Transcriptional factor cAMP response element binding protein (CREB) mediates PTH signaling in osteoblasts. P: phosphorylation; Ub: ubiquitination.

Figure 2

BMP signaling and negative regulation in bone formation. Smad-dependent-BMP signaling binds to receptor type II (R-II) and receptor type I (R-I) and then the signaling transduces to their Smads. Activated Smads form a complex with Smad4 and then translocate into the nucleus where they interact with other transcription factors to trigger target gene expression. Neogenin regulates BMP receptor association and Smad1/5/8 signaling. Activated Smads regulate expression of transcriptional factors and transcriptional coactivators important in osteoblasts (Dlx5, Runx2 and Osx). Smad6 binds type I BMP receptor and prevents Smad1/5/8 to be activated. Non-Smad-dependent TAK1 signaling pathway also regulates bone formation. The interplay between BMPs and Wnt signaling affects bone formation . BMPRIA signaling upregulates Sost expression primarily through Smad-dependent signaling, while it upregulates DKK1 through Smad-dependent and non-Smad-dependent signaling. Both Sost and DKK1 inhibit canonical Wnt signaling, leading to a decrease in bone mass. P: phosphorylation; Ub: ubiquitination.