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

Mengrui Wu,Guiqian Chen,Yi-Ping Li

doi:10.1038/boneres.2016.9

Mengrui Wu, Guiqian Chen + Show 1 more

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https://doi.org/10.1038/boneres.2016.9

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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.

Highlights

The transforming growth factor-β (TGF-β) superfamily comprises TGF-βs, Activin, bone morphogenetic proteins (BMPs) and other related proteins.[1,2,3,4] TGF-β superfamily members act through a heteromeric receptor complex, comprised of type I and type II receptors at the cell surface that transduce intracellular signals via Smad complex or mitogen-activated protein kinase (MAPK) cascade.[1,2,3,4] At least 29 and probably up to 42 TGF-β superfamily members, five type II receptors and seven type I receptors are encoded by the human genome.[2]
Our understanding of BMP and TGF-β signaling is advanced with the generation of related mouse models, heritable human disease genetic studies and other new technologies including high-throughput screening
Specificity and versatility of BMP and TGF-β signaling are controlled by various ligand-receptor combinations, and transduced by co-Smad/R-Smad complex or MAPK cascade

Summary

Introduction

The transforming growth factor-β (TGF-β) superfamily comprises TGF-βs, Activin, bone morphogenetic proteins (BMPs) and other related proteins.[1,2,3,4] TGF-β superfamily members act through a heteromeric receptor complex, comprised of type I and type II receptors at the cell surface that transduce intracellular signals via Smad complex or mitogen-activated protein kinase (MAPK) cascade.[1,2,3,4] At least 29 and probably up to 42 TGF-β superfamily members, five type II receptors and seven type I receptors are encoded by the human genome.[2]. SUMMARY AND PERSPECTIVE BMP and TGF-β signaling pathways have important roles in skeletal development and postnatal skeleton homeostasis, by crosstalking with multiple signaling pathways, such as Wnt, Hedgehog, Notch, and FGF. Our understanding of BMP and TGF-β signaling is advanced with the generation of related mouse models, heritable human disease genetic studies and other new technologies including high-throughput screening.

Results

Conclusion