RESUMEN
Anti-cholinergic agents are used in the treatment of several pathological conditions. Therapy regimens aimed at up-regulating cholinergic functions, such as treatment with acetylcholinesterase inhibitors, are also currently prescribed. It is now known that not only is there a neuronal cholinergic system but also a non-neuronal cholinergic system in various parts of the body. Therefore, interference with the effects of acetylcholine (ACh) brought about by the local production and release of ACh should also be considered. Locally produced ACh may have proliferative, angiogenic, wound-healing, and immunomodulatory functions. Interestingly, cholinergic stimulation may lead to anti-inflammatory effects. Within this review, new findings for the locomotor system of a more widespread non-neuronal cholinergic system than previously expected will be discussed in relation to possible new treatment strategies. The conditions discussed are painful and degenerative tendon disease (tendinopathy/tendinosis), rheumatoid arthritis, and osteoarthritis.
RESUMEN
Limited information is available concerning the existence of a cholinergic system in the human Achilles tendon. We have studied pain-free normal Achilles tendons and chronically painful Achilles tendinosis tendons with regard to immunohistochemical expression patterns of the M(2) muscarinic acetylcholine receptor (M(2)R), choline acetyltransferase (ChAT), and vesicular acetylcholine transporter (VAChT). M(2)R immunoreactivity was detected in the walls of blood vessels. As evidenced via parallel staining for CD31 and alpha-smooth muscle actin, most M(2)R immunoreactivity was present in the endothelium. M(2)R immunoreactivity also occured in tenocytes, which regularly immunoreact for vimentin. The degree of M(2)R immunoreactivity was highly variable, tendinosis tendons that exhibit hypercellularity and hypervascularity showing the highest levels of immunostaining. Immunoreaction for ChAT and VAChT was detected in tenocytes in tendinosis specimens, particularly in aberrant cells. In situ hybridization revealed that mRNA for ChAT is present in tenocytes in tendinosis specimens. Our results suggest that autocrine/paracrine effects occur concerning the tenocytes in tendinosis. Up-regulation/down-regulation in the levels of M(2)R immunoreactivity possibly take place in tenocytes and blood vessel cells during the various stages of tendinosis. The presumed local production of acetylcholine (ACh), as evidenced by immunoreactivity for ChAT and VAChT and the detection of ChAT mRNA, appears to evolve in response to tendinosis. These observations are of importance because of the well-known vasoactive, trophic, and pain-modulating effects that ACh is known to have and do unexpectedly establish the presence of a non-neuronal cholinergic system in the Achilles tendon.
Asunto(s)
Tendón Calcáneo , Comunicación Celular/fisiología , Fibras Colinérgicas/metabolismo , Receptor Muscarínico M2/metabolismo , Tendinopatía/metabolismo , Tendón Calcáneo/anatomía & histología , Tendón Calcáneo/metabolismo , Tendón Calcáneo/patología , Adulto , Colina O-Acetiltransferasa/genética , Colina O-Acetiltransferasa/metabolismo , Regulación hacia Abajo , Femenino , Humanos , Hibridación in Situ , Masculino , Persona de Mediana Edad , Receptor Muscarínico M2/genética , Tendinopatía/patología , Regulación hacia Arriba , Proteínas de Transporte Vesicular de Acetilcolina/genética , Proteínas de Transporte Vesicular de Acetilcolina/metabolismoRESUMEN
Results of recent studies using immunohistochemistry show evidence of an occurrence of catecholamine production in the cells (tenocytes) of patellar tendons exhibiting tendinopathy (tendinosis). In the present study, antibodies against the catecholamine-synthesizing enzyme tyrosine hydroxylase (TH) and alpha1-adrenoreceptors were applied to sections of specimens of normal and tendinosis Achilles tendons. In situ hybridization using a probe detecting human TH mRNA was also utilized. It was found that sympathetic innervation was very scarce. On the other hand, there were distinct alpha1-adrenoreceptor immunoreactions in blood vessel walls. Interestingly, tenocytes, particularly from tendinosis samples in which the tenocytes showed an abnormal shape (not the typical slender appearance), displayed TH immunoreactions and reactions for TH mRNA. Of further interest was the finding of alpha1-adrenoreceptor immunoreactions in tenocytes. The observations show not only evidence of local catecholamine production at the protein level, which was the case in recent studies for the patellar tendon, but also at the mRNA level. The observations suggest that the tenocytes, especially those with disfigured appearances in tendinosis, can produce catecholamines and also that they can respond to sympathetic transmitters. This is of interest as adrenergic stimulation in other parts of the body is known to induce degenerative/apoptotic and proliferative events, features which are seen in Achilles tendinosis. These observations are completely new findings concerning the human Achilles tendon. It is likely that locally produced catecholamines and the occurrence of autocrine/paracrine effects of these substances are of great relevance during the process of tendinosis.
Asunto(s)
Tendón Calcáneo/metabolismo , Catecolaminas/metabolismo , Inmunohistoquímica/métodos , Hibridación in Situ/métodos , Tendinopatía/metabolismo , Tendón Calcáneo/inervación , Adulto , Biopsia , Catecolaminas/genética , Femenino , Expresión Génica , Regulación de la Expresión Génica , Humanos , Masculino , Persona de Mediana Edad , Neuropéptido Y/metabolismo , ARN Mensajero/metabolismo , Receptores Adrenérgicos alfa 1/genética , Receptores Adrenérgicos alfa 1/metabolismo , Sistema Nervioso Simpático , Tendinopatía/patología , Tendinopatía/cirugía , Tirosina 3-Monooxigenasa/genética , Tirosina 3-Monooxigenasa/metabolismoRESUMEN
Pain-free normal Achilles tendons and chronic painful Achilles tendons were examined by the use of antibodies against a general nerve marker (protein gene-product 9.5, PGP9.5), sensory markers (substance P, SP; calcitonin gene-related peptide, CGRP), and immunohistochemistry. In the normal tendons, immunoreactions against PGP9.5 and against SP/CGRP were encountered in the paratendinous loose connective tissue, being confined to nerve fascicles and to nerve fibers located in the vicinity of blood vessels. To some extent, these immunoreactions also occurred in the tendon tissue proper. Immunoreaction against PGP9.5 and against SP/CGRP was also observed in the tendinosis samples and included immunoreactive nerve fibers that were intimately associated with small blood vessels. In conclusion, Mechanoreceptors (sensory corpuscles) were occasionally observed, nerve-related components are present in association with blood vessels in both the normal and the tendinosis tendon.
Asunto(s)
Tendón Calcáneo/inervación , Tendón Calcáneo/patología , Biomarcadores/análisis , Tendón Calcáneo/irrigación sanguínea , Tendón Calcáneo/lesiones , Tendón Calcáneo/cirugía , Adulto , Anticuerpos/metabolismo , Biopsia , Péptido Relacionado con Gen de Calcitonina/metabolismo , Femenino , Humanos , Masculino , Persona de Mediana Edad , Sustancia P/metabolismo , Ubiquitina Tiolesterasa/metabolismoRESUMEN
In this investigation the microdialysis technique was used to study the concentrations of lactate in Achilles tendons with painful chronic tendinosis and in normal pain-free tendons. In four patients (mean age 40.7 years) with a painful thickening localized at the 2-6 cm level in the Achilles tendon (chronic Achilles tendinosis) and in five controls (mean age 37.2 years) with normal Achilles tendons the local concentrations of lactate were registered under resting conditions. All tendons were examined using ultrasonography. In the tendons with tendinosis the painful thickening corresponded to a widened tendon and structural tendinosis changes. Normal tendons showed no widening and a normal structure. A standard microdialysis catheter was inserted into the Achilles tendon under local anesthesia. Samplings were done every 15 min during a 4 h period. The results showed significantly higher mean concentrations of lactate in tendons with tendinosis compared to normal tendons (2.15 mmol/l vs. 1.14 mmol/l). The lactate concentrations in the tendons with tendinosis were stable, and approximately twofold higher than in the normal tendons during the whole 4 h investigation period. In conclusion, the higher concentrations of lactate in Achilles tendons with painful tendinosis indicate that there are anaerobic conditions in the area with tendinosis. The importance of this finding for the pathogenesis and pain mechanisms in this chronic condition needs to be further investigated.