Transforming growth factor Beta family: insight into the role of growth factors in regulation of fracture healing biology and potential clinical applications

Abstract

The transforming growth factor beta (TGF-β) family forms a group of three isoforms, TGF-β1, TGF-β2, and TGF-β3, with their structure formed by interrelated dimeric polypeptide chains. Pleiotropic and redundant functions of the TGF-β family concern control of numerous aspects and effects of cell functions, including proliferation, differentiation, and migration, in all tissues of the human body. Amongst many cytokines and growth factors, the TGF-β family is considered a group playing one of numerous key roles in control of physiological phenomena concerning maintenance of metabolic homeostasis in the bone tissue. By breaking the continuity of bone tissue, a spread-over-time and complex bone healing process is initiated, considered a recapitulation of embryonic intracartilaginous ossification. This process is a cascade of local and systemic phenomena spread over time, involving whole cell lineages and various cytokines and growth factors. Numerous in vivo and in vitro studies in various models analysing cytokines and growth factors' involvement have shown that TGF-β has a leading role in the fracture healing process. This paper sums up current knowledge on the basis of available literature concerning the role of the TGF-β family in the fracture healing process.

Figure 1

A schematic representation of TGF-β superfamily. TGF-β: transforming growth factor beta; GDF: growth and differentiation factor; ACT: activin; INH: inhibin; other ligands include Müllerian inhibiting substance (MIS) or anti-Müllerian hormone (AMH), left-right determination factor (Lefty), and nodal growth differentiation factor (Nodal); GDNF: glial-derived neurotrophic factors; BMPs: bone morphogenetic proteins.

Figure 2

A schematic representation of TGF-β different forms occurring during synthesis, secretion, and activation.

Figure 3

TGF-β associated intracellular canonical and noncanonical signaling pathways. Perpendicular line indicates an inhibitory effect; TGF-β: transforming growth factor beta; TβRI: transforming growth factor, beta receptor type I; TβRII: transforming growth factor, beta receptor type II; P: phosphate group; SARA: Smad anchor for receptor activation; Smad2/3: Smad family member 2/3; Smad6/7: Smad family member 6/7; Smad4: Smad family member 4.

Figure 4

A schematic representation of TGF-β interactions and effects in fracture site. TGF-β: transforming growth factor beta; MSCs: mesenchymal stem cells; VEGF: vascular endothelial growth factor.