TGF-β/BMP signaling and other molecular events: regulation of osteoblastogenesis and bone formation

Abstract

Transforming growth factor-beta (TGF-β)/bone morphogenetic protein (BMP) plays a fundamental role in the regulation of bone organogenesis through the activation of receptor serine/threonine kinases. Perturbations of TGF-β/BMP activity are almost invariably linked to a wide variety of clinical outcomes, i.e., skeletal, extra skeletal anomalies, autoimmune, cancer, and cardiovascular diseases. Phosphorylation of TGF-β (I/II) or BMP receptors activates intracellular downstream Smads, the transducer of TGF-β/BMP signals. This signaling is modulated by various factors and pathways, including transcription factor Runx2. The signaling network in skeletal development and bone formation is overwhelmingly complex and highly time and space specific. Additive, positive, negative, or synergistic effects are observed when TGF-β/BMP interacts with the pathways of MAPK, Wnt, Hedgehog (Hh), Notch, Akt/mTOR, and miRNA to regulate the effects of BMP-induced signaling in bone dynamics. Accumulating evidence indicates that Runx2 is the key integrator, whereas Hh is a possible modulator, miRNAs are regulators, and β-catenin is a mediator/regulator within the extensive intracellular network. This review focuses on the activation of BMP signaling and interaction with other regulatory components and pathways highlighting the molecular mechanisms regarding TGF-β/BMP function and regulation that could allow understanding the complexity of bone tissue dynamics.

Inhibition of adenosine monophosphate-activated protein kinase suppresses bone morphogenetic protein-2-induced mineralization of osteoblasts <i>via</i> Smad-independent mechanisms

“…Runx2 and Osx are important transcription factors for osteoblast differentiation and bone formation [16][17][18]. BMP-2 signal is known to increase expressions of Runx2 and Osx in osteoblasts [1,2], and in our study, we also confirmed that BMP-2 significantly increased both Runx2 and Osx in MC3T3-E1 cells. Interestingly, AMPK inhibition significantly reversed the expression of Runx2, whereas it did not affect the expression of Osx.…”

“…belong to transforming growth factor-β superfamily, bind to BMP receptors and transduce signals [1,2]. BMPs are known to be powerful osteo-inductive cytokines, and numerous studies have shown that BMP-2, one of BMP family members, enhances osteoblastic differentiation and mineralization through Smad signals and non-Smad pathways such as mitogen-activated protein kinase (MAPK) [1,2].…”

“…BMPs are known to be powerful osteo-inductive cytokines, and numerous studies have shown that BMP-2, one of BMP family members, enhances osteoblastic differentiation and mineralization through Smad signals and non-Smad pathways such as mitogen-activated protein kinase (MAPK) [1,2]. BMP-2 increases expressions of transcription factors such as runt-related transcription factor 2 (Runx2), osterix (Osx) and Dlx-5, which are essential regulators of osteoblast differentiation, resulting in promoting osteoblastic differentiation [1,2].…”

Effect of sclerostin removal <i>in vivo</i> on experimental periodontitis in mice

“…receptor activator of NFκB ligand (RANKL)], and related pathways [e.g. mitogen-activated protein kinase (MAPK)] (8,9).…”

The Role of Signaling Pathway on Osteoprogenitor Cell Behavior and Bone Formation

“…TGF-β acts through the heteromeric receptor complex, comprised of type I and type II receptors at the cell surface that transduces intracellular signals by Smad complex or MAPK cascade (12)(13)(14)(15)(16)(17). At least 29 and probably up to 42 TGF-β, five type II receptors and seven type I receptors are encoded by the human genome (18,19).…”