Aoao Wang
Xinbo Ma2†
Zhenrui Jiao
Peng Wang- 1Medical School of Chinese PLA, Beijing, China
- 2Department of Chemistry, Capital Normal University, Beijing, China
- 3Senior Department of Orthopaedics, The Fourth Medical Center of PLA General Hospital, Beijing, China
- 4Department of Neurosurgery, The First Medical Center of Chinese PLA General Hospital, Beijing, China
Pulsed electromagnetic field (PEMF) stimulation is a prospective non-invasive and safe physical therapy strategy for accelerating bone repair. PEMFs can activate signalling pathways, modulate ion channels, and regulate the expression of bone-related genes to enhance osteoblast activity and promote the regeneration of neural and vascular tissues, thereby accelerating bone formation during bone repair. Although their mechanisms of action remain unclear, recent studies provide ample evidence of the effects of PEMF on bone repair. In this review, we present the progress of research exploring the effects of PEMF on bone repair and systematically elucidate the mechanisms involved in PEMF-induced bone repair. Additionally, the potential clinical significance of PEMF therapy in fracture healing is underscored. Thus, this review seeks to provide a sufficient theoretical basis for the application of PEMFs in bone repair.
1 Introduction
Non-union or delayed bone healing is a general orthopaedic disease with difficult healing. The probability of a delayed healing fracture is 5%–10% worldwide (Valiya Kambrath et al., 2020). Multiple bone defects, such as severe injuries, surgical removal of infected bones or tumours, and congenital skeletal anomalies, can reduce the regenerative capacity of bones, thereby affecting patient health and quality of life (El-Rashidy et al., 2017; Collon et al., 2021; Li et al., 2021). Major treatments for bone defects include autologous and allogeneic bone grafting, bone grafting with vascularised tips, the Masquelet technique, and bone tissue engineering (Wang and Yeung, 2017; Hofmann et al., 2020; Zhang et al., 2020; Dalisson et al., 2021). Autologous bone grafting is considered the gold standard for the clinical treatment of bone defects. However, autografting techniques have some unavoidable disadvantages, including limited bone volume, increased bleeding and surgery time, and pain in the donor area (Yu et al., 2020; Zhu et al., 2021; He et al., 2022). Pulsed electromagnetic fields (PEMFs) are non-invasive, safe, and have wide indications. Therefore, they have been increasingly used to treat bone diseases, such as fractures and delayed bone healing, in recent years. This review briefly discusses recent research progress on the application of PEMFs in bone repair, with a particular focus on the molecular mechanisms underlying PEMF-induced bone repair. Furthermore, this review aims to provide a sufficient theoretical basis for the clinical application of PEMFs in bone repair.
2 Research progress on PEMF applications in bone repair
Norton et al. (1977) first attempted the electrical stimulation method to treat bone non-union in 1812, achieving some progressive results. However, he did not have the relevant theoretical foundation for the clinical application of this method. In 1953, Yasuda (1977a) reported the presence of piezoelectric effects in bone tissue, leading to a considerably increased focus on electrical signals in bone. Yasuda (1977b) later examined rabbit bone repair using external electrodes, revealing that bone connected to the negative electrode would grow a bone scab in the direction of the anode under electrical stimulation. Furthermore, electrical stimulation can promote bone scab growth without relying on mechanical external forces. These findings led to a preliminary understanding of the role of electrical stimulation in bone growth, repair, and reconstruction. Thus, Qiu et al. (2020) pioneered the use of PEMFs to treat bone fractures in the 1970s, demonstrating that PEMFs promote fracture healing. In 1979, PEMFs were approved by the United States Food and Drug Administration Agency as a safe and effective treatment for non-healing bone (Cadossi et al., 2020).
PEMFs play an unusual role in the treatment of fractures, bone defects, and bone non-union. They artificially provide electromagnetic signals to the target area, thereby mobilising the tissues or organs at the site of injury to actively play an osteogenic role. All electromagnetic field devices work by generating a small amount of current within the bone; they only differ in the modes of action. The earliest type of electrical stimulation was invasive direct current (DC) stimulation. This technique utilised a current generator that delivered DC stimulation to a designated area via a metal wire and electrodes. The negative electrode was implanted in the area of bone repair, whereas the positive electrode was placed in the nearby soft tissue (Kooistra et al., 2009). However, the current generator is usually surgically removed after 6–9 months or after healing occurs. Therefore, the wires and electrodes may not be removed; this can lead to complications, such as re-infection and injury (Leppik et al., 2020). Contrastingly, non-invasive capacitive coupling involves placing two capacitive plates on the skin on either side of the fracture area. An external power source is subsequently connected to create an electric field with a voltage gradient between the two plates. Despite the obvious advantages of capacitively coupled stimulation, including small size, light weight, non-invasiveness, and ease of use, patients must change the batteries daily; this can present a problem of patient noncompliance (Cook et al., 2015). Inductive coupling is the basic principle for applying PEMFs. It involves the use of two electromagnetic coils connected to a signal generator over the skin. The coils generate an electromagnetic field that induces a time-varying secondary electric field within the bone to trigger enhanced growth and remodel biological effects on the bone (Yuan et al., 2018) (Figure 1). As a non-invasive physical factor therapy, PEMFs reduce pain, improve bone quality, and improve the functional prognosis of patients. As such, they are recommended as an effective physical therapy factor by domestic and international guidelines (Khalifeh et al., 2018). PEMFs improve bone metabolism by generating a specific frequency and size of pulsed current and using the resonance effect to change the bioelectricity and biomagnetic field of the body. Corresponding biological changes can occur when the frequency of the pulsed current generated by PEMFs matches the cyclotron resonance frequency of key ions (e.g., Na+, K+, and Ca2+), owing to the alteration of ion channel activity (Tong et al., 2017). In addition, high-frequency electric fields can penetrate the cytoplasm to affect mitochondrial activity and regulate energy metabolism levels (Chalidis et al., 2011). Pettersen et al. (2021) recently found that PEMFs markedly contribute to improved osteoblast survival and soluble collagen production. Furthermore, there was no significant difference in pH between stimulated experimental groups and the controls. Similarly, Kim et al. (2006) demonstrated that PEMFs induce osteoblast proliferation and vascular endothelial growth factor (VEGF) production. In vivo and ex vivo studies have shown the effects of electromagnetic fields on bone density, bone tissue morphology, bone marrow mesenchymal stem cells, osteoblasts, and osteoclasts (Zhou et al., 2019). Table 1 lists recent in vivo studies conducted on the use of electromagnetic fields to treat fractures in animal models. Table 2 lists the bioeffects of electromagnetic fields on osteoblasts and osteoclasts in vitro. The optimal waveform and parameter regimen for a particular site of fracture, as well as the electromagnetic field sensation and signalling mechanisms in osteoblasts, remain unclear. Therefore, further exploration of these parameters and mechanisms is required to guide clinical treatment (Maziarz et al., 2016; Yan et al., 2022).
FIGURE 1. Schematic diagram demonstrating the mechanisms of clinical electrical stimulation devices.
TABLE 1. Animal-level studies of electromagnetic fields for the treatment of fractures.
TABLE 2. Studies of electromagnetic fields bioeffects on osteoblasts and osteoclasts.
3 Mechanisms underlying osteogenesis induced by PEMFs
PEMFs primarily function through electromagnetic signals that can activate cell membrane ion channels and regulate cell signalling pathways to promote the directional migration and differentiation of osteoblasts, nerve regeneration, and blood vessel growth. Furthermore, they promote bone repair, a considerably complex process. However, their specific mechanisms remain unclear. At a macroscopic level, the introduction of electromagnetic fields creates an energetic electric field in the body to regulate cell proliferation and differentiation, thereby mediating bone repair (Zhao et al., 2006; Isaacson and Bloebaum, 2010; Reid and Zhao, 2014; Vadlamani et al., 2019). At a microscopic level, electromagnetic signals may affect cell membrane polarisation or ionic displacement, thereby altering intracellular homeostasis and regulating some cellular behaviours (Sundelacruz et al., 2008). PEMFs induce faster passage of ions through the cell membrane, contributing to signalling in the interior of the cell and regulating membrane potential and the cytokinesis axis for osteogenesis (Martin-Granados and McCaig, 2014; Kim et al., 2020). These findings demonstrate that electromagnetic fields play an important role in bone reconstruction. Thus, studying the mechanism of electromagnetic fields affecting bone regeneration and how they affect the behaviour of bone cells and regulate cell physiological activities could facilitate an in-depth understanding of the bone repair process.
3.1 Effects of PEMFs on bone cells
The positive osteogenic effects of PEMFs at the cellular level demonstrated its potential mechanism in promoting osteogenesis (Huang et al., 2008; Leppik et al., 2020; deVet et al., 2021). The use of capacitively coupled electric fields on human cranial osteoblasts revealed substantial upregulation of the expression of many transforming growth factor-β (TGF-β) family genes (TGF-β1, β2, and β3) and fibroblast growth factor-2 (FGF-2) and enhanced ALP mRNA expression. The proteins encoded by these genes play pivotal roles in fracture healing. Bodamyali et al. (1998) used PEMFs to verify alterations in mRNA levels of TGF-β and bone morphogenetic protein 2 (BMP-2) in osteoblasts. The effects of varying pulse waveforms of PEMFs on osteoblast proliferation and differentiation showed variability. Zhou et al. observed that square electromagnetic fields promoted osteoblast proliferation but did not support osteogenic differentiation. Conversely, SEMFs inhibited cell proliferation while enhancing osteogenic differentiation. In contrast, triangular electromagnetic fields had no effect on cell proliferation but induced the strongest osteogenic activity (Zhou et al., 2014). Moreover, PEMFs can modulate osteoclast formation, differentiation, and activity by altering the electromagnetic frequency. Hong et al. (2014) discovered that 45 Hz PEMFs inhibited RANKL-induced IκB phosphorylation to hinder osteoclast formation. Conversely, 7.5 Hz PEMFs promoted osteoclast differentiation by activating extracellular regulated protein kinase (ERK) and p38 mitogen-activated protein kinase (MAPK). Although scholars are increasingly investigating the effects of PEMFs on cells, the precise mechanisms underlying cellular sensitivity, interpretation, and transformation of electromagnetic signals necessitate further investigation (Eischen-Loges et al., 2018). Skeletal and bone tissue encompass numerous cell types, including mesenchymal stem cells, chondrocytes, chondroblasts, osteoblasts, and osteoclasts. Electromagnetic fields influence bone and bone tissue by modulating the behaviour of these bone-related cells. Given the significant roles of osteoblasts and osteoclasts in fracture healing and the maintenance of bone homeostasis, this review comprehensively evaluates the effects and potential mechanisms of PEMFs on osteoblasts and osteoclasts.
3.1.1 Osteoblasts
Osteoblasts are direct contributors to bone formation that also regulate the proliferation and differentiation of osteoclasts through various mechanisms. This pivotal role makes these cells essential for bone regeneration. Nonetheless, the impact of PEMFs on osteoblasts remains a subject of contention. PEMFs exhibit a ‘window effect’ and can yield reproducible osteogenic outcomes. In addition, different intensities of PEMFs and varying time points chosen for analysis may have different effects. However, most studies have shown that PEMFs can promote the expression of genes and proteins through specific signalling pathways in osteoblasts, thereby accelerating their proliferation (Chang et al., 2004b; Ercan and Webster, 2008; Lin and Lin, 2011), differentiation (Eischen-Loges et al., 2018; Hou et al., 2019; Leppik et al., 2019), and mineralisation (Wiesmann et al., 2001; Qi et al., 2018). Figure 2 shows a schematic representation of molecular pathways activated by PEMFs in osteoblasts.
FIGURE 2. Schematic representation of molecular pathways activated by PEMFs in osteoblasts. AC = adenylyl cyclase. ALP = alkaline phosphatase. APC = adenomatous polyposis coli. BMP = bone morphogenetic protein. BSP = bone sialoprotein. AXIN = axis inhibition protein. CaM = calmodulin. cAMP = cyclic adenosine monophosphate. cGMP = cyclic guanosine monophosphate. CGRP = calcitonin gene-related peptide. COL1 = type I collagen. CREB = cyclic adenosine monophosphate-responsive element binding protein. ERK = extracellular regulated protein kinases. GSK3 = glycogen synthase kinase 3. IGF = insulin-like growth factor. MAPK = mitogen-activated protein kinase. mTOR = mammalian/mechanistic target of rapamycin. NICD = notch intracellular domain. NOS = nitric oxide synthase. OCN = osteocalcin. OPN = osteopontin. PKA = protein kinase A. PKG = protein kinase G. PTH = parathyroid hormone. Runx2 = runt-related transcription factor 2. sGC = guanylyl cyclase. Smad = drosophila mothers against decapentaplegic. TGF-β = transforming growth factor-β.
Electromagnetic fields regulate the expression of downstream osteogenesis-related genes and proteins by activating the Wnt/β-catenin signalling pathway, thereby enhancing the functions of associated osteoblasts, such as proliferation, differentiation, and mineralisation, to promote osteogenesis (Zhai et al., 2016). Mounting evidence indicates a close association between PEMFs and the Wnt/β-catenin signalling pathway in osteogenesis. For instance, both gene and protein expression of the classical Wnt/β-catenin signalling pathway (including Wnt1, LRP6, and β-catenin) were significantly upregulated following exposure to PEMFs during the proliferation and differentiation stages of MC3T3-E1 cells (Zhou et al., 2015; Jing et al., 2016). Moreover, PEMF intervention reduced the expression of dickkopf1 (DKK1), which typically inhibits the Wnt signalling pathway (Fathi and Farahzadi, 2017). In addition, PEMF-enhanced Wnt/β-protein signalling considerably increased the expression of proliferation-phase-related target genes CCND1 and CCNE1 and differentiation-phase-related genes ALP, OCN, COL 1, and RUNX-2. These genes accelerated osteoblast proliferation, differentiation, and mineralisation (Sun et al., 2010; Clark et al., 2014; Zhai et al., 2016; Fathi and Farahzadi, 2017).
Ion channels are transmembrane proteins embedded in the lipid bilayer of the cell membrane. Furthermore, they are hydrophilic micropore channels that allow selective passage of ions through the cell membrane. Ca2+ is an important cellular mediator with roles in several activities, such as cell proliferation, differentiation, and apoptosis. The transient increase in intracellular Ca2+ is an immediate effect of electrical signal stimulation on cellular response. Various electrical stimuli (e.g., DC, PEMFs, and piezoelectric stimulation) can alter intracellular Ca2+ levels by inducing Ca2+ influx or release from intracellular stores. This promotes osteoblast proliferation and osteogenic protein expression, potentially due to the accumulation of charge on the cell membrane, ultimately leading to the opening of voltage-gated calcium channels (VGCCs) (Kim et al., 2009; Xu et al., 2009; Shuai et al., 2018; Cai et al., 2021). Exposure to electromagnetic fields directly activates VGCCs in the plasma membrane, and the channel can trigger multiple regulatory responses through the enzymatic action of Ca2+/calmodulin (CaM)-dependent nitric oxide synthase (NOS) (Pall, 2013). Xu et al. used signalling pathway inhibitors to conclude that capacitively coupled electrical stimulation, which regulates osteoblast proliferation, is mediated by VGCCs (verapamil inhibition); this elevated intracellular calcium ion concentrations and increased phospholipase A2 (PLA2) activity (bromophenyl bromide blockade). The increased PLA2 activity led to cyclooxygenase-dependent prostaglandin E2 synthesis (blocked by anti-inflammatory pain). Contrastingly, the elevated intracellular calcium ion concentrations led to CaM activation (blocked by N-(6-aminohexyl)-5-chloro-1-naphthalenesulphonamide hydrochloride, W-7). In addition, PEMFs promoted the differentiation of osteogenesis-associated cells by altering the Ca2+ oscillation pattern to resemble that of osteoblasts. Calcium oscillations can improve the efficiency and specificity of gene expression and direct cell differentiation.
High intracellular levels of Ca2+ can activate the NO/cyclic guanosine monophosphate (cGMP)/protein kinase G (PKG) pathway, owing to crosstalk between the Ca2+ and NO pathways (Jeandroz et al., 2013). Moreover, NO regulates intercellular information transfer and affects tissue blood flow. Thus, low NO levels promote osteoblast proliferation, whereas high concentrations inhibit the proliferation and differentiation of osteoblasts. Cheng et al. examined the effects of SEMF on osteogenesis through the NO-cGMP-PKG pathway by measuring ALP activity, Osterix (OSX) gene expression, and mineralised bone nodules. NOS activity was markedly higher than that in the control group after SEMF treatment. Additionally, OSX gene expression, ALP activity, and mineralised bone nodules were increased. Corresponding blockers were subsequently used to block the NO-cGMP-PKG pathway to determine whether SEMF-stimulated osteoblast maturation and mineralisation would be inhibited; the corresponding indices were all reduced (Cheng et al., 2011). As extracellular signals, electromagnetic signals belong to the first messengers of the cell and can act directly on VGCCs in the osteoblast membrane to increase Ca2+ inward flow. The inward-flowing Ca2+ combines with CaM to activate NOS, leading to increased NO production that consequently increases cGMP synthesis. Subsequently, cGMP activates PKG (Cheng et al., 2011; Pilla et al., 2011; Rangaswami et al., 2012; Zhong et al., 2012), which regulates gene transcription and mediates osteoblast proliferation and differentiation.
The MAPK signalling pathway transmits extracellular signals to the inside of the cell to control various cellular processes, such as proliferation, differentiation, migration, and death. This pathway is one of the important pathways through which electromagnetic fields cause the proliferation and differentiation of osteoblasts. Conventional MAPKs include ERK1/2, JNK, and p38. Yumoto et al. (2015) found that electromagnetic field radiation to osteoblast MC3T3-E1 cells induced the ERK1/2 and p38 MAPK pathways to enhance proliferation and upregulate the expression of various growth factors, including VEGF and platelet-derived growth factor. Ehnert et al. found that ELF-PEMFs increased total protein content and ALP activity and promoted the formation of a mineralised matrix by triggering the MAPK/ERK1/2 signalling pathway in osteoblasts. Similarly, inhibition of the ERK1/2 signalling pathway with U0126 prevented the activation of ALP activity and matrix mineralisation. In addition, the positive effects of ELF-PEMFs on osteoblast function were impaired (Ehnert et al., 2015). The increase in total protein content and ALP activity following ELF-PEMF treatment in osteoblasts was accompanied by a substantial upregulation of mitochondrial activity. This is consistent with a recent report that electromagnetic fields can promote osteogenic differentiation and bone anabolism by activating mitochondrial oxidative phosphorylation in bone progenitor cells and osteoblasts. However, the exact signalling pathway of their action is unknown (Hollenberg et al., 2021). In addition, PEMFs promote the expression of antioxidant enzymes (Poh et al., 2018) and enhance the activity of cytoprotective enzymes (Ehnert et al., 2017) through the MAPK/ERK signalling pathway, thereby shaping the microenvironment that promotes osteogenic differentiation.
TGF-β signalling pathways can promote osteoblast proliferation and early differentiation to osteoblast-like cells. These pathways are involved in PEMF-induced osteogenesis. BMP belongs to the TGF-β family and is a major factor inducing bone and cartilage formation in vivo. BMP initiates signalling cascade responses through typical Smad-dependent and atypical Smad-independent signalling pathways (Carreira et al., 2014; Salazar et al., 2016). Xie et al. found that PEMFs could activate the BMP-Smad1/5/8 signalling pathway by upregulating the expression of BMP II receptors on primary cilia, thereby promoting osteoblast differentiation and maturation in rats. Thus, the knockdown of BMP II receptors in osteoblasts reduces the promotion of osteogenic differentiation and maturation by PEMFs (Xie et al., 2016). Smad7, an antagonist of the TGF-β signalling pathway, is the putative target gene of miR21-5p, and PEMFs decreased Smad7 expression. RUNX2 expression was increased by PEMF treatment. However, the miR21-5p inhibitor prevented the PEMF-induced RUNX2 expression in differentiating cells. These findings demonstrate that PEMFs regulate the expression of microRNA21 to activate TGF-β signalling and promote osteoblast differentiation (Selvamurugan et al., 2017).
The mTOR signalling pathway is an important molecular cascade involved in various physiological cellular processes, such as cell cycle and metabolic regulation, transcription, and translation, as well as cell differentiation and apoptosis. Activation of this pathway by PEMFs has been reported. Ferroni et al. (2018) revealed that PEMFs increase the expression of mTOR pathway-related proteins, such as AKT, MAPK kinase, and RRAGA. Furthermore, inhibitors of the mTOR pathway can reduce the osteogenic capacity of PEMFs. Considerable upregulation of the expression of bone-specific genes due to activation of Akt has been observed in cells after exposure to PEMFs at selected parameters (Poh et al., 2018).
The Notch signalling pathway is highly evolutionarily conserved. It is involved in important physiological activities, such as cell survival, proliferation, differentiation, and homeostatic regulation in vivo. When Notch receptors and their ligands interact, the Notch intracellular domain (NICD) is released and translocated to the nucleus to activate the transcription of target genes (Tian et al., 2017). The expression of the Notch receptor, its ligand DLL4, and target genes (Hey1, Hes1, and Hes5) was upregulated during PEMF-induced osteogenic differentiation of human bone marrow mesenchymal stem cells. Furthermore, application of Notch pathway inhibitors effectively suppressed the expression of osteogenic markers, including RUNX2, Dlx5, OSX, Hes1, and Hes5, which further explains the activation of the Notch pathway by PEMFs during osteogenesis (Bagheri et al., 2018).
3.1.2 Osteoclasts
Physiological bone remodelling relies on a delicate equilibrium between osteoblast- and osteoclast-mediated bone formation and resorption, respectively. Osteoclasts, originating from the monocyte-macrophage lineage, exclusively regulate bone resorption. PEMFs can affect osteoclast function, thereby altering skeletal phenotypes. Moreover, they can impede the formation of osteoclasts, thereby reducing their numbers, downregulating the expression of osteoclast-related genes such as TRAP and CTSK, and diminishing the levels of inflammatory factors, including tumour necrosis factor-alpha and interleukin-1β. Additionally, PEMFs impact the differentiation and maturation of osteoclasts by inhibiting the activities of osteoclast transcription factors. Furthermore, they activate the T-cell nuclear factor and hinder the nuclear translocation of Ca2+ (Zhang et al., 2017; Song et al., 2018; Tschon et al., 2018; Noh et al., 2020). Insulin-like growth factor (IGF), the most abundant growth factor within the bone matrix, promotes osteoclast differentiation by regulating the expression of RANK and RANKL. Additionally, it facilitates the dynamic interaction between osteoblasts and osteoclasts, contributing to the maintenance of bone mass equilibrium during bone remodelling (Wang et al., 2006). Electromagnetic fields can markedly increase the mRNA expression level of IGF-1 in rat femur tissue in vitro to promote bone formation and inhibit bone resorption (Zhou et al., 2016). In addition, PEMFs at different frequencies can produce varying effects through different pathways: low-frequency stimulation enhances osteoclast differentiation and activity, mainly by activating the ERK and p38 MAPK pathways. Contrastingly, high-frequency stimulation inhibits osteoclast differentiation and reduces bone resorption through suppressed RANKL-induced phosphorylation of IκB (Hong et al., 2014). Hong et al. found that osteoclastogenic markers, such as NFATc1, TRAP, CTSK, MMP9, and DC-STAMP, were highly expressed at 7.5 Hz electromagnetic fields, whereas they were decreased at 45 Hz. Similarly, Nam found that electromagnetic fields at 10 G intensity and 40 Hz frequency reduced NFATc4 expression by decreasing TRPV1 and phosphorylated cyclic adenosine monophosphate-responsive element binding protein (CREB) levels, which regulated RANKL-induced osteoclast differentiation (Nam et al., 2023). Owing to the lack of clinical trial validation, the study of the mechanisms of different parameters is only at the theoretical stage. Thus, more valuable data could be obtained through clinical validation in the future.
3.2 Nerves
The nervous system regulates the development of various tissues, organs, and systems in the body. Bone tissue is also innervated by its corresponding peripheral nerves. Thus, the mechanisms underlying the promotion of fracture healing through the regulation of neuronal activity have garnered research interest. Most nerves in bone are neuropeptide-containing fibres, such as Aδ-fibres and C-fibres, which predominantly (>50%) express the calcitonin gene-related peptide (CGRP) and are sensitive to mechanical, chemical, and electrical stimuli (Lau et al., 2015; Yuen-Chi Lau et al., 2017; Brazill et al., 2019). CGRP, a 37-residue peptide produced by specific neurons through selective splicing of the calcitonin gene, is an important neuropeptide involved in bone growth and metabolism. It is produced in the sensory nerve fibres of bone tissue at the posterior root ganglion of the spinal cord and transported to the nerve endings to perform its in vivo regulatory and biological functions in the form of secretory granules (Tepper, 2018; Hendrikse et al., 2019). Clinical and experimental studies have confirmed that electromagnetic fields act on the peripheral nervous system to promote the biosynthesis and release of this peptide, which is involved in bone repair and regeneration (Naot et al., 2019; Mi et al., 2022). Electromagnetic field signals promote CGRP biosynthesis and release by activating the Ca2+/calmodulin-dependent protein kinase II/CREB signalling pathway. CGRP subsequently binds to target cell-specific G protein-coupled receptors to activate AC and elevate intracellular cAMP levels. Moreover, the cAMP-PKA signalling system mediates the essential pathway required to promote bone formation. Furthermore, the activation of PKA catalyses subunit phosphorylation and nuclear translocation, which phosphorylates CREB to activate the c-fos and c-jun families of transcription factors. This process ultimately enables the recognition of DNA-binding sites by Runx-2 and OCN in their promoter regions and accelerates osteoblast differentiation (Wang et al., 2019). This pathway also regulates the expression balance between important transcription factors for bone formation and resorption (e.g., RANKL, osteoprotegerin (OPG)), resulting in considerably reduced mRNA expression of RANKL and a substantial increase in the mRNA expression of OPG. This inhibits osteoclast formation and function and enhances fracture healing and bone metabolism (Villa et al., 2006; Ding et al., 2013; Zhang et al., 2016; Xu et al., 2020). The relationship between nerves and osteogenesis has been investigated from multiple perspectives. However, the acceleration of osteogenesis by electromagnetic fields through the neuronal secretion of CGRP warrants further exploration.
3.3 Blood vessels
Osteogenesis and angiogenesis, including cell-cell communication between vascular cells and osteoblasts, are essential for bone repair. VEGF is a highly specific vascular endothelial cell growth factor that binds to its receptor and activates a downstream signalling cascade, thereby controlling the survival, proliferation, and migration of vascular endothelial cells, which subsequently promotes neovascularisation and vascular permeability. VEGF contributes to endothelial mesenchymal stem cell aggregation into the vascular plexus, which plays a crucial role in neoangiogenesis and haemodialysis at the fracture site. H-type blood vessels can induce bone formation, and VEGF regulation of angiogenic processes has been closely linked to H-type blood vessels (Peng et al., 2020; Rodríguez-Merchán, 2021). In addition, electromagnetic field signals activate the VEGF signalling pathway to increase blood supply to the fracture region, thereby promoting bone repair (Hopper et al., 2009; Chen et al., 2018). Chen et al. (2018) showed that electromagnetic field signals activate VEGF receptors, leading to activated downstream components, such as PI3k/Akt, ERK1/2, and JNK. Furthermore, endothelial cell tubulogenesis was attenuated using inhibitors. Electromagnetic field-regulated angiogenesis during bone tissue regeneration can act through multiple pathways, including FGF, IGF, and platelet-derived growth factor pathways (Tepper et al., 2004; Chen et al., 2018; Yuan et al., 2018).
4 Clinical implications of PEMFs on bone healing
PEMFs affect biological tissues by generating electromagnetic fields of specific frequencies and intensities. They are widely used to treat various diseases and symptoms in clinical settings. Furthermore, their clinical application has extended to bone healing. In a randomised controlled trial, Shi et al. conducted a long-term follow-up on patients with fractures treated using PEMFs. Their findings indicated that early application of PEMF therapy significantly improves healing rates and reduces overall pain duration in patients with long bone fractures (Shi et al., 2013). Despite these positive outcomes, some studies have raised questions about the effectiveness of PEMF therapy. Hannemann et al. observed no significant differences in fracture healing in the PEMF group, sparking controversy over the therapeutic effects of this therapy (Hannemann et al., 2014). Furthermore, the assessment of clinical trial results on bone repair involving PEMFs raises concerns about the reliability of the outcomes. However, the inconsistency in PEMF parameters and treatment protocols used in different trials may affect the comparability of studies. Additionally, individual variations among patients and other factors before and after treatment may impact trial results. Thus, despite current research indicating the potential benefits of PEMFs in bone fracture repair, further standardised clinical trials are needed to confirm their efficacy. Furthermore, combining PEMF with other therapeutic interventions could synergistically enhance bone fracture repair outcomes. However, further in-depth research into the specific mechanisms and optimal application methods is required to fully leverage these synergistic effects. This could provide a foundation for optimised treatment strategies that better accommodate individual patient differences. Finally, existing research findings can facilitate the development of standardised guidelines for the use of PEMFs in bone repair, ensuring consistency and feasibility in clinical practice.
5 Limitations of PEMF therapy
The clinical application of PEMFs in bone repair has shown several limitations. Firstly, the diversity of treatment protocols poses a significant challenge. Variations in PEMF parameters, such as frequency, intensity, and treatment duration, in existing studies lead to inconsistency in optimal application methods. Moreover, the lack of standardised treatment protocols makes it difficult to compare different studies and formulate uniform treatment guidelines in clinical practice. Secondly, the variability in individual patient responses is a major issue. The physiological response of the human body to PEMFs may be influenced by factors such as age, sex, and comorbidities. However, there remains a lack of sufficient personalised research, making it challenging to accurately predict patient responses to PEMF therapy. This hinders the implementation of personalised treatment in clinical settings. Additionally, the demand for standardised guidelines highlights the knowledge gap in the use of PEMFs in bone repair treatment. The lack of clear guidelines for PEMF application makes it challenging for physicians to determine the optimal treatment approach in practical settings, thereby increasing uncertainty for both patients and medical institutions when choosing PEMF therapy. To overcome these obstacles, more large-scale studies, personalised research, and clear treatment guidelines are needed to advance the clinical application of PEMFs and maximise their potential in bone repair.
6 Conclusion
The active role of PEMFs in the treatment of bone-related diseases and their possible mechanisms have garnered considerable research interest. Some potential mechanisms underlying PEMF function have been elucidated, providing a theoretical and clinical basis for further application of electromagnetic fields to promote fracture healing. Electromagnetic fields can enhance the expression of bone-related genes and cellular activity by regulating ion channels and activating cellular signalling pathways. This ultimately alters the behaviour or function of osteoblasts to promote bone production and remodelling. However, the lack of consistent study parameters makes PEMF effects scientifically challenging to evaluate. Therefore, high-quality clinical studies and basic experiments are required to further clarify the optimal therapeutic parameters and molecular mechanisms of PEMFs. Such in-depth investigation could ensure the optimisation of electromagnetic fields to a more effective and accurate alternative therapy for the treatment of bone disease and regeneration.
Author contributions
AW: Conceptualization, Resources, Writing–original draft, Writing–review and editing. XM: Writing–original draft, Writing–review and editing. JB: Resources, Writing–original draft. ZJ: Writing–original draft. QZ: Writing–original draft. PW: Supervision, Writing–review and editing. YZ: Conceptualization, Supervision, Writing–review and editing.
Funding
The author(s) declare financial support was received for the research, authorship, and/or publication of this article. This work was funded by National Natural Science Foundation of China (82151312, 82272493). The Beijing Science Nova Program (20220484155). Haidian Frontier Project of Beijing Natural Science Foundation (No. L212067), Capital clinical diagnosis and treatment technology research and transformation application project (Z201100005520060).
Conflict of interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
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Keywords: pulsed electromagnetic fields, osteoblast, osteoclast, mechanisms of osteogenesis, signalling pathway, bone regeneration
Citation: Wang A, Ma X, Bian J, Jiao Z, Zhu Q, Wang P and Zhao Y (2024) Signalling pathways underlying pulsed electromagnetic fields in bone repair. Front. Bioeng. Biotechnol. 12:1333566. doi: 10.3389/fbioe.2024.1333566
Received: 05 November 2023; Accepted: 15 January 2024;
Published: 24 January 2024.
Edited by:
Bin Li, Soochow University, ChinaReviewed by:
Zhonghai Li, First Affiliated Hospital of Dalian Medical University, ChinaShi-Cong Tao, Shanghai Jiao Tong University, China
Copyright © 2024 Wang, Ma, Bian, Jiao, Zhu, Wang and Zhao. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Peng Wang, wangpeng301@foxmail.com; Yantao Zhao, userzyt@qq.com
†These authors have contributed equally to this work and share first authorship