Type III transforming growth factor beta receptor regulates vascular and osteoblast development during palatogenesis

Abstract

Background Cleft palate occurs in up to 1:1000 live births and is associated with mutations in multiple genes. Palatogenesis involves a complex choreography of palatal shelf elongation, elevation, and fusion. Transforming growth factor β (TGFβ) and bone morphogenetic protein 2 (BMP2) canonical signaling is required during each stage of palate development. The type III TGFβ receptor (TGFβR3) binds all three TGFβ ligands and BMP2, but its contribution to palatogenesis is unknown. Results The role of TGFβR3 during palate formation was found to be during palatal shelf elongation and elevation. Tgfbr3-/- embryos displayed reduced palatal shelf width and height, changes in proliferation and apoptosis, and reduced vascular and osteoblast differentiation. Abnormal vascular plexus organization as well as aberrant expression of arterial (Notch1, Alk1), venous (EphB4), and lymphatic (Lyve1) markers was also observed. Decreased osteoblast differentiation factors (Runx2, alk phos, osteocalcin, col1A1, and col1A2) demonstrated poor mesenchymal cell commitment to the osteoblast lineage within the maxilla and palatal shelves in Tgfbr3-/- embryos. Additionally, in vitro bone mineralization induced by osteogenic medium (OM+BMP2) was insufficient in Tgfbr3-/- palatal mesenchyme, but mineralization was rescued by overexpression of TGFβR3. Conclusions These data reveal a critical, previously unrecognized role for TGFβR3 in vascular and osteoblast development during palatogenesis.

Betaglycan (TβRIII) is a Key Factor in TGF-β2 Signaling in Prepubertal Rat Sertoli Cells

“…We could clearly show that silencing of TIMP3 as well as of betaglycan strongly attenuated TGF-β2-dependent but not TGF-β1-dependent phosphorylation of Smad2 and of Smad3. Silencing of TIMP3 as well as of betaglycan attenuated cell proliferation of 93RS2 Sertoli cells which is in accordance to significant decreases in the percentage of proliferating cells in betaglycan -/embryos [50]. Our results further corroborate our assumption that betaglycan and TIMP3 are pivotal for TGF-β2, but not for TGF-β1 signaling.…”

Gene expression profiles in guided bone regeneration using combinations of different biomaterials: a pilot animal study

“…; Hill et al. ). The NF1 gene encodes the neurofibromin protein that is important for regulating osteoblast proliferation and differentiation (Yu et al.…”

“…IGF1 (insulin-like growth factors-1) belongs to the insulin-like growth factor family and plays a role in both bone formation and bone resorption by facilitating the early commitment of progenitor cells into osteoblasts (Koch et al 2005) and regulating osteoclastogenesis . SMAD2 is a signal transducer molecule that mediates transforming growth factor (TGF-b) signaling, and hence it plays an important role in multiple cellular processes during intramembranous ossification (Nishimura et al 2003;Hill et al 2015). The NF1 gene encodes the neurofibromin protein that is important for regulating osteoblast proliferation and differentiation (Yu et al 2005;Wu et al 2006;Kolanczyk et al 2007;Schindeler & Little 2008).…”

Cellular and molecular mechanisms of cleft palate development

“…TgfβR3 binds all three Tgfβ ligands as well as BMP2. The loss of TgfβR3 results in arrested palatal shelf elevation and elongation and interfered and also led to atypical expression of both TGFβ and BMP signaling pathways within the palatal shelves . Loeys‐Dietz syndrome, which includes craniosyostosis, cleft palate, and hypertelorism is associated with mutations in genes encoding TGF‐β receptors 1and 2 ( TGFBR1 and TGFBR2 ), as well as TGF‐β2 .…”

“…The loss of TgfβR3 results in arrested palatal shelf elevation and elongation and interfered and also led to atypical expression of both TGFβ and BMP signaling pathways within the palatal shelves. 17 Loeys-Dietz syndrome, which includes craniosyostosis, cleft palate, and hypertelorism is associated with mutations in genes encoding TGF-β receptors 1and 2 (TGFBR1 and TGFBR2), as well as TGF-β2. 18 As TGFβ1 and 2 have been shown to have an effect on inducing chondrogensis and osteogenesis, knowledge of these genetic mutations in a patient with a cleft may aid in surgical planning and in anticipation of possible complications following repair.…”