Joint Innervation Research Articles

Sports and osteoarthritis.

Participation in sports improves general health but increases the risk of osteoarthritis. This review analyzes the relationships among increased joint use, joint injuries, and injury-induced joint degeneration that causes posttraumatic osteoarthritis. The purpose is to help people who participate in sports minimize their risk of joint degeneration. Participation in sports that cause minimal joint impact and torsional loading by people with normal joints and neuromuscular function may cause osteophyte formation, but it has minimal, if any, effect on the risk of osteoarthritis. In contrast, participation in sports that subject joints to high levels of impact and torsional loading increases the risk of injury-induced joint degeneration. People with abnormal joint anatomy or alignment, previous joint injury or surgery, osteoarthritis, joint instability, articular surface incongruity or dysplasia, disturbances of joint or muscle innervation, or inadequate muscle strength have increased risk of joint damage during participation in athletics. Gaining the benefits of participation in athletics while minimizing the risk of osteoarthritis requires understanding of the relationships between sports participation and joint injury and the relationships between joint injury and joint degeneration. People who wish to participate in sports should have an evaluation of their joint structure and function, muscle strength, and neuromuscular function, and people with a history of joint injury or mild osteoarthritis should select sports that have limited risk of accelerating joint degeneration.

Sports, joint injury, and posttraumatic osteoarthritis.

Participation in sports increases the risk of joint injuries that can lead to posttraumatic osteoarthritis, a clinical syndrome caused by trauma-initiated joint degeneration that results in permanent and often progressive joint pain and dysfunction. Minimizing the risk of joint injuries and helping people with osteoarthritis participate in regular physical activity, including some sports, requires understanding of the relationships between joint use, joint injury, and joint degeneration. Lifelong participation in sports that cause minimal joint impact and torsional loading by individuals with normal joints and neuromuscular function does not increase the risik of posttraumatic osteoarthritis. In contrast, participation in sports that subject joints to high levels of impact and torsional loading increases the risk of joint injury and subsequent joint degeneration. Immediate diagnosis and appropriate treatment and rehabilitation following joint injuries decrease the risk of subsequent injuries and posttraumatic osteoarthritis. Individuals with abnormaljoint anatomy or alignment, previous significant joint injury, osteoarthritis, joint surgery, joint instability, disturbances of joint or muscle innervation or inadequate muscle strength have increased risk of joint damage during participation in athletics. These individuals can benefit from regular exercise, including selected sports, but they should have an evaluation of their joint structure and function, muscle strength, and neuromuscular function before participating in vigorous physical activity.

Fluorescence immunohistochemistry and confocal scanning laser microscopyA protocol for studies of joint innervation

We have developed a reliable technique for labeling and examining neural structures in soft tissues associated with articular joints and have tested it in human wrist joints under various specimen-related conditions. The labeling protocol employs an immunohistochemical process with a panneuronal marker (PGP 9.5) as the primary antibody and Alexa Fluor 488 as the fluorescing secondary antibody. Imaging was done using a confocal laser scanning microscope, which produced exceptionally detailed three-dimensional images of nerve endings and transiting nerve fibers from thick sections of wrist joint ligaments obtained from human cadavers. The protocol provided a practical postmortem window for specimen acquisition and processing without significant apparent worsening of image quality. The images produced are resistant to fading with repeated exposure to a fluorescent light source, which gives many opportunities for observation. Background staining is minimal, producing high contrast labeling of target tissues, which, in turn, enhances image analysis.

Evidence for a neuropathic contribution to the development of spontaneous knee osteoarthrosis in a mouse model.

Previous work has shown a progressive, age-related loss of knee joint innervation in the C57BL6Nia mouse. We did three experiments to describe further the loss and determine whether it might contribute to the development of knee osteoarthrosis in this model. Immunocytochemistry showed that the percentage of neurons expressing substance P and calcitonin gene-related peptide increased with age, indicating a relatively selective loss of mechanoreceptors. Histological examination of knee joints of mice at various ages showed that loss of joint innervation always preceded histological changes of cartilage degeneration. The mice usually developed a mild form of osteoarthrosis, but surgical ablation of joint innervation caused the development of severe patellofemoral osteoarthrosis. The findings are consistent with the hypothesis that an age-related loss of joint innervation may contribute to the development of osteoarthrosis.

Cortical projection of the rat knee joint innervation and its processing in the somatosensory areas SI and SII.

In recent years the rat knee joint has become an important model for the study of nociception of deep tissues. In contrast to the cortical processing of superficial pain, the knowledge about the processing of deep pain evoked by noxious stimuli in tissues such as tendons, bone, and joint is sparse. To obtain a basis for further functional studies, the projections of the knee joint in the cerebral cortex were determined. Cortical surface potentials evoked by electrical stimulation of the posterior articular nerve were recorded by a platinum ball electrode. Evoked activity was found in the primary somatosensory area SI in an area of about 3 x 3 mm on the contralateral side. Its center was located about 3 mm caudal to the bregma and about 3 mm lateral to the superior sagittal sinus. A small projection in SII was found on the lateral side of the cortex about 6 mm lateral from SI. This area had a size of about 1 x 1 mm, and the amplitudes of the potentials were smaller but had similar latencies to those in SI. An additional projection with small potentials and longer latencies was observed in SI on the ipsilateral side. Cooling of the contralateral SI revealed deprivation of the ipsilateral evoked potentials in SI whereas the potentials in SII remained unchanged. These data indicate that information from the knee joint is processed in parallel in SI and SII on the contralateral side and that there is an additional serial processing in SI on the ipsilateral side.

Composition of the medial and posterior articular nerves of the mouse knee joint

The number and the distribution of fiber size in the medial (MAN) and posterior (PAN) articular nerves of the mouse knee joint were studied by electron microscopy. The MAN contained 75 - 28 nerve fibers consisting of 63 - 24 unmyelinated and 12 - 6 myelinated fibers. The PAN was composed of 195 - 50 nerve fibers, namely 129 - 28 unmyelinated and 66 - 24 myelinated fibers. A skewed unimodal distribution of the unmyelinated nerve fiber diameters was seen in both nerves ranging from 0.1 to 1.2 w m with a maximum between 0.3 and 0.6 w m. The myelinated nerve fibers in the MAN ranged from 1 to 8 w m with a peak between 2 and 5 w m. In the PAN, their diameters ranged from 1 to 12 w m with a clearly visible peak at 4-5 w m and a plateau at 8-9 w m that may represent a second maximum. These data show that the knee joint innervation of the mouse is comparable to those of the cat and rat concerning the types of nerve fibers and the composition of the two nerves. However, in relation to the much smaller area of tissue to be innervated the total number of primary afferents is considerable smaller in the mouse.

Thenar branch of the median nerve and innervation of the trapeziometacarpal joint

Denervation has been proposed successfully for chronic wrist pain. This procedure is not commonly performed for degenerative osteoarthritis of the trapeziometacarpal joint. According to the classic anatomical descriptions of the wrist innervation, it seems that the thenar branch of the median nerve (TBMN) is the only nerve of the wrist for which no articular branches are clearly defined. The aim of this study is to complete the few anatomical descriptions of the trapeziometacarpal joint innervation with microdissections of the TBMN. Ten wrist and hand specimens from fresh cadavers were dissected by the same operator under magnification (3.5-12x). The TBMN was identified at its origin from the median nerve and followed in the thenar muscles. All the divisions of the TBMN were identified and followed to their terminal branches. The TBMN divided in at least two main branches, one each to the opponens and to the abductor pollicis brevis. In all but one specimen, the branch to the opponens pollicis muscle passed over or into its medial aspect to spread on the palmar side of the trapezium. Each dissected articular branches were histologically confirmed. Our results show a clear participation of the TBMN in the innervation of the trapeziometacarpal joint. The lack of knowledge of this anatomical feature may explain the inconstant results obtained with selective denervation of the trapeziometacarpal joint.

Intradiscal electrothermal treatment for chronic discogenic low back pain: a prospective outcome study with minimum 1‐year follow‐up. (SOAR, Physiatry Medical Group, Menlo Park, CA) Spine 2000;25:2622–2627.

Intradiscal electrothermal treatment for chronic discogenic low back pain: a prospective outcome study with minimum 1‐year follow‐up. (SOAR, Physiatry Medical Group, Menlo Park, CA) <i>Spine</i> 2000;25:2622–2627.

Neurovascular plasticity in the knee joint of an arthritic mouse model

Lower numbers of neuropeptide-containing fibers in arthritic joints have been found as compared to control joints. This may be the result of fiber depletion, necrosis of fibers, or proliferation of soft tissues without neural sprouting. To discriminate between these possibilities, we studied the relationships between soft tissue proliferation, changes in vascularity of synovial tissues, and changes in joint innervation during arthritis. Arthritis was induced in the knee joint of mice by a single subpatellar injection of methylated bovine serum albumin after previous immunization. Antibodies to protein gene product 9.5, S-100, and growth-associated protein-43 (GAP-43) were used to study the general innervation pattern. Antibodies to calcitonin gene-related peptide (CGRP), vasointestinal polypeptide (VIP), substance P (SP), and tyrosine hydroxylase (TH) were used to localize sensory (SP, CGRP, VIP) and sympathetic (TH) fibers. Blood vessels of the joint were studied with ink perfusion, GAP-43, and a vascular marker (LF1). Directly after the induction of arthritis, the synovial cavity was enlarged and filled with leukocytes. From day 4 onward, small sprouting blood vessels penetrated the avascular mass of cells in the joint cavity. After 1 week, the vascular sprouting activity and GAP-43 immunoreactivity were maximal, and after 2 weeks, vascular sprouting activity diminished. In the subsequent period, the synovia slowly regained their prearthritic appearance and thickness. The most pronounced changes in the general staining pattern of CGRP, SP, VIP, and TH were found in the periosteum. From 2 days to 4 weeks after the induction of arthritis, the layer of SP, CGRP, and VIP fibers in the femoral periosteum was thicker and more irregular. GAP-43 staining showed many terminal varicosities, which suggested sprouting of nerve fibers. From 2 days to 2 weeks after the induction of arthritis, the SP and CGRP fibers in the periosteum showed gradual depletion. In the thickened subsynovial tissues that were revascularized, no ingrowth of neural elements was found. As the total number of nerve fibers in the synovial tissue did not change, large parts of the synovia directly facing the joint cavity were not innervated at 1 week after the induction of arthritis. These results strongly suggest that periosteal SP and CGRP fibers were depleted during arthritis. Synovial proliferation without concomitant fiber growth is the main cause of the reduced number of immunocytochemically detectable fibers in the mouse arthritic knee joint.

Dual Role for Noradrenergic Innervation of Lymphoid Tissue and Arthritic Joints in Adjuvant-Induced Arthritis

The role of noradrenergic innervation in the disease outcome of adjuvant-induced arthritis (AA) has been examined following (1) systemic administration of guanethidine and (2) local application of 6-hydroxydopamine (6-OHDA) into the lymph nodes that drain the hind limbs (DLN). Sympathetic denervation by these different neurotoxins produced directionally opposite effects on disease outcome. These conflicting findings could be explained from differential denervation of sympathetic nerves in key target tissues that result from different routes of neurotoxin administration. Alternatively, these conflicting data could be due to differences in the mechanisms by which guanethidine and 6-OHDA destroy sympathetic nerve terminals. In this study, we compared disease outcome in AA following systemic and local DLN application of 6-OHDA to determine whether the route of administration is important to the development and progression of AA. Bilateral local DLN application of 6-OHDA or vehicle was performed 1 day before injection of Freund's complete adjuvant (CFA) to induce arthritis. For systemic denervation, 6-OHDA or vehicle was given by ip injections on days 1, 3, and 5 prior to CFA challenge and then once a week. Local DLN application of 6-OHDA resulted in significant increases in dorsoplantar width in arthritic rats by 27 days following CFA treatment compared to those of non-denervated arthritic rats. In contrast, systemic denervation in arthritic rats significantly decreased dorsoplantar widths 27 days after CFA treatment compared to those in sympathetically intact arthritic animals. X-ray analysis confirmed these findings. Further, local DLN application of 6-OHDA exacerbated the disease regardless of whether the neurotoxin was administered prior to immunization with CFA or closer to the time of disease onset. Our findings indicate that the route of 6-OHDA administration for denervation of sympathetic innervation is an important parameter in determining disease outcome, presumably due to differential sympathetic denervation of target tissues that are involved in disease development and progression. 6-OHDA administration into local DLN denervated these lymph nodes, but spared sympathetic innervation of the hind limbs, a pattern of sympathetic denervation that resulted in disease exacerbation. In contrast, systemic 6-OHDA administration which denervated both the arthritic joints and the secondary lymphoid organs attenuated the severity of AA. This study supports a dual role for NA innervation in modulating the severity of AA by innervation of the arthritic joints and lymphoid organs.

Propioceptores articulares y musculares

La función de los mecanorreceptores de las articulaciones y músculos se considera asociada a&#x0D; la propiocepción. Sin embargo, existen evidencias de que la propiocepción no sólo depende del&#x0D; morfotipo de mecanorreceptor presente en dichos tejidos sino también de las propiedades de las&#x0D; neuronas sensitivas primarias y las fibras sensitivas asociadas a ellos, así como de su proyección&#x0D; sobre el asta posterior de la médula espinal. Este artículo resume las bases morfológicas de la&#x0D; propiocepción a nivel del sistema nervioso periférico, analizando: a) las neuronas sensitivas&#x0D; primarias propioceptivas; b) los tipos de fibras nerviosas sensitivas que llegan a los propioceptores;&#x0D; c) la inervación sensitiva de articulaciones y músculos; d) los morfotipos de mecanorreceptores&#x0D; asociados a la propiocepción; e) los datos recientes obtenidos a partir de animales deficientes en&#x0D; factores clave para el desarrollo del sistema propioceptor.

Deterioration of sensory joint innervation as an enabling factor for development of arthrosis. An animal experiment study of the rat model

In the present study we investigated the influence of an altered sensible joint innervation on the development of knee osteoarthritis in a wistar rat model of osteoarthritis. Capsaicin (8-methyl-N-vanillyl-6-noneamide) mediated partial sensible knee joint denervation was performed in a group of 16 male wistar rats. Twelve rats without alterations of the sensible knee joint innervation served as controls. In both groups, half of the rats underwent strenuous running exercises (total running load of 20 km) in a running wheel by intracranial self-stimulation, while the other half did not have any running load. In rats without running, there were no histological sings of knee osteoarthritis according to the Mankin score. In contrast, in rats running a total of 20 km significant osteoarthritis changes were observed. Hereby, in rats without altered sensible knee joint innervation, osteoarthritis was mostly classified as mild or moderate, while severe osteoarthritis was the predominant finding in the knee joints of the rats with partial sensible knee joint denervation. In conclusion, our study gives strong evidence for the hypothesis that an altered sensible joint innervation works as a contributing factor in the development of osteoarthritis.

Coexistence of enkephalin- and tyrosine hydroxylase-like immunoreactivities in nerve fibers of the temporomandibular joint capsule of the guinea pig.

The innervation of joints has been suggested to play an important role for their normal function as well as for the pathogenesis of chronic arthritic conditions. It is therefore important to elucidate the functional anatomy of this innervation. The expression of methionine enkephalin-like immunoreactivity (ENK-LI) and tyrosine hydroxylase (TH)-LI as well as their possible colocalization were examined in the temporomandibular joint of the guinea pig: Nerve fibers with ENK-LI were demonstrated in the synovium of the guinea pig temporomandibular joint capsule with the use of indirect immunofluorescence. The ENK+ fibers were found close to the surface of the synovial membrane, deeper in the synovium, and at the walls of blood vessels. Coexistence of ENK- and TH-LI was observed frequently in the synovial nerve fibers. After removal of the superior cervical ganglion (SCG), the ENK-containing nerve fibers were reduced substantially in number on the operated side or were completely absent if the cervical sympathetic trunk was also excised. The findings indicate that the majority of fibers with ENK-LI derive from the SCG ENK may act as a neuromodulator on the catecholaminergic nerves and may also have an analgesic effect in the joint.

Coexistence of enkephalin‐ and tyrosine hydroxylase‐like immunoreactivities in nerve fibers of the temporomandibular joint capsule of the guinea pig

Background The innervation of joints has been suggested to play an important role for their normal function as well as for the pathogenesis of chronic arthritic conditions. It is therefore important to elucidate the functional anatomy of this innervation. Methods The expression of methionine enkephalin-like immunoreactivity (ENK-LI) and tyrosine hydroxylase (TH)-LI as well as their possible colocalization were examined in the temporomandibular joint of the guinea pig. Results Nerve fibers with ENK-LI were demonstrated in the synovium of the guinea pig temporomandibular joint capsule with the use of indirect immunofluorescence. The ENK+ fibers were found close to the surface of the synovial membrane, deeper in the synovium, and at the walls of blood vessels. Coexistence of ENK- and TH-LI was observed frequently in the synovial nerve fibers. After removal of the superior cervical ganglion (SCG), the ENK-containing nerve fibers were reduced substantially in number on the operated side or were completely absent if the cervical sympathetic trunk was also excised. Conclusions The findings indicate that the majority of fibers with ENK-LI derive from the SCG. ENK may act as a neuromodulator on the catecholaminergic nerves and may also have an analgesic effect in the joint. Anat. Rec. 251:226–229, 1998. © 1998 Wiley-Liss, Inc.

Athletics and osteoarthritis.

Athletes, and an increasing number of middle aged and older people who want to participate in athletics, may question whether regular vigorous physical activity increases their risk of developing osteoarthritis. To answer this, the clinical syndrome of osteoarthritis must be distinguished from periarticular soft tissue pain associated with activity and from the development of osteophytes. Sports that subject joints to repetitive high levels of impact and torsional loading increase the risk of articular cartilage degeneration and the resulting clinical syndrome of osteoarthritis. However, moderate habitual exercise does not increase the risk of osteoarthritis; selected sports improve strength and mobility in older people and people with mild and moderate osteoarthritis. People with abnormal joint anatomy or alignment, previous significant joint injury or surgery, joint instability, above-average body weight, disturbances of joint or muscle innervation or inadequate muscle strength probably have increased risk of osteoarthritis. These people and those with early osteoarthritis can benefit from regular physical activity, but they should have a careful evaluation of their joint structure and function before participation. They should consider measures that decrease the intensity and frequency of impact and torsional loading of joints, including use of sports equipment that decreases joint impact loading, maintaining or improving muscle strength, tone, and general conditioning so that muscle contractions help protect joints from injury and high impact, and decreasing body weight.

Selective ablation of rat knee joint innervation with injected immunotoxin: a potential new model for the study of neuropathic arthritis.

Neuropathic arthropathy is a severe chronic degenerative condition associated with decreased or absent sensory innervation of the involved joint. Existing animal models of neuropathic arthritis are limited by the technical difficulties of obtaining either highly selective or complete joint denervation in a minimally invasive fashion. We undertook experiments to determine the feasibility of using the newly described method of selective neuronal lesioning with injected immunotoxin as a means of creating a more tractable model of neuropathic arthritis. Retrograde tracing with fluorochrome revealed that the knee joint of the female Wistar rat is supplied by 581 +/- 31 (mean +/- SD) joint afferents. Immunohistochemistry confirmed that virtually all sensory neurons in the rat express the cell surface receptor Thy 1. Injection of rat knee joints with an immunotoxin targeted toward Thy 1 resulted in the selective ablation of an average of 88% of the joint afferents identified with fluorochrome that are normally found in the ipsilateral L3 and L4 ganglia.

Neuropathic Arthropathy: Review of Current Knowledge.

Neuropathic arthropathy is a chronic, progressive degenerative disorder affecting one or more peripheral or vertebral articulations, which develops as the result of a disturbance in the normal sensory (pain or proprioceptive) innervation of joints. Diabetes, syphilis, and syringomelia are the most commonly associated clinical entities. When neuropathic arthropathy is suspected, careful clinical evaluation should be performed to identify an underlying neurologic disorder. Patient education, joint protection, and early recognition of fractures are the most important general management principles. Surgery can be considered in cases of advanced joint destruction when there is significant disability.

Electromyographic response of the porcine multifidus musculature after nerve stimulation.

In this study, a porcine model was used to study whether a nerve reaction in the anulus fibrosus of a lumbar disc or in a facet joint capsule could cause a muscular response in the multifidus musculature. To determine if there is an interrelationship between the intervertebral disc and facet joint innervation and the multifidus musculature as a possible pain mechanism. The innervation of the anulus fibrosus of the intervertebral disc and the capsule of the facet joint is well described in the literature, although the functions of these nerves are poorly understood. An interrelationship between this innervation and the paraspinal musculature has not been previously described. Fifteen adult pigs were used to measure the electromyographic response in the multifidus musculature to electrical stimulation of the lateral region of the disc anulus and the facet joint capsule in the L1-L2 motion segment. Motor unit action potentials were recorded using three sets of bipolar needle electrodes placed into the deepest fascicles of the multifidus, bilateral to the L2, L3, and L4 spinous processes. The effect of lidocaine injection into the facet joint and subperiosteal muscle detachment on the electromyographic response were studied. Stimulation of the disc anulus fibrosus induced reactions in the multifidus on multiple levels and on the contralateral side, whereas stimulation of the facet joint capsule induced reactions predominantly on the same side and segmental level as the stimulation. Introduction of lidocaine into the facet joint resulted in a significantly reduced electromyographic response to either stimulation, with the most drastic reduction seen when stimulating the facet joint capsule. Subperiosteal detachment of the paraspinal muscles prevented any muscular response. Stimulation of the disc and the facet joint capsule produced contractions in multifidus fascicles. The clinical implications are that there may be interactive responses between injured or diseased structures, i.e., disc or facet joints, and the paraspinal musculature. Activation of the multifidus muscles may have a stabilizing effect, constraining the motion of the lumbar spine. Longstanding muscular contraction may produce ischemic conditions and may be a potential source of pain.

A simple method for a specific retrograde labelling of dorsal root and sympathetic ganglion cells innervating the knee joint of the cat

To examine the biochemical characteristics of primary afferents and sympathetic efferents innervating the normal and inflamed knee joint of the cat, the corresponding perikarya have to be labelled retrogradely. In the present study we used an injection of the fluorescent dye Fast Blue through the intact skin and the patellar ligament into the centre of the knee joint cavity and examined the efficiency of this kind of labelling. The segmental distributions of labelled cell profiles in cryostat sections of dorsal root ganglia (DRG) and paravertebral ganglia of the sympathetic trunk agreed with data obtained previously after applying the dye at the transected end of the two main articular nerves. The soma size distribution of labelled DRG cells was identical to previous results indicating that the perikarya labelled in the present study may be a representative proportion of the knee joint innervation. Axotomy of the medial and posterior articular nerves reduced the number of labelled cell profiles of about 85%. Taken together, these data indicate that an injection of Fast Blue into the knee joint cavity of the cat revealed a highly specific and efficient retrograde labelling of the neuronal cell bodies innervating the knee joint.

Neuropeptidergic innervation of equine synovial joints

Summary Immunocytochemical analysis of equine synovial membranes revealed presence of several neuropeptides, including substance P (sp), neurokinin A, and neuropeptide Y, in nerves of the radiocarpal, middle carpal, and metacarpophalangeal (fetlock) joints. Within the subsynovium, these neuropeptides were located perivascularly, whereas in the fronds, only neuropeptide Y was restricted to the vessels of the synovial membrane. Only sp and neurokinin A were found in the intimal layer. The intimal layer of the metacarpophalangeal joint contained more sp-immunoreactive fibers than were observed in the intimal layer of the radiocarpal joint. Substance P also was detected in the synovial fluid from all 3 joints, but mean ± sd concentrations were significantly different only between the middle carpal joint (37.56 ± 5.48 fmol/ml; n = 6) and the metacarpophalangeal joint (55.80 ± 8.33 fmol/ml; n = 5) and between the middle carpal joint and the radiocarpal joint (52.43 ± 14.60 fmol/ml; n = 7).