ReviewEffects of pulsed electromagnetic fields on articular hyaline cartilage: review of experimental and clinical studies
Introduction
Hyaline articular cartilage is an avascular and specialized functional tissue with low cellularity, high water content, and a dense extracellular matrix (ECM) [26]. The tissue-specific mechanical properties of articular cartilage are dependent on the ECM structure and composition, which accounts for about 90% of cartilage wet weight, and is mainly composed of collagen type II, proteoglycans (PG) (in particular, aggrecan, hyaluronic acid), cations and water [45]. The complex structure of articular cartilage enables this tissue to perform its biomechanical role but appears to hinder repair, as lesions without further surgical treatment often progress into long-term degeneration and osteoarthritis (OA) [17], [26]. Even in the absence of injuries, accidents and other joint traumas, articular spontaneous degeneration occurs and prevalence studies indicate that the majority of people over the age of 65 have some form of OA [48].
OA is characterized by a degeneration of hyaline articular cartilage. The breakdown of the cartilage matrix leads to the development of fibrillations, clefts and ulcerations and the disappearance of the full-thickness surface of the joint. This process is accompanied by bone changes with osteophyte formation and thickening of the subchondral bone [43]. Even if changes in the subchondral bone resulting in loss of its stock absorbing capacity could transfer the stress of loading directly to the articular cartilage with secondary changes in the cartilage, OA is usually considered to be a primary disorder of chondrocyte proliferation and function with secondary changes in bone and it is often associated with an inflammatory response [16], [30]. Chondrocytes are the single cellular component of hyaline cartilage and are responsible for matrix synthesis and turnover, while the state of the matrix has a direct influence on chondrocyte function. The number of chondrocytes, their rate of proliferation, metabolic activity and ability to respond to various stimuli are inversely related to the age of the organism [38], [47].
Moreover, cytokines are considered to be an important link in OA since they are produced by cells present in the OA joints and because they are responsible, at least in part, for the changes seen in cartilage damage, synovial membrane, subchondral bone and osteophyte formation [41]. Local release of catabolic cytokines and enzymes such as interleukin 1β (IL-1β), tumor necrosis factor-α (TNF-α), interleukin 6 (IL-6), metalloproteinases (MMP), aggrecanases that is high in OA in response to tissue damage, and inflammation cause a depletion of glycosaminoglycans (GAGs) and suppress type II collagen synthesis [41], [45]. Blockade of these cytokines by natural antagonists in OA cartilage, where they are overexpressed, can up-regulate gene expression of the matrix molecules and enhance matrix repair [36]. Furthermore, anabolic cytokines, such as insulin-like growth factor-I (IGF-I), TGFβ-1, inhibit the catabolic effects of pro-inflammatory cytokines [41] and may stimulate useful synthetic processes.
So, controlling chondrocyte death, proliferation, function, response to anabolic and catabolic stimuli, matrix synthesis, matrix degradation and joint inflammation is the most important target of a potential chondroprotective treatment, that is to say a therapy that retards or stabilizes the progression of established OA by altering the underlying pathological processes [1].
Many drugs or substances have been recently introduced for the treatment of OA including cyclooxyganes inhibitors, hyaluronic acid, chondroitin sulfate, and glucosamine sulfate [5], [25], [53], [62]; however the majority of them can relieve pain and increase function, but do not modify the complex pathological processes that occur in these tissues, which are unable to balance undergoing catabolic and anabolic pathways [34]. In addition, such therapy for OA is unlikely to have a direct effect at the subchondral bone level [42], [54].
Pulsed electromagnetic fields (PEMFs) have a number of well-documented physiological effects on cells and tissues including the upregulation of gene expression of members of the TGFβ super family, the preservation of ECM integrity of cultured cartilage explants, the increase in GAG levels in embryonic and immature cartilage and in an experimental model of decalcified bone matrix-induced endochondral ossification [2], [11], [24], [32], [33], [56]. An anti-inflammatory action has also been shown because of a direct effect on adenosine A2a receptors on cell membranes [63]. Several anti-inflammatory drugs are mediated via adenosine receptors and the modulation of the adenosine-receptor-mediated pathway may offer novel methods for treatment of inflammation in the presence of joint diseases [6].
Therefore, there is a strong rationale supporting the in vivo use of biophysical stimulation with PEMFs for the treatment of OA.
In the present paper some experimental (in vitro and in vivo) and clinical studies on the effect of PEMFs on hyaline articular cartilage will be summarized. We searched the English language literature of the MEDLINE database, for the period January 1990 to December 2004 (keywords or title words: PEMFs and cartilage/chondrocytes/osteoarthritis). Articles were included in the review if they were related to the use of PEMFs on hyaline articular cartilage tissue or cells. The search included in vitro, animal and human studies. We excluded reviews and papers with not available full manuscripts. Finally, we excluded papers published before 1990 in an attempt to examine the most up-to-date methodology and outcome measures. We were left with six in vitro, two in vivo and five clinical papers.
Section snippets
In vitro studies: PEMF effects on cartilage cell and tissue cultures
The studies summarized in Table 1 on the in vitro effect of PEMFs on hyaline articular chondrocytes and articular cartilagineous tissue have appeared in the literature over the last 10 years [13], [14], [15], [22], [44], [52]. They considered different pathogenetic aspects (chondrocyte proliferation, ECM synthesis, secretory activity and inflammation).
More precisely, PEMFs were tested in human and animal monolayer chondrocyte cultures and tissue explants and their effects were investigated by
In vivo studies: PEMF therapeutic efficacy on OA lesions
Because subchondral bone, bone marrow, synovial cells, chondrocytes and synovial fluid all contribute to the development of OA and to the healing of defects of articular cartilage, the use of animal models is essential both to understanding the process of repair and assessing the value of new therapeutic regimens [55]. Many techniques have been employed by researchers to create secondary OA lesions in animals and especially in rabbits, by means of surgical interventions that cause mechanical
Clinical studies
Although the different animal models of OA have characteristics similar to the human disease, none of them has proven to be a true model of OA and therefore, any treatment has to be finally tested in clinical trials. PEMF stimulation is still under investigation for use in patients with OA [53]. However, even if different physical parameters and exposure times of stimulation were used, positive results were obtained in clinical studies [28], [39], [46], [60], [61].
In 1993, Trock et al. [60]
Discussion and conclusion
In western countries the impact of OA on public health and the significant costs that musculoskeletal conditions generate will be of increasing burden [9]. Our understanding in the treatment of OA evolves as knowledge of the underlying pathophysiology of the condition improves. Previous concepts on OA pathogenesis focused only on the role of chondrocytes in the synthesis and degradation of the ECM. In fact, chondrocytes are the only cell type that constitutes articular cartilage and are
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