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

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. How bone morphogenetic protein (BMP), discovered in 1965, interacts within a complex network to form bone is not yet clearly understood. Disturbances in BMP activity are linked to a wide range of autoimmune diseases, cancers and skeletal diseases including fibrodysplasia ossificans progressiva. In their review Md. Shaifur Rahman from Tissue Banking and Biomaterial Research Unit, Atomic Energy Research Establishment, Dahka, Bangladesh, and his colleagues focus on the structure of BMP and its receptors, and the pathways it uses to regulate and stimulate bone growth. A large number of factors and targets have now been identified for the BMP pathways. This has led to the discovery of a complex interactive network that researchers are still trying to understand. Knowing more about how the pathways affect the transformation of bone-forming cells at different developmental stages would help to develop potential therapies for bone-related diseases.