Arthritis and Pain. Neurogenic origin of joint pain

Arthritis pain affects millions of people worldwide yet we still have only a limited understanding of what makes our joints ache. This review examines the sensory innervation of diarthroidal joints and discusses the neurophysiological processes that lead to the generation of painful sensation. During inflammation, joint nerves become sensitized to mechanical stimuli through the actions of neuropeptides, eicosanoids, proteinase-activated receptors and ion channel ligands. The contribution of immunocytes to arthritis pain is also reviewed. Finally, the existence of an endogenous analgesic system in joints is considered and the reasons for its inability to control pain are postulated.     

骨关节炎相关细胞因子及蛋白的研究进展

骨关节炎（osteoarthritis,OA）是人体中轴关节及外周运动关节最常见的退行性疾病,该病的临床症状表现为疼痛、关节僵硬和关节活动受限,罹患该病非常痛苦,严重影响生活质量,是成年人疼痛、运动功能障碍和致残的常见原因之一。OA是临床上常见的骨关节疾病,老年人多发,是老年人丧失劳动力的重要原因,对社会经济影响很大。国内外对OA的发病机制做了大量的研究,但其确切的病因及病理机制尚未完全阐明。目前,OA没有特效治愈方法,治疗目标局限于使用止痛药来缓解疼痛,并最终行人工关节置换手术。即使人工关节置换手术成功,人造关节寿命也是有限的,其他严重问题还有植入物的松动和失败等。因此,对该病病因、病理机制的探索成为目前的热点和焦点,也是解决OA这个问题的关键。本文就近年来研究较热门的骨关节炎相关细胞因子及蛋白做一综述。     

Percutaneous radiofrequency lumbar rhizolysis (rhizotomy).

Low back pain may arise from degenerative changes in the posterior joints of the lumbar spine. These joints are innervated by a branch of the posterior primary ramus, which follows an anatomically constant course. Pain impulses from these joints can be interrupted by coagulating this nerve with a radiofrequency wave, the probe having been placed in the area of the nerve percutaneously. Percutaneous lumbar rhizolysis was carried out under local anesthesia on an outpatient basis in 82 patients, most of whom had multiple level rhizolysis. Rhizolysis was successful in 67% of patients with mechanical low back pain without evidence of disc herniation and nerve-root compression or psychogenic pain, who had not previously undergone an operation for relief of the pain.     

Increase in facet joint loading after nucleotomy in the human lumbar spine

Low-back pain has been related to degenerative changes after nucleotomy. Although several etiologies for pain after nucleotomy have been proposed, there is evidence of pain arising in the facet joints in general, which may be related to changes in load transfer. This study addresses the effect of nucleotomy on facet joint loading.     

Magnetic resonance imaging changes of sacroiliac joints in patients with recent-onset inflammatory back pain: inter-reader reliability and prevalence of abnormalities

To study the inter-reader reliability of detecting abnormalities of sacroiliac (SI) joints in patients with recent-onset inflammatory back pain by magnetic resonance imaging (MRI), and to study the prevalence of inflammation and structural changes at various sites of the SI joints.     

RHEUMATOID ARTHRITIS—Diagnosis in Peripheral Joint Affliction

The diagnosis of rheumatoid arthritis in a typical case depends upon a history of pain and swelling of various joints throughout the body. In the first stages the disease usually involves only the small joints of the hands and feet, but sooner or later it spreads to the larger joints. This may be accompanied by fibrosis of one or more joints, causing disability ranging from disuse of one joint up to total incapacity. Diagnosis in early or atypical cases is often impossible until the patient has been under observation a long time. It is important that diagnosis be made as early as possible, in order that appropriate therapy may be started and ankylosis and disability of the joints prevented.Since laboratory procedures and roentgen films do not show early changes, emphasis is placed on the history and physical examination for diagnosis.     

Rheumatoid arthritis; diagnosis in peripheral joint affliction

The diagnosis of rheumatoid arthritis in a typical case depends upon a history of pain and swelling of various joints throughout the body. In the first stages the disease usually involves only the small joints of the hands and feet, but sooner or later it spreads to the larger joints. This may be accompanied by fibrosis of one or more joints, causing disability ranging from disuse of one joint up to total incapacity. Diagnosis in early or atypical cases is often impossible until the patient has been under observation a long time. It is important that diagnosis be made as early as possible, in order that appropriate therapy may be started and ankylosis and disability of the joints prevented. Since laboratory procedures and roentgen films do not show early changes, emphasis is placed on the history and physical examination for diagnosis.     

Leukocyte trafficking and pain behavioral responses to a hydrogen sulfide donor in acute monoarthritis

Hydrogen sulfide (H(2)S) is an endogenous gaseous mediator with the ability to modulate tissue inflammation and pain. The aim of this study was to determine the effect of an H(2)S donor (Na(2)S) on leukocyte-endothelium interactions, blood flow, and pain sensation in acutely inflamed knee joints. Acute arthritis was induced in urethane anesthetized C57bl/6 mice by intra-articular injection of kaolin/carrageenan (24-h recovery), and the effect of local administration of Na(2)S on leukocyte trafficking was measured by intravital microscopy. Synovial blood flow was measured in inflamed knees by laser Doppler perfusion imaging. Finally, the effect of an intra-articular injection of Na(2)S on joint pain in control and inflamed rats was determined by hindlimb incapacitance and von Frey hair algesiometry. Local administration of an H(2)S donor to inflamed knees caused a dose-dependent reduction in leukocyte adherence and an increase in leukocyte velocity. These effects could be inhibited by coadministration of the ATP-sensitive K(+) channel blocker glibenclamide. Local administration of Na(2)S to inflamed joints caused a pronounced vasoconstrictor response; however, there was no observable effect of Na(2)S on joint pain. These findings establish H(2)S as a novel signaling molecule in rodent knee joints. H(2)S exhibits potent anti-inflammatory properties, but with no detectable effect on joint pain.     

Magnetic resonance imaging changes of sacroiliac joints in patients with recent-onset inflammatory back pain: inter-reader reliability and prevalence of abnormalities

To study the inter-reader reliability of detecting abnormalities of sacroiliac (SI) joints in patients with recent-onset inflammatory back pain by magnetic resonance imaging (MRI), and to study the prevalence of inflammation and structural changes at various sites of the SI joints. Sixty-eight patients with inflammatory back pain (at least four of the five following criteria: symptom onset before age 40, insidious onset, morning stiffness, duration >3 months, improvement with exercise--or three out of five of these plus night pain) were included (38% male; mean age, 34.9 years [standard deviation 10.3]; 46% HLA-B27-positive; mean symptom duration, 18 months), with symptom duration <2 years. A MRI scan of the SI joints was made in the coronal plane with the following sequences: T1-weighted spin echo, short-tau inversion recovery, T2-weighted fast-spin echo with fat saturation, and T1-spin echo with fat saturation after the administration of gadolinium. Both SI joints were scored for inflammation (separately for subchondral bone and bone marrow, joint space, joint capsule, ligaments) as well as for structural changes (erosions, sclerosis, ankylosis), by two observers independently. Agreement between the two readers was analysed by concordance and discordance rates and by kappa statistics. Inflammation was present in 32 SI joints of 22 patients, most frequently located in bone marrow and/or subchondral bone (29 joints in 21 patients). Readers agreed on the presence of inflammation in 85% of the cases in the right SI joint and in 78% of the cases in the left SI joint. Structural changes on MRI were present in 11 patients. Ten of these 11 patients also showed signs of inflammation. Agreement on the presence or absence of inflammation and structural changes of SI joints by MRI was acceptable, and was sufficiently high to be useful in ascertaining inflammatory and structural changes due to sacroiliitis. About one-third of patients with recent-onset inflammatory back pain show inflammation, and about one-sixth show structural changes in at least one SI joint.     

Elastic and viscoelastic properties of the human pubic symphysis joint: effects of lateral impact joint loading

The human pelvis is susceptible to severe injury in vehicle side impacts owing to its close proximity to the intruding door and unnatural loading through the greater trochanter. Whereas fractures of the pelvic bones are diagnosed with routine radiographs (x-rays) and computerized tomography (CT scans), non-displaced damage to the soft tissues of pubic symphysis joints may go undetected. If present, trauma-induced joint laxity may cause pelvic instability, which has been associated with pelvic pain in non-traumatic cases. In this study, mechanical properties of cadaveric pubic symphysis joints from twelve normal and eight laterally impacted pelves were compared. Axial stiffness and creep responses of these isolated symphyses were measured in tension and compression (perpendicular to the joint). Bending stiffness was determined in four primary directions followed by a tension-to-failure test. Loading rate and direction correlated significantly (p<0.05) with stiffness and tensile strength of the unimpacted joints, more so than donor age or gender. The impacted joints had significantly lower stiffness in tension (p <0.04), compression (p<0.003), and posterior bending (p<0.03), and more creep under a compressive step load (p<0.008) than the unimpacted specimens. Tensile strength was reduced following impact, however, not significantly. We concluded that the symphysis joints from the impacted pelves had greater laxity, which may correlate with post-traumatic pelvic pain in some motor vehicle crash occupants.     

Fibroblast-like synovial cells from normal and inflamed knee joints differently affect the expression of pain-related receptors in sensory neurones: a co-culture study

Innervation of the joint with thinly myelinated and unmyelinated sensory nerve fibres is crucial for the occurrence of joint pain. During inflammation in the joint, sensory fibres show changes in the expression of receptors that are important for the activation and sensitization of the neurones and the generation of joint pain. We recently reported that both neurokinin 1 receptors and bradykinin 2 receptors are upregulated in dorsal root ganglion (DRG) neurones (the cell bodies of sensory fibres) in the course of acute and chronic antigen-induced arthritis in the rat. In this study, we begin to address mechanisms of the interaction between fibroblast-like synovial (FLS) cells and sensory neurones by establishing a co-culture system of FLS cells and DRG neurones. The proportion of DRG neurones expressing neurokinin 1 receptor-like immunoreactivity was not altered in the co-culture with FLS cells from normal joints but was significantly upregulated using FLS cells from knee joints of rats with antigen-induced arthritis. The proportion of DRG neurones expressing bradykinin 2 receptors was slightly upregulated in the presence of FLS cells from normal joints but upregulation was more pronounced in DRG neurones co-cultured with FLS cells from acutely inflamed joints. In addition, the expression of the transient receptor potential V1 (TRPV1) receptor, which is involved in inflammation-evoked thermal hyperalgesia, was mainly upregulated by co-culturing DRG neurones with FLS cells from chronically inflamed joints. Upregulation of neurokinin 1 receptors but not of bradykinin 2 and TRPV1 receptors was also observed when only the supernatant of FLS cells from acutely inflamed joint was added to DRG neurones. Addition of indomethacin to co-cultures inhibited the effect of FLS cells from acutely inflamed joints on neurokinin 1 receptor expression, suggesting an important role for prostaglandins. Collectively, these data show that FLS cells are able to induce an upregulation of pain-related receptors in sensory neurones and, thus, they could contribute to the generation of joint pain. Importantly, the influence of FLS cells on DRG neurones is dependent on their state of activity, and soluble factors as well as direct cellular contacts are crucial for their interaction with neurones.     

A biomechanical model on muscle forces in the transfer of spinal load to the pelvis and legs.

Based on musculoskeletal anatomy of the lower back, abdominal wall, pelvis and upper legs, a biomechanical model has been developed on forces in the load transfer through the pelvis. The aim of this model is to obtain a tool for analyzing the relations between forces in muscles, ligaments and joints in the transfer of gravitational and external load from the upper body via the sacroiliac joints to the legs in normal situations and pathology. The study of the relation between muscle coordination patterns and forces in pelvic structures, in particular the sacroiliac joints, is relevant for a better understanding of the aetiology of low back pain and pelvic pain. The model comprises 94 muscle parts, 6 ligaments and 6 joints. It enables the calculation of forces in pelvic structures in various postures. The calculations are based on a linear/non-linear optimization scheme. To gain a better understanding of the function of individual muscles and ligaments, deviant properties of these structures can be preset. The model is validated by comparing calculations with EMG data from the literature. For agonistic muscles, good agreement is found between model calculations and EMG data. Antagonistic muscle activity is underestimated by the model. Imposed activity of modelled antagonistic muscles has a minor effect on the mutual proportions of agonistic muscle activities. Simulation of asymmetric muscle weakness shows higher activity of especially abdominal muscles.     

Frequency and severity of musculoskeletal symptoms in humans during an outbreak of trichinellosis caused by Trichinella britovi

Musculoskeletal symptoms such as myalgia are well-known features in the course of trichinellosis; however, the characteristics of musculoskeletal findings have been described in detail in only 1 study. The present study was aimed to determine the joint and muscle symptoms in subjects diagnosed with acute trichinellosis at our rheumatology unit during a Trichinella britovi outbreak that occurred in Izmir, Turkey, in 2004. In total, 98 patients (55 females, 43 males; mean age 32.3 +/- 10.9 yr) were included in the study. A detailed history and full musculoskeletal examination were obtained in each patient. A self-administered questionnaire developed for recording the musculoskeletal symptoms was completed monthly until all the symptoms were resolved. Pain at the joints, restriction of movements (in shoulders, elbows, wrists, knees, ankles, and temporomandibular joints), myalgia, and muscle weakness (neck and shoulder girdle, muscles of the upper and forearm, back, thigh, and calf muscles) were assessed in every patient. Eosinophil counts, serum levels of creatine kinase, and lactate dehydrogenase also were analyzed. The most frequent musculoskeletal symptoms were muscle pain (86 cases [87.8%]), joint pain (83 [84.7%]), subjective muscle weakness (75 [76.5%]), and restriction of joint movements (63 [64.3%]). Calves, upper arm, neck and shoulder girdle, and forearms were the most affected muscle groups. Muscle pain was reported more frequently in the upper than in the lower extremities and during activity. The most frequent painful joints were shoulders, knees, wrists, and ankles. Upper extremity joints were affected more frequently than the lower extremity joints (77.6 vs. 70.4%). Joint pain occurred more frequently at rest. Both muscle weakness and restriction of joint movements were reported in and around the most frequently affected regions. No evidence of arthritis and objective muscle weakness was noted on physical examination in any patient. Musculoskeletal symptoms in the course of T. britovi infection are frequent but with an excellent prognosis. Joint pain in people suffering from acute trichinellosis may occur more frequently than reported previously.     

Temporal expression patterns of distinct cytokines and M1/M2 macrophage polarization regulate rheumatoid arthritis progression

Molecular Biology Reports - Rheumatoid arthritis (RA) is an autoimmune disease characterized by chronic inflammation of synovial joints and often associated with chronic pain. Chronic joint...     

Mathematical modelling of cytokines,MMPs and fibronectin fragments in osteoarthritic cartilage

Journal of Mathematical Biology - Osteoarthritis (OA) is a degenerative disease which causes pain and stiffness in joints. OA progresses through excessive degradation of joint cartilage, eventually...     

Urolithin A improves mitochondrial health,reduces cartilage degeneration,and alleviates pain in osteoarthritis

Osteoarthritis (OA) is the most common age‐related joint disorder with no effective therapy. According to the World Health Organization, OA affects over 500 million people and is characterized by degradation of cartilage and other joint tissues, severe pain, and impaired mobility. Mitochondrial dysfunction contributes to OA pathology. However, interventions to rescue mitochondrial defects in human OA are not available. Urolithin A (Mitopure) is a natural postbiotic compound that promotes mitophagy and mitochondrial function and beneficially impacts muscle health in preclinical models of aging and in elderly and middle‐aged humans. Here, we showed that Urolithin A improved mitophagy and mitochondrial respiration in primary chondrocytes from joints of both healthy donors and OA patients. Furthermore, Urolithin A reduced disease progression in a mouse model of OA, decreasing cartilage degeneration, synovial inflammation, and pain. These improvements were associated with increased mitophagy and mitochondrial content, in joints of OA mice. These findings indicate that UA promotes joint mitochondrial health, alleviates OA pathology, and supports Urolithin A''s potential to improve mobility with beneficial effects on structural damage in joints.     

Bone and joint tuberculosis: a continuing problem.

Although tuberculous disease of bones and joints is becoming uncommon, it still occurs and may cause devastating sequelae. It is frequently not diagnosed prior to the onset of permanent damage to the joints or spine; the most important reason for this delay may be the fact that it is not considered in the differential diagnosis of monoarthritis or back pain. Most persons with the disease have other evidence of tuberculosis. Not infrequently an aggressive approach (including synovial biopsy or surgical exploration of the back) is needed to confirm the diagnosis when there are no other clues.     

Dietary polyphenols and mechanisms of osteoarthritis

Osteoarthritis is a condition caused in part by injury, loss of cartilage structure and function, and an imbalance in inflammatory and anti-inflammatory pathways. It primarily affects the articular cartilage and subchondral bone of synovial joints and results in joint failure, leading to pain upon weight bearing including walking and standing. There is no cure for osteoarthritis, as it is very difficult to restore the cartilage once it is destroyed. The goals of treatment are to relieve pain, maintain or improve joint mobility, increase the strength of the joints and minimize the disabling effects of the disease. Recent studies have shown an association between dietary polyphenols and the prevention of osteoarthritis-related musculoskeletal inflammation. This review discusses the effects of commonly consumed polyphenols, including curcumin, epigallocatechin gallate and green tea extract, resveratrol, nobiletin and citrus fruits, pomegranate, as well as genistein and soy protein, on osteoarthritis with an emphasis on molecular antiosteoarthritic mechanisms.     

Central mechanisms of visceral pain

Deep pain arising from muscle, joints, connective tissue, and the viscera is different in character and quality from pain arising from cutaneous structures. Deep pains, particularly visceral pain, are poorly localized, typically referred or transferred to a cutaneous site, and generally produce strong emotional and autonomic responses and tonic muscle contractions. Despite the prevalence and clinical importance of deep pains, it is only relatively recently that investigative efforts have begun to focus on the mechanisms of deep pain. The present report briefly reviews the development and use of a model of visceral pain that employs constant pressure distension of the colon and rectum as a noxious stimulus. Converging behavioral, pharmacological, and physiological evidence that colorectal distension is a valid, reliable, noxious, visceral stimulus is presented.     

Muscle recruitment strategies can reduce joint loading during level walking

Joint inflammation, with consequent cartilage damage and pain, typically reduces functionality and affects activities of daily life in a variety of musculoskeletal diseases. Since mechanical loading is an important determinant of the disease process, a possible conservative treatment is the unloading of joints. In principle, a neuromuscular rehabilitation program aimed to promote alternative muscle recruitments could reduce the loads on the lower-limb joints during walking. The extent of joint load reduction one could expect from this approach remains unknown. Furthermore, assuming significant reductions of the load on the affected joint can be achieved, it is unclear whether, and to what extent, the other joints will be overloaded. Using subject-specific musculoskeletal models of four different participants, we computed the muscle recruitment strategies that minimised the hip, knee and ankle contact force, and predicted the contact forces such strategies induced at the other joints. Significant reductions of the peak force and impulse at the knee and hip were obtained, while only a minimal effect was found at the ankle joint. Adversely, the peak force and the impulse in non-targeted joints increased when aiming to minimize the load in an adjacent joint. These results confirm the potential of alternative muscle recruitment strategies to reduce the loading at the knee and the hip, but not at the ankle. Therefore, neuromuscular rehabilitation can be targeted to reduce the loading at affected joints but must be considered carefully in patients with multiple joints affected due to the potential adverse effects in non-targeted joints.