TGF-β and BMP signaling in osteoblast, skeletal development, and bone formation, homeostasis and disease

Abstract

Transforming growth factor-beta (TGF-β) and bone morphogenic protein (BMP) signaling has fundamental roles in both embryonic skeletal development and postnatal bone homeostasis. TGF-βs and BMPs, acting on a tetrameric receptor complex, transduce signals to both the canonical Smad-dependent signaling pathway (that is, TGF-β/BMP ligands, receptors, and Smads) and the non-canonical-Smad-independent signaling pathway (that is, p38 mitogen-activated protein kinase/p38 MAPK) to regulate mesenchymal stem cell differentiation during skeletal development, bone formation and bone homeostasis. Both the Smad and p38 MAPK signaling pathways converge at transcription factors, for example, Runx2 to promote osteoblast differentiation and chondrocyte differentiation from mesenchymal precursor cells. TGF-β and BMP signaling is controlled by multiple factors, including the ubiquitin-proteasome system, epigenetic factors, and microRNA. Dysregulated TGF-β and BMP signaling result in a number of bone disorders in humans. Knockout or mutation of TGF-β and BMP signaling-related genes in mice leads to bone abnormalities of varying severity, which enable a better understanding of TGF-β/BMP signaling in bone and the signaling networks underlying osteoblast differentiation and bone formation. There is also crosstalk between TGF-β/BMP signaling and several critical cytokines' signaling pathways (for example, Wnt, Hedgehog, Notch, PTHrP, and FGF) to coordinate osteogenesis, skeletal development, and bone homeostasis. This review summarizes the recent advances in our understanding of TGF-β/BMP signaling in osteoblast differentiation, chondrocyte differentiation, skeletal development, cartilage formation, bone formation, bone homeostasis, and related human bone diseases caused by the disruption of TGF-β/BMP signaling.

Figure 1

TGF-β signaling in bone. TGF-β is synthesized as a latent protein stored in the ECM, whose activation depends on osteoclastic bone resorption. Active TGF-βs binds to tetrameric receptor complex comprising two TGF-β types I receptors (TβRI) and two type II receptors (TβRII). TβRII transphosphorylases TβRI to induce Smad-dependent and non-Smad-dependent signaling. In the Smad-dependent signaling, phosphorylated R-Smad (Smad2 or 3) complexes with Smad4 and co-translocates into the nuclei, where they recruit co-factors to regulate target gene expression. In the non-Smad-dependent pathway, phosphorylated TAK1 recruit TAB1 to initiate the MKK-p38 MAPK or MKK–ERK1/2 signaling cascade. Smad7 negatively regulate Smad signaling by preventing R-Smad phosphorylation, targeting R-Smad for ubiquitin–proteasome degradation with Smurf2 and inhibiting R-smad/co-Smad complex nuclei translocation. Arkadia positively regulates Smad signaling by targeting Smad7 for ubiquitin–proteasome degradation. MAPK phosphorylates Runx2 to promote its transcriptional activity while Smad2/3 recruits HDACs to antagonize Runx2 activity. TGF-β–Smad signaling promotes proliferation, chemotaxis, and early differentiation of osteoprogenitor. However, it inhibits osteoblast maturation, mineralization, and transition into osteocyte. It also inhibits osteoclast differentiation by decreasing RANKL/OPG secretion ratio, although it promotes osteoclastogenesis via directly binding with receptors on the osteoclast. TGF-β, transforming growth factor-β.

Figure 2

BMP signaling in bone. BMP activity is antagonized by cognate binding proteins, including Noggin, Grem1, Chordin, CHL, and Fellistatin. BMPs bind to homomeric type II receptors, which transphosphorylases homomeric type I receptor to induce Smad-dependent and non-Smad-dependent signaling. In the Smad-dependent signaling, phosphorylated R-Smad (Smad1, 5, or 8) complexes with Smad4 and co-translocates into the nuclei, where they recruit co-factors and Runx2 to regulate osteogenic gene expression, for example, Runx2, Dlx5, and Osx. In the non-Smad-dependent pathway, phosphorylated TAK1 recruit TAB1 to initiate the MKK-p38 MAPK or MKK–ERK1/2 signaling cascade. MAPK phosphorylates Runx2, Dlx5, and Osx to promote their transcriptional activity. MAPK also phosphorylates Runx2 to promote the formation of Smad–Runx2 complex. I-Smad (Smad6 or 7) negatively regulates Smad signaling by preventing R-Smad phosphorylation, targeting R-Smad or type I receptor for ubiquitin–proteasome degradation with Smurf1 and inhibiting R-smad/co-Smad complex nuclei translocation. Arkadia positively regulates Smad signaling by targeting I-Smads for ubiquitin–proteasome degradation. Ubc9/SUMO complex negatively regulates Smad signaling by targeting Smad4 for ubiquitin–proteasome degradation. BMP–Smad signaling promotes almost every step during osteoblast differentiation and maturation. BMP, bone morphogenetic protein.

Figure 3

Crosstalk between BMP, TGF-β, and other signaling during osteoblast differentiation. BMP has dual roles in Wnt signaling. On one hand, BMP inhibits Wnt/β-catenin signaling by increasing Wnt antagonist Dkk1 and Sost expression and by preventing β-catenin nuclei translocation. On the other hand, BMP promotes Wnt/β-catenin signaling by forming co-transcriptional complex with β-catenin/TCF/LEF/Runx2, by increasing Wnt expression, by antagonizing Dvl function and by decreasing b-TrCP expression. BMP signaling promotes FGF, Hh, PTHrP signaling by increasing IHH expression, increasing FGF expression, decreasing Ptch1 expression, respectively. BMP is essential for IHH-induced osteoblast differentiation. FGF, IHH, Wnt, and PTHrP signaling all promotes BMP2 expression so as to enhance BMP signaling. FGF and IHH signaling is essential for BMP-induced osteoblast differentiation. TGF-β antagonizes PTHrP signaling through TGF-β type II receptor complexing and internalizing together with PTHrP receptor (PPR). TGF-β promotes Wnt activity by increasing Wnt ligands expression and decreasing Axin expression. Fibroblast growth factor (FGF) and Wnt all increase TGF-β expression to promote TGF-β signaling. BMP, bone morphogenetic protein; PTHrP, parathyroid hormone-related peptide; TGF-β, transforming growth factor-β.

Figure 4

Crosstalk between BMP, TGF-β and other signaling in the growth plate. In the epiphyseal growth plate, differentiating chondrocytes are organized into four layers, including resting zone (RZ), proliferation zone (PZ), hypertrophic zone (HZ), and calcified zone (CZ). The calcified zone was gradually replaced by the trabecular bone (TB). Positive regulating cytokines (→) and negative regulating cytokines (--|) of each zone are listed on the left adjacent to them. BMP, bone morphogenetic protein; FGF, fibroblast growth factor; IHH, Indian hedgehog; PTHrP, parathyroid hormone-related peptide; SHH, Sonic hedgehog; TGF-β, transforming growth factor-β.