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

Poniatowski ŁA, Wojdasiewicz P, Gasik R, Szukiewicz D - Mediators Inflamm. (2015)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of General and Experimental Pathology with Centre for Preclinical Research and Technology (CePT), Second Faculty of Medicine, Medical University of Warsaw, Pawińskiego 3c, 02-106 Warsaw, Poland.

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.

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Related in: MedlinePlus

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.
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fig4: 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.

Mentions: TGF-β and BMP families belong to the best known groups of compounds having the effect on the bone tissue [168]. The bone tissue is the largest TGF-β reservoir in the body, and it contains more than 200 μg/kg of wet weight, whereas thrombocytes represent the most concentrated source of TGF-β around 20 mg/kg of wet weight [169, 170]. Almost every cell in a body is able to synthesise and respond to TGF-β ligands, and, in a case of cell lineages engaged in the bone healing process, this response also depends on differentiation degree of a relevant cell, presence of other cells, and an effect of other cytokines and growth factors. A moment when the bone tissue continuity is disrupted following an injury or osteotomy is also the moment when TGF-β starts to fulfill its physiological role in the processes of proliferation, differentiation, and synthesis of cartilage and bone tissue, collectively known as the bone healing process (Figure 4). Cellular effects caused by TGF-β attachment to cell surface can be viewed as specific connection between the inflammatory and the repair phases during fracture healing. The main sources of TGF-β present during the bone healing process are practically all cells involved in that process, incoming blood platelets, and the surrounding ECM releasing TGF-β following a mechanical injury causing tissue ischaemia and local change in pH, facilitating release not only of TGF-β, but also of other growth factors, such as PDGF, VEGF, or BMP-2 [171, 172]. Functionally, multidirectional TGF-β effects are based on autocrine and paracrine signalling and, in the cellular aspect, on induction of ECM production and ossification, resulting in bone healing. One of the most important TGF-β functions is its chemotactic ability, enabling recruitment of MSC, chondroprogenitor cells, osteoprogenitor cells, fibroblasts, and immune cells such as macrophages, monocytes, and T-cells [173–177]. At the same time, at early stages, TGF-β inhibits activation, proliferation, and differentiation of osteoclasts and moreover induces their apoptosis and additionally promotes development of callus and prevents its premature resorption, as only during the remodelling phase TGF-β becomes a regulator of its activity [178–181].


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

Poniatowski ŁA, Wojdasiewicz P, Gasik R, Szukiewicz D - Mediators Inflamm. (2015)

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.
© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4325469&req=5

fig4: 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.
Mentions: TGF-β and BMP families belong to the best known groups of compounds having the effect on the bone tissue [168]. The bone tissue is the largest TGF-β reservoir in the body, and it contains more than 200 μg/kg of wet weight, whereas thrombocytes represent the most concentrated source of TGF-β around 20 mg/kg of wet weight [169, 170]. Almost every cell in a body is able to synthesise and respond to TGF-β ligands, and, in a case of cell lineages engaged in the bone healing process, this response also depends on differentiation degree of a relevant cell, presence of other cells, and an effect of other cytokines and growth factors. A moment when the bone tissue continuity is disrupted following an injury or osteotomy is also the moment when TGF-β starts to fulfill its physiological role in the processes of proliferation, differentiation, and synthesis of cartilage and bone tissue, collectively known as the bone healing process (Figure 4). Cellular effects caused by TGF-β attachment to cell surface can be viewed as specific connection between the inflammatory and the repair phases during fracture healing. The main sources of TGF-β present during the bone healing process are practically all cells involved in that process, incoming blood platelets, and the surrounding ECM releasing TGF-β following a mechanical injury causing tissue ischaemia and local change in pH, facilitating release not only of TGF-β, but also of other growth factors, such as PDGF, VEGF, or BMP-2 [171, 172]. Functionally, multidirectional TGF-β effects are based on autocrine and paracrine signalling and, in the cellular aspect, on induction of ECM production and ossification, resulting in bone healing. One of the most important TGF-β functions is its chemotactic ability, enabling recruitment of MSC, chondroprogenitor cells, osteoprogenitor cells, fibroblasts, and immune cells such as macrophages, monocytes, and T-cells [173–177]. At the same time, at early stages, TGF-β inhibits activation, proliferation, and differentiation of osteoclasts and moreover induces their apoptosis and additionally promotes development of callus and prevents its premature resorption, as only during the remodelling phase TGF-β becomes a regulator of its activity [178–181].

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of General and Experimental Pathology with Centre for Preclinical Research and Technology (CePT), Second Faculty of Medicine, Medical University of Warsaw, Pawińskiego 3c, 02-106 Warsaw, Poland.

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.

Show MeSH
Related in: MedlinePlus