Osteoporosis is a systemic skeletal disease, characterized by the reduction of bone mass and the skeletal architecture's impairment as a whole. Theron is essentially disease's definitions on anatomopathological criteria, which attribute to the skeleton particular characteristics of fragility, such as making bone prone to fracture even after minor trauma.
Skeletal fragility can be diagnosed, thanks to current sensitometric methods, even in the absence of symptoms and fractures. Being a condition that heightens the risk of fracture, but that does not make itself necessary for the definition of the disease, osteoporosis can evolve in a completely asymptomatic way for a long time, in some cases even for a lifetime.
The US FDA has approved pulsed electromagnetic fields (PEMFs) as a safe and effective treatment for nonunion of bone. Despite its clinical use, the mechanisms of action of electromagnetic stimulation of the skeleton have been elusive. Recently, cell membrane receptors have been identified as the site of action of PEMF and provide a mechanistic rationale for clinical use. This review highlights key processes in cell responses to PEMF as follows: (1) signal transduction through A2A and A3 adenosine cell membrane receptors and (2) dose-response effects on the synthesis of structural and signaling extracellular matrix (ECM) components. Through these actions, PEMF can increase bone and cartilage's structural integrityECM's structural integrity, enhance enhance repair, and alter the homeostatic balance of signaling cytokines, producing anti-inflammatory effects. PEMFs exert a pro anabolic effect on the bone and cartilage matrix and a chondroprotective effect counteracting inflammation's catabolic effects in the joint environment. Understanding of PEMF membrane targets and the specific intracellular pathways involved, culminating in the synthesis of ECM proteins and reducing inflammatory cytokines, should enhance confidence in the clinical use of PEMF and identify clinical conditions likely to be affected by PEMF exposure.
The musculoskeletal system is highly responsive to its physicochemical environment. Bone and cartilage cells respond to changes in mechanical stress, fluid flow, pH, and pO2 by altering their phenotype and expressing a range of signaling and structural molecules that result, in particular, in an altered extracellular matrix (ECM) organization and associated biomechanical properties. Response to mechanical stress is perhaps the best recognized and intuitively obvious skeletal environmental condition, facilitating adaptation and modeling to changing biomechanical and environmental requirements, perhaps through intermediary strain-associated signaling events. In addition to mechanical stress, skeletal tissues, both bone, and cartilage, demonstrate an exquisite sensitivity to electrical and electromagnetic stimulation.
Responses of skeletal cells to pulsed electromagnetic fields (PEMF) have been exploited therapeutically with devices that expose tissues to appropriately configured fields to stimulate ECM synthesis for bone and cartilage repair. This review highlights key processes in cell responses to PEMF as follows: (1) signal transduction through cell membrane adenosine receptors (ARs), (2) the activation of osteoinductive pathways, and (3) the synthesis of skeletal ECM including structural and signaling molecules. These actions are reflected physiologically in the bone as the healing of fractures, osteotomies, nonunions, and joints, as the modulation of cartilage damage and reduction in catabolic and inflammatory cytokines in arthritis. Understanding the cellular responses to PEMF will inform clinical studies, may point to key issues that need further investigation, and will be relevant in promoting bone and cartilage repair, tissue engineering and regeneration in a repair mode, and damping inflammation in arthritis. Understanding the pathways of the activity of PEMFs provides a solid mechanistic basis for their clinical use.
There is strong evidence supporting a role for adenosine and its receptors in bone homeostasis and skeletal pathology, including osteoporosis and arthritis.4 Furthermore, adenosine, acting through the A2A receptor, inhibits osteoclast differentiation, and increases the rate of new bone formation in bone defects.5 A2A signaling also promotes the Wnt/β-catenin pathway regulating bone formation.6
Although the transmembrane signal recognition processes of PEMF are incompletely understood, the specific mechanism of interaction between PEMF and the cell membrane was reported by Varani et al.7 They identified for the first time that ARs were the main target of PEMF stimulation in inflammatory cells; ARs play a pivotal role in the regulation of inflammatory processes, with both pro-inflammatory and anti-inflammatory effects.8 It has been demonstrated that PEMF exposure induces a notable increase in A2A and A3 AR density on the cell membrane of chondrocytes, synoviocytes, and osteoblasts8 (Figure 1). Notably, A1 and A2B receptors were not influenced by the same exposure conditions. Moreover, in the presence of the specific A2A receptor agonist, PEMF exposure synergized with the agonist and induced a notable increase in intracellular cyclic adenosine monophosphate (cAMP) levels. On the contrary, the specific A2A receptor antagonist's presence blocked the effects of both the agonist and PEMF stimulation, suggesting that PEMFs specifically act through the activation of A2A ARs with a pharmacologic-like mechanism. The agonist activity of PEMF for the A2A and the A3 ARs is particularly relevant because it inhibits the NF-kB pathway, a key regulator of the expression of matrix metalloproteinases and several genes involved in responses to inflammation.9 Cohen et al. 10 showed in vivo that an experimental A2A agonist drug reduced cartilage damage in a rabbit model of septic arthritis of the knee. These observations formed the basis for the application of PEMF for chondroprotection of articular cartilage from the catabolic effects of joint inflammation, as discussed in more detail later.
Despite its clinical use, the mechanisms of action of electromagnetic stimulation of the skeleton have been elusive, and PEMF has been viewed as a “black box.” In the past 25 years, research has successfully identified cell membrane receptors and osteoinductive pathways as sites of action of PEMF and provides a mechanistic rationale for clinical use. Understanding of PEMF membrane targets and the specific intracellular and extracellular pathways involved, culminating in the synthesis of ECM proteins and reduction in inflammatory cytokines, should enhance confidence in the clinical use of PEMF and the identification of clinical conditions likely to be affected by PEMF exposure.
The biological effects of PEMF treatment and favorable effects on the skeletal system are the results of notable research efforts conducted internationally by the orthopedic community. They have attracted much interest from other medical specialties such as wound and tendon healing, rheumatology, and neurology that may be able to take advantage of the experiences developed with bone and cartilage treatments.
De Mattei M, Fini M, Setti S, et al.: Proteoglycan synthesis in bovine articular cartilage explants exposed to different low-frequency low-energy pulsed electromagnetic fields. Osteoarthritis Cartilage 2007;15:163–168.
Parent D, Franco-Obregon A, Frohlich J, et al.: Enhancement of mesenchymal stem cell chondrogenesis with short-term low intensity pulsed electromagnetic fields. Sci Rep 2017;7:9421.
Aaron RK, Ciombor DM, Keeping H, Wang S, Capuano A, Polk C: Power frequency fields promote cell differentiation coincident with an increase in transforming growth factor-beta(1) expression. Bioelectromagnetics 1999;20:453–458.
Ham J, Evans BA: An emerging role for adenosine and its receptors in bone homeostasis. Front Endocrinol (Lausanne) 2012;3:113.
Mediero A, Wilder T, Cronstein B: Adenosine receptors stimulate bone regeneration, in Biology and Pathology of Bone and Joint: Osteoclasts, Osteoblasts and Bone Remodeling. Boston, MA, ACR/ARP Annual Meeting, 2014, Abstract 19.
Borhani S, Corciulo C, Larranaga Vera A, Cronstein B: Signaling at adenosine A2A receptor (A2aR) in osteoblasts; crosstalk with Wnt/β-catenin signaling pathway, in Osteoarthritis and Joint Biology — Basic Science Poster I. Chicago, IL, ACR/ARP Annual Meeting, 2018, Abstract 1047.
Varani K, Gessi S, Merighi S, et al.: Effect of low-frequency electromagnetic fields on A2A adenosine receptors in human neutrophils. Br J Pharmacol 2002;136:57–66.
Varani K, Vincenzi F, Ravani A, et al.: Adenosine receptors as a biological pathway for the anti-inflammatory and beneficial effects of low-frequency low energy pulsed electromagnetic fields. Mediators Inflamm 2017;2017:2740963.
Massari L, Benazzo F, Falez F, et al.: Biophysical stimulation of bone and cartilage: State of the art and future perspectives. Int Orthop, 2019;43:539–551.
Cohen SB, Gill SS, Baer GS, Leo BM, Scheld WM, Diduch DR: Reducing joint destruction due to septic arthrosis using an adenosine2A receptor agonist. J Orthop Res 2004;22:427–435.
Aaron RK, Boyan B, Ciombor DM, Schwartz Z, Simon BJ: Stimulation of growth factor by electric and electromagnetic fields. Clin Orthop Rel Res 2004;419:30–37.
Aaron RK, Wang S, Ciombor DM: Upregulation of basal TGFß1 levels by EMF coincident with chondrogenesis — skeletal repair and tissue engineering implications. J Orthop Res 2002;20:233–240.
13. Zhou J, He H, Yang L, et al.: Effects of pulsed electromagnetic fields on bone mass and Wnt/beta-catenin signaling pathway in ovariectomized rats. Arch Med Res 2012;43:274–282.
Lin CC, Lin RW, Chang CW, Wang GJ, Lai KA: Single-pulsed electromagnetic field therapy increases osteogenic differentiation through Wnt signaling pathway and sclerostin downregulation. Bioelectromagnetics 2015;36:494–505.
Cai J, Shao X, Yang Q, et al.: Pulsed electromagnetic fields modify the adverse effects of glucocorticoids on bone architecture, bone strength, and porous implant osseointegration rescuing bone-anabolic actions. Bone 2020;133:115266.
Zhai M, Jing D, Tong S, et al.: Pulsed electromagnetic fields promote in vitro osteoblastogenesis through a Wnt/beta-catenin signaling-associated mechanism. Bioelectromagnetics 2016;37:152–162.
Jing D, Li F, Jiang M, et al.: Pulsed electromagnetic fields improve bone microstructure and strength in ovariectomized rats through a Wnt/Lrp5/beta-catenin signaling-associated mechanism. PLoS One 2013;8:e79377.
Wu S, Yu Q, Lai A, Tian J: Pulsed electromagnetic field induces Ca(2+)-dependent osteoblastogenesis in C3H10T1/2 mesenchymal cells through the Wnt-Ca(2+)/Wnt-beta-catenin signaling pathway. Biochem Biophys Res Commun 2018;503:715–721.
Pan Y, Dong Y, Hou W, et al.: Effects of PEMF on microcirculation and angiogenesis in a model of acute hindlimb ischemia in diabetic rats. Bioelectromagnetics 2013;34:180–188.
Tepper OM, Callaghan MJ, Chang EI, et al.: Electromagnetic fields increase in vitro and in vivo angiogenesis through endothelial release of FGF-2. FASEB J 2004;18:1231–1233.
Hopper RA, VerHalen JP, Tepper O, et al.: Osteoblasts stimulated with pulsed electromagnetic fields increase HUVEC proliferation via a VEGF-A independent mechanism. Bioelectromagnetics 2009;30:189–197.
Goto T, Fujioka M, Ishida M, Kuribayashi M, Ueshima K, Kubo T: Noninvasive up-regulation of angiopoietin-2 fibroblast growth factor-2 in bone marrow by pulsed electromagnetic field therapy. J Orthop Sci 2010;15:661–665.
Petecchia L, Sbrana F, Utzeri R, et al.: Electro-magnetic field promotes osteogenic differentiation of BM-hMSCs through a selective action on Ca(2+)-related mechanisms. Sci Rep 2015;5:13856.
