PDGF

Platelet-derived growth factor, PDGF, is a dimeric protein, composed by two subunits of four (PDGF-A, PDGF-B, PDGF-C, and PDGF-D) [17, 18]. The four monomers conserve a very similar structure, having a cysteine-rich region that allows, by making SS-bounds with another monomer, to reach its three-dimensional active structure [19]. The receptors are PDGFR-α and PDGFR-β, both being tyrosine kinase, and each one has a different affinity depending on the PDGF subunit. These receptor combinations give two homodimeric and one heterodimeric receptor, with a variable affinity for all different PDGF [18, 19].

The PDGF has mitogenic properties as a very strong mesenchymal cell activator [20]. This growth factor is also chemotactic in fibroblasts, smooth muscle cells, and inflammatory cells and promotes the synthesis of the extracellular matrix components such as glycosaminoglycan or proteoglycan [21, 22]. Besides, PDGF modulates other important processes such as endocytosis and cell migration [22]. PDGF also plays a very important role in reparation and regenerative processes and is one of the first discovered growth factors [21]. PDGF in conjunction with FGF simulate smooth muscle proliferation.

TGF-β

Transforming growth factor beta, TGF-β, is a superfamily related by its structure. The structure is based on a cysteine region maintained by SS-bounds. There are, in this family, different subfamilies such as bone morphogenetic proteins (BMPs), activine/inhibine subfamily, and TGF-β subfamily (with TGF-β1, TGF-β2, and TGF-β) [23]. TFG-β has many different functions as proliferation, migration, and cell metabolism. It stimulates or inhibits cell differentiation and proliferation depending on its concentration, tissue environment, and cell type [22]. It is a growth inhibitor by cell cycle inhibition in the epithelial cell [24], stimulates chemotaxis, acts as a fibrogenic agent, and increases collagen, fibronectin, and proteoglycan expression. It inhibits protease expression in the extracellular matrix, functions as an osteoclast mitogen, an immune system regulator, and possesses anti-inflammatory power [22, 25]. In addition, it regulates other growth factor actions by activating or inhibiting their effects. In muscle, it stimulates differentiation and proliferation of the myoblasts, but studies showed that the primary effects of TGF-β1 over-expression in skeletal muscles are muscle wasting and endomysial fibrosis [26].

IGF

There are two members in the insulin growth factor, (IGF), family, IGF-I, and IGF-II. They have a 62% sequential homology with each other and 47% with insulin. Both have a region with three points of SS-bounds [27]. They are synthetized in many tissues, IGF-II mostly in foetal development and IGF-I in adult tissues. IGF-I has an autocrine–paracrine effect and an endocrine effect after entering into the circulation system [21]. The main biological functions of IGF are cellular replication, synthesis of glycogen, proteins and glycosaminoglycan, and the transport of glucose and amino acids throughout the cell membrane [22]. IGF also plays an important role in the locomotor system, such as increasing cartilage and bone formation and decreasing extracellular matrix degradation [28]. The IGF-I released by platelets or produced by fibroblasts can promote cell migration from the vascular endothelium to reparation–regeneration tissue areas, leading to an increase of the neovascularization [29]. IGF is a necessary stimulus for myoblast differentiation and proliferation and is a powerful promoter of muscle differentiation through PI3K/Akt pathway [30].

FGF

Fibroblast growth factor, FGF, is a family of growth factors with 22 members, from FGF-1 to FGF-23, and four receptors are identified, FGFR1, FGFR2, FGFR3, and FGFR4. FGFs are present in many tissues, such as in the hypophysis, brain, adrenal cortex, retina, ovary, and bone [28]. They are released by the vascular endothelium, macrophages, and platelets [22]. The main characteristic of FGF is that they are affine to heparin, which means that the components of the cellular matrix which have heparin can regulate FGF activity [29]. The main biological activity is the mitogenic, chemotactic, and angiogenic capacity over many cells [22]. The angiogenic property is very important in the neovascularization processes in tissue healing [24]. FGF contributes to proliferation of myoblasts. When this factor stops functioning, the myoblasts merge selectively (depending on the kind of fibre they are going to form) originating primary microtubules. FGF and PDGF stimulate smooth muscle proliferation.

EGF

Epidermal growth factor, EFG, is a polypeptide with a spatial structure of three loops connected by three SS-bounds [29]. This structure is very important for distinguishing the EFG from other growth factors because its plasma level is very low, almost undetectable. EGF receptors have a tyrosine-kinase activity domain and are present in many cell types. EGFs act in epithelial cells, keratinocytes, fibroblasts, chondrocytes, and smooth muscle cells amongst others [22]. EGF stimulates mitogenesis, increasing DNA, RNA, and protein production in fibroblasts and in endothelial cells. Besides, it seems to stimulate neovascularization, epithelial cells migration and growth, and differentiation of the keratinocytes [22, 24]. EGF also stimulates differentiation and proliferation of myoblasts in muscle.

VEGF

There are five isoforms of vascular endothelial growth factor, VEGF, that result from alternative mRNA splicing of a single VEGF gene, all of them with similar functions [31]. VEGF is very important in the embryologic development of the cardiovascular system, in the angiogenesis of the retina, and in other neovascularization processes. VEGF is also known for being an important factor in pathological angiogenesis such as the tumour growth [32]. The VEGF biological activity is regulated by binding and activating to tyrosine-kinase receptors; these receptors are VEGFR-1, VEGFR-2, and VEGFR-3; and they are expressed especially in endothelial cells. After binding, VEGF induces collagenase and gelatinase synthesis, which are part of the early stage of angiogenesis. Besides, it induces α-integrin expression, which is fundamental in neovascularization processes, leading to a vasodilatation and increased vascular permeability and endothelial cell and monocyte migration [21]. In general terms, VEGF is fundamental in the tissue reparation–regeneration processes, like the rest of the growth factors. It plays an important role in early migration and proliferation phases, but is more active after the inflammatory process being determinant in the proliferation and remodelling phases where it acts as a great stimulant of angiogenesis [33]. In muscle, VEGF possesses a role in stimulating skeletal muscle fibre regeneration (acting on myogenic cells). It presents, apart from the very well-known pro-angiogenic activity, apoptosis prevention and promotes muscle fibre growth [34]. At least two pathways are set in motion, PI3K/Akt inhibiting apoptosis and controlling myofibre size [35], and MAPK increasing MyoD protein expression [36].

NGF

Nerve growth factor, NGF, is a molecule with three subunits, α, β (this is the bioactive one), and γ. NGF was discovered acting on nerve cells regulating growth and differentiation during embryonic development [37], but it is also present on other cell types such as inflammatory cells, fibroblasts, and endothelial cells. It is capable of stimulating migration and proliferation in endothelial cells and promoting vascular maturation and extracellular matrix remodelling [38]. NGF contributes to accelerate the cicatrization processes by modulating inflammatory phases, migration, angiogenesis, and tissue remodelling [37]. Some studies revealed that after a break in a bone, NGF is increased during bone healing process.

HGF

Hepatocyte growth factor, HGF, is a multifunctional factor secreted by some mesenchymal cells after a tissue damage, and it is also in platelet alpha granules [39, 40]. HGF is a protein with mitogenic properties in endothelial cells and stimulates cell migration. Besides, it has a powerful synergic activity with VEGF in endothelial cells [39].