Growth factors (GFs) belong to an extensive and diverse group of signaling molecules that regulate fundamental cellular processes such as proliferation, differentiation, migration, and survival. GFs, which mediate intercellular communication, are indispensable for embryonic development, maintenance of tissue homeostasis, regeneration, and repair of damaged tissues.

Growth factors bind to specific membrane receptors and activate intracellular signaling pathways. These pathways regulate cellular responses depending on the tissue type and physiological state based on the tissue type and the current state of the body.

Extensive data on the molecular mechanisms of actions of growth factors, which have been collected over the past few decades, resulted in successful integration of the data into clinical practice. Today, growth factor-based medications or therapies aimed at stimulating their local release are used in regenerative medicine, treatment of chronic wounds, orthopedics, dentistry, ophthalmology, cosmetology and other fields.

Growth factors are categorized based on their structural characteristics and the specific receptors they bind to. Thus, nine distinct growth factor families are identified:

  1. Epidermal Growth Factor (EGF) Family;
  2.  Fibroblast Growth Factor (FGF) Family;
  3.  Platelet-Derived Growth Factor (PDGF) Family;
  4.  Nerve Growth Factor (NGF) Family;
  5.  Vascular Endothelial Growth Factor (VEGF) Family;
  6.  Transforming Growth Factor-beta (TGF-β) Family, including Bone Morphogenetic Proteins (BMP);
  7.  Insulin-like Growth Factor (IGF) Family;
  8.  Hepatocyte Growth Factor (HGF) Family;
  9.  Hematopoietic Growth Factor Family.

Each growth factor binds to a specific cellular receptor, mainly belonging to the family of receptor tyrosine kinases, ensuring the specificity of signal transmission and subsequent cellular response [1]. In regenerative medicine and orthopedics, some growth factors belonging to the EGF, FGF, PDGF, BMP, and VEGF families are heavily applied as they regulate cellular proliferation, angiogenesis, migration, and differentiation of cells.

THE EGF FAMILY IN CLINICAL PRACTICE

EGF contains a well-preserved EGF-like domain required for binding to the epidermal growth receptor EGFR (EGFR, also known as HER1 or ErbB1) that acts as a single-chain transmembrane receptor with a tyrosine kinase activity [2]. EGFR activation sets off cascades of intracellular signaling pathways, including ERK/MAPK (Ras-ERK), PI3K/Akt/mTOR, PLC-γ1-PKC, and JAK-STAT, which ultimately stimulates proliferation of keratinocytes, fibroblasts, endothelial cells and promotes fibronectin production [3].

Understanding the molecular mechanisms underlying EGF activity to regulate cell proliferation, migration, and differentiation has served as the basis for exploring its therapeutic potential. The first clinical trial of a topical EGF formulation designed to promote tissue regeneration was conducted in the USA in 1989. Subsequently, intravenous, oral, and rectal administration routes of recombinant EGF were investigated, significantly expanding the understanding of how it might be used to treat patients [4].

EGF is primarily used in regenerative medicine to treat acute and chronic wounds of various etiologies, including traumatic and postoperative injuries, burns, pressure sores, diabetic ulcers, ulcerative lesions of the mucous membranes, mucositis of the oral cavity, perforations of the eardrum, as well as correction of alopecia and radiation or chemotherapeutic dermatitis [5]. To date, Heberprot-P® is the only medication based on a growth factor, which is approved for use in the Russian Federation. It consists of recombinant human EGF, which is biologically manufactured using Saccharomyces cerevisiae yeast. To accelerate wound closure [6], Heberprot-P® is administered as part of a comprehensive treatment plan for diabetic foot syndrome. It targets severe, long-standing neuropathic or neuroischemic wounds that penetrate as deep as the tendons, joints, or bone tissues [6]. This medication is included into the acting clinical guidelines approved by the Russian Ministry of Health for managing diabetic foot syndrome in patients with type 1 and type 2 diabetes. According to the guidelines, the agent is used to stimulate healing in deep ulcers post-surgery and to control infection [7].

Recent systematic reviews and network meta-analyses confirm the efficacy of EGF in treatment of diabetic ulcers. Specifically, a meta-analysis of 51 randomized controlled trials (RCTs) involving 3401 patients showed that EGF, PDGF, and platelet-rich plasma (PRP) significantly improved the healing rate compared to standard therapy. Based on efficacy rankings, EGF ranked first in terms of wound healing rates and demonstrated high efficiency in shortening the healing time. Another network meta-analysis confirmed that EGF is the most effective growth factor for increasing complete epithelialization rates in trophic ulcers.

In a randomized clinical trial of Heberprot-P®, the rate of complete epithelialization for trophic ulcers increased from 6.7% to 63.3% by week 8 (p < 0.00001), while the percentage of patients with a defect size under 1 cm2 rose from 46.7% to 80% by week 12 (p = 0.0326) [8]. No major amputations or oncological diseases were recorded during the observational study. The recurrence rate was 5.8%, the adverse events were predominantly mild, and no confirmed causal association was found between serious complications and the treatment [9].

The therapeutic potential of the FGF family

Growth factors of the FGF family interact with FGFR1–FGFR4 receptor tyrosine kinases in a complex with heparan sulfate. This interaction primarily activates the RAS/MAPK (ERK), PI3K/ AKT, PLCγ, and STAT signaling pathways, ultimately driving cell proliferation, migration, survival, and differentiation, as well as angiogenesis and tissue regeneration [10]. The family representative, bFGF, is a powerful mitogen targeting fibroblasts and endothelial cells. In Japan, it is widely used to stimulate tissue repair in burn injuries, chronic lesions, and recent wounds. A clinical trial evaluating Trafermin, a recombinant bFGF formulation, is currently underway in Russia for the treatment of patients with burn wounds requiring autodermoplasty [11]. In Europe and the United States, KEPIVANCE® (palifermin) has been approved. It is a human keratinocyte growth factor (KGF) produced via recombinant DNA technology in an E. coli system. It decreases both the incidence and duration of severe oral mucositis [1, 13, 14, 15]. However, the marketing authorization for palifermin was withdrawn in the European Union due to commercial reasons, whereas the drug remains accessible in the United States.

In recent years, emerging data have highlighted the therapeutic efficacy of FGF in alternative fields. In dentistry, for example, recombinant human FGF-2 (rhFGF-2) is currently being investigated as a therapeutic agent for periodontal regeneration. Data from a RCT showed that a 12-month course of therapy with rhFGF-2 (both alone and in combination with an autogenic bone graft) was resulted in a statistically significant improvement in clinical attachment level and enhanced filling of bone defects. At the same time, the combined approach resulted in the highest degree of bone defect filling (an average of 2.6 mm versus 1.2 mm in the group receiving only the autogenous bone graft), though between-group differences regarding clinical attachment level improvements were not statistically significant. These data indicate that FGF-2 promotes regeneration of periodontal hard tissues, thereby opening new prospects for treatment of severe periodontitis.

The PDGF family in regenerative medicine

PDGF interacts with PDGFRα/β receptors to activate the RAS/MAPK, PI3K/AKT, and PLCγ cascades, thereby inducing chemotaxis and proliferation of fibroblasts and smooth muscle cells, as well as synthesis of extracellular matrix components. Owing to these properties, PDGF has been used as a therapeutic agent in orthopedics and regenerative medicine [3]. Several human recombinant PDGF-based products have obtained regulatory approval in the United States, Europe, and some other countries. [1] These include Regranex® for treating diabetic foot ulcers and growth factor-enhanced bone grafts such as Augment® and GEM 21S® [1]. According to a recent meta-analysis, PDGF significantly reduces diabetic foot ulcer area and demonstrates a favorable safety profile.

Bone morphogenetic proteins (BMP) in bone tissue engineering

Bone grafts and implants containing BMPs are also widely used in bone tissue engineering. Being members of the TGF-β superfamily, bone morphogenetic proteins (BMPs) bind to BMPR-I (ALK2/3/6) and BMPR-II serine/threonine kinase receptors. They primarily activate the canonical SMAD1/5/8–SMAD4 pathway, non-canonical p38 MAPK, ERK, JNK, and PI3K/AKT cascades, thereby stimulating the osteogenic and chondrogenic differentiation of mesenchymal stem cells, bone tissue formation and regeneration [12]. In dentistry and maxillofacial surgery, methods to enhance osseointegration and bone regeneration with growth factor concentrates derived from the autologous blood (such as PRP, PRF, and CGF) of the patient are being actively explored. A systematic review has demonstrated that combining these concentrates with bone grafts during sinus lifting promotes early vascularization, reduces inflammation, and accelerates healing, thereby improving the quality of the newly formed bone tissue.

Nerve growth factor (NGF)

Nerve growth factor (NGF) interacts primarily with high-affinity receptor tyrosine kinase TrkA and low-affinity receptor p75NTR to activate the RAS/MAPK (ERK), PI3K/AKT, and PLCγ signaling pathways, thereby ensuring survival, growth, differentiation, and regeneration of neurons, and restoring innervation and tissue repair. Oxervate® (cenegermin), a therapeutic agent based on recombinant human NGF, helps maintain corneal innervation and structural integrity in patients with neurotrophic keratitis [13]. Research is also exploring the use of other growth factors, such as placental growth factor (PlGF) used for treatment of peripheral nerve injuries. Currently, clinical trials are underway to evaluate the efficacy of PlGF injections.

The role of the IGF family

IGF-1 regulates numerous physiological processes and body systems, including bone tissue (osteogenesis, remodeling, and mineralization), muscular system (growth and maintenance of muscle mass), skin and epithelium (re-epithelialization and barrier tissue restoration), connective tissue (fibroblast activation and extracellular matrix synthesis), and the hematopoietic system (bone marrow niche and stem cell regulation). These biological effects are mediated predominantly through IGF1R-dependent signaling pathways, specifically PI3K/AKT/ mTOR and RAS/MAPK (ERK) [1, 3, 14]. Despite the broader potential spectrum of biological effects, recombinant human IGF-1, which is available as Increlex® (mecasermin), is utilized in clinical practice exclusively as a replacement therapy for severe primary IGF-1 deficiency. It is also provided to patients with growth hormone insensitivity syndrome (Laron syndrome) or those presenting with growth hormone gene deletions [1].

Current investigations in Russia evaluate the safety and pharmacokinetics of a therapeutic agent based on mechano-growth factor (MGF) belonging to the IGF family. The investigation is carried out in healthy volunteers. The drug was manufactured utilizing recombinant DNA technology within a Saccharomyces cerevisiae system [15]. MGF, an isoform of insulin-like growth factor 1 (IGF-1), lacks a distinct, specific receptor and mediates its biological effects primarily through the IGF-1R tyrosine kinase receptor, triggering the PI3K/Akt, MAPK/ ERK, and RhoA–YAP signaling cascades. Consequently, this pathway upregulates chondrocyte migration and extracellular matrix synthesis, suppresses inflammation and partially modulates cartilage tissue repair following a mechanical injury [12].

Hematopoietic growth factors

Hematopoietic growth factors (EPO, G-CSF, GM-CSF, and TPO) bind to cytokine receptors (EPOR, G-CSFR, GM-CSFR, and MPL) to activate primarily the JAK2/STAT signaling pathways, as well as the PI3K/AKT and MAPK/ERK cascades. This molecular activation regulates erythropoiesis, granulocytopoiesis, and megakaryocytopoiesis. It also modulates mobilization of hematopoietic stem cells from the bone marrow into the peripheral blood [16, 17]. At present, the clinical application of hematopoietic growth factors is primarily focused on treatment of hematopoiesis disorders. Recombinant erythropoietin formulations (such as EPOGEN/ PROCRIT® in the USA and NeoRecormon® in Europe) [1] are indicated for treating anemias of diverse etiologies, whereas recombinant thrombopoietin (Tebiao®, China) is utilized to stimulate thrombocytopoiesis in chemotherapy-induced and immune thrombocytopenia [18].

Prospects for the VEGF family

Factors of the VEGF family bind to VEGFR1–3 receptor tyrosine kinases, activating the PLCγ/PKC/MAPK, PI3K/AKT, and Src signaling pathways, which subsequently induces angiogenesis and neovascularization of ischemic tissues, increases vascular permeability, and promotes granulation tissue formation and wound healing [19]. Despite the fact that preclinical studies discuss the utility of VEGF in stimulating angiogenesis and osteogenesis, its clinical application as a therapeutic growth factor currently remains limited [20]. However, a network meta-analysis demonstrates that VEGF achieves the second highest rank in terms of efficacy for stimulating diabetic ulcer healing, surpassed only by EGF.

Hepatocyte growth factor (HGF)

Hepatocyte growth factor (HGF) binds to the c-Met receptor tyrosine kinase, activating the RAS/MAPK, PI3K/ AKT, Wnt/β-catenin, and JAK/STAT signaling pathways, which subsequently induces proliferation, migration, and survival of hepatocytes, endothelial cells, and epithelial cells. It stimulates angiogenesis, morphogenesis, and regeneration in the liver, kidneys, and lungs, promotes wound healing and reduces fibrosis [1, 21]. Despite the wide range of potential therapeutic effects, the clinical application of recombinant HGF remains restricted at present (partly due to its short half-life) and focuses primarily on the treatment of hepatic and renal diseases, as well as the development of c-Met inhibitors in oncology [1, 22].

Targeted therapy and novel agonists targeting growth factor receptors

Understanding the molecular pathways governing signal transmission via growth factor receptors and their downstream signaling cascades has provided the basis for the design of targeted oncological agents such as monoclonal antibodies and small-molecule tyrosine kinase inhibitors. Monoclonal antibodies competitively inhibit ligand binding to the extracellular domain of the receptor, whereas small-molecule inhibitors target the ATP-binding part of the intracellular tyrosine kinase domain, thereby preventing the activation of signaling cascades. Anti-VEGF and anti-EGFR therapies have become widely adopted in clinical practice [1, 22].

The biological activity of bacterial, plant, and synthetic agonists targeting growth factor receptors is also under active investigation [21–24], allowing researchers to identify new approaches for modulating growth factor signaling pathways for therapeutic purposes. For instance, data generated from our own investigations [21, :lit_25–26] demonstrate that internalin B (InlB), a bacterial agonist of the HGF receptor derived from the pathogen Listeria monocytogenes, is capable of mimicking HGF activity. The agonist can also stimulate hepatocyte proliferation and accelerate hepatic regeneration in a rat model of partial hepatectomy [:lit_21].

The comparative characteristics of growth factors are presented in the table.

Thus, growth factors represent a promising tool in modern medicine. Accumulated evidence demonstrates that growth factors effectively promote healing of chronic wounds, especially diabetic ulcers, where EGF and PDGF work best. Expanded knowledge of these molecular mechanisms of action and clinical evidence emerging from recent meta-analyses and RCTs drive the development of novel therapeutic strategies and broaden the clinical indications for growth factors across various medical fields.