IL24 Expression in Synovial Myofibroblasts: Implications for Female Osteoarthritis Pain through Propensity Score Matching Analysis.

(1) Introduction: Despite documented clinical and pain discrepancies between male and female osteoarthritis (OA) patients, the underlying mechanisms remain unclear. Synovial myofibroblasts, implicated in synovial fibrosis and OA-related pain, offer a potential explanation for these sex differences. Additionally, interleukin-24 (IL24), known for its role in autoimmune disorders and potential myofibroblast production, adds complexity to understanding sex-specific variations in OA. We investigate its role in OA and its contribution to observed sex differences. (2) Methods: To assess gender-specific variations, we analyzed myofibroblast marker expression and IL24 levels in synovial tissue samples from propensity-matched male and female OA patients (each n = 34). Gene expression was quantified using quantitative polymerase chain reaction (qPCR). The association between IL24 expression levels and pain severity, measured by a visual analog scale (VAS), was examined to understand the link between IL24 and OA pain. Synovial fibroblast subsets, including CD45-CD31-CD39- (fibroblast) and CD45-CD31-CD39+ (myofibroblast), were magnetically isolated from female patients (n = 5), and IL24 expression was compared between these subsets. (3) Results: Females exhibited significantly higher expression of myofibroblast markers (MYH11, ET1, ENTPD2) and IL24 compared to males. IL24 expression positively correlated with pain severity in females, while no correlation was observed in males. Further exploration revealed that the myofibroblast fraction highly expressed IL24 compared to the fibroblast fraction in both male and female samples. There was no difference in the myofibroblast fraction between males and females. (4) Conclusions: Our study highlights the gender-specific role of myofibroblasts and IL24 in OA pathogenesis. Elevated IL24 levels in females, correlating with pain severity, suggest its involvement in OA pain experiences. The potential therapeutic implications of IL24, demonstrated in autoimmune disorders, open avenues for targeted interventions. Notwithstanding the limitations of the study, our findings contribute to understanding OA's multifaceted nature and advocate for future research exploring mechanistic underpinnings and clinical applications of IL24 in synovial myofibroblasts. Additionally, future research directions should focus on elucidating the precise mechanisms by which IL24 contributes to OA pathology and exploring its potential as a therapeutic target for personalized medicine approaches.

The cholinergic system in joint health and osteoarthritis: a narrative-review.

Osteoarthritis (OA) poses a major health and economic burden worldwide due to an increasing number of patients and the unavailability of disease-modifying drugs. In this review, the latest understanding of the involvement of the cholinergic system in joint homeostasis and OA will be outlined. First of all, the current evidence on the presence of the cholinergic system in the normal and OA joint will be described. Cholinergic innervation as well as the non-neuronal cholinergic system are detected. In a variety of inflammatory diseases, the classic cholinergic anti-inflammatory pathway lately received a lot of attention as via this pathway cholinergic agonists can reduce inflammation. The role of this cholinergic anti-inflammatory pathway in the context of OA will be discussed. Activation of this pathway improved the progression of the disease. Secondly, chondrocyte hypertrophy plays a pivotal role in osteophyte formation and OA development; the impact of the cholinergic system on hypertrophic chondroblasts and endochondral ossification will be evaluated. Cholinergic stimulation increased chondrocyte proliferation, delayed chondrocyte differentiation and caused early mineralisation. Moreover, acetylcholinesterase and butyrylcholinesterase affect the endochondral ossification via an acetylcholine-independent pathway. Thirdly, subchondral bone is critical for cartilage homeostasis and metabolism; the cholinergic system in subchondral bone homeostasis and disorders will be explored. An increase in osteoblast proliferation and osteoclast apoptosis is observed. Lastly, current therapeutic strategies for OA are limited to symptom relief; here the impact of smoking on disease progression and the potential of acetylcholinesterase inhibitors as candidate disease-modifying drug for OA will be discussed.

Galantamine in rheumatoid arthritis: A cross talk of parasympathetic and sympathetic system regulates synovium-derived microRNAs and related pathogenic pathways.

The acetylcholinesterase inhibitor, galantamine, has shown therapeutic effect in rat model of rheumatoid arthritis. Hence, the current study aims at determining the mode of action of galantamine by examining different synovium-derived microRNAs (miRs) and their related pathogenic pathways. The study also focuses on how parasympathetic and sympathetic pathways in the synovial tissue could affect the mode of action and anti-arthritic effect of galantamine. Chemical sympathectomy was initiated in 12 adjuvant arthritic rats by exposure to 6-hydroxydopamine (6-OHDA; 2 × 50 mg/kg) on day 9 after adjuvant injection and again (2 × 100 mg/kg) one week later. Six rats were treated with galantamine (2.5 mg/kg/day) to explore the influence of sympathetic impairment on galantamine effect. Another twelve additional adjuvant arthritic rats were exposed to the selective α7 nicotinic acetylcholine receptor blocker methylcaconitine citrate (MLA; 5.6 mg/kg/day), 15 min before galantamine treatment. As control, six adjuvant arthritic rats were treated with galantamine alone. Treatment proceeded for 5 days, from day 14 till day 18 post-adjuvant injection. Different miRs and their related pathogenic pathways were examined. Tyrosine hydroxylase (TH) expression was also measured in joint tissue. Galantamine affected the expression of the different miRs and their related parameters. Both, 6-OHDA and MLA, interrupted the anti-inflammatory/anti-arthritic effect of galantamine to different extent. Additionally, TH expression in the synovium was affected by galantamine, suggesting a novel pathogenic target in the treatment of rheumatoid arthritis.

Synovial nerve fiber density decreases with naturally-occurring osteoarthritis in horses.

OBJECTIVE: To measure the nerve fiber density in synovial membranes from healthy and OA equine joints and to investigate the relationship between synovial innervation and OA severity, synovial vascularity and synovitis. DESIGN: Twenty-five equine metacarpophalangeal joints were collected post-mortem. The joints were dissected and the macroscopic lesions of the articular cartilage were scored. Synovial membrane specimens (n = 50) were harvested, fixed, sectioned and scored histologically. Immunohistochemical staining and immunofluorescence with S-100 protein, that identifies nerve fibers, and ⍺-actin, that stains vascular smooth muscle, were also performed on site-matched specimens and the relationships between these tissues was interrogated. RESULTS: The nerve fiber density was higher in the superficial layer (≤200 µm) of the synovium when compared to the deeper layer in control equine joints (mean difference (95% C.I.): 0.054% (0.018%, 0.11%)). In osteoarthritic joints, synovial innervation decreased in the superficial layer with increasing macroscopic OA score (ß (SEM), 95% C.I.: -0.0061 (0.00021), -0.0011, -0.00017). The blood vessel density was also higher in the superficial layer of the synovium compared to the deep layer in the control (mean difference (95% C.I.): 1.1% (0.36%, 2.3%)) and OA (mean difference (95% C.I.): 0.60% (0.22%, 1.2%)) equine joints. Moreover, considering all synovial specimens, higher nerve fiber density in the deep layer positively correlated with blood vessel density (ß (SEM), 95% C.I.: 0.11 (0.036), 0.035, 0.18). CONCLUSION: The reduction in nerve fiber density with advanced cartilage degeneration suggests that peripheral neuropathy is associated with equine OA. Whether this link is associated with neuropathic pain, requires further investigation.

Histopathological analysis of the posterior cruciate ligament in primary osteoarthritis.

BACKGROUND: According to some authors, the indication of an arthroplasty maintaining the posterior cruciate ligament (PCL) demands adequate structural preservation and proprioceptive function of this ligament. The nervous fibers contained in the synovial neurovascular bundle (NVB) around the PCL are involved in proprioception. A study evaluating the grade of PCL and NVB degeneration by using clinical, radiological, and perioperative parameters in knee arthritis patients, in theory, could help surgeons in the decision of preserving or not preserving the PCL in a particular patient. QUESTIONS: (1) Can the degree of the PCL collagen fibers degeneration be predicted by clinical, radiographic, and perioperative parameters in knee arthritis patients? (2) Is the NVB histological degeneration status predictable using clinical, radiographic, and perioperative parameters in the same subset of patients? (3) Is there a correlation between the degree of the PCL collagen fibers degeneration and NVB status in knee arthritis patients? METHODS: Eighty-nine PCLs (85 patients) obtained from total knee replacement surgery were studied. The histologic degeneration of PCL collagen fibers and the NVB status (preserved, degenerated, not detected) were evaluated. These histological degeneration patterns were correlated with clinical and radiographic parameters and with anterior cruciate ligament (ACL) status. RESULTS: A small prevalence of preserved NVB was related to Grades IV and V of Ahlbäck's classification, ACL absence, and severe PCL degeneration. The clinical and radiological parameters studied were not able to predict the grade of histological degeneration of the PCL. CONCLUSIONS: Ahlbäck's classification and ACL status provided useful information about NVB integrity. LEVEL OF EVIDENCE: Basic Science Level IV.

Cervical spine meniscoids: an update on their morphological characteristics and potential clinical significance.

PURPOSE: Cervical spine meniscoids are intra-articular folds of synovial membrane that have been theorised to have potential clinical significance in neck pain. Recent anatomical and clinical research has re-visited the pathoanatomical capacity of these structures. The purpose of this review is to discuss cervical spine meniscoid morphology in light of recently published work, to provide an update on the plausible relevance of these structures to clinical practice. METHODS: Narrative review critically discussing basic science and clinical research regarding cervical spine meniscoids, with focus upon implications for clinical practice. RESULTS: Basic science research indicates that cervical spine meniscoids can be innervated and appear to vary in morphology in the presence of articular degeneration. In a clinical population, associations have been observed between cervical spine meniscoid morphology and presence of cervical spine symptoms. CONCLUSIONS: Recent studies regarding cervical spine meniscoid morphology provide further evidence of pathoanatomical capacity of these structures. Further research is required, however, in clinical populations to empirically investigate specific theorised mechanisms of cervical spine meniscoid involvement in neck pain.

Predominance of synovial sensory nerve fibers in arthrofibrosis following total knee arthroplasty compared to osteoarthritis of the knee.

BACKGROUND: So far, there exists no golden standard for the treatment of arthrofibrosis (AF) following total knee arthroplasty (TKA). Although pain is a hallmark of AF, nociceptive nerve fibers have never been investigated in affected joint tissue. METHODS: A total of 24 patients with osteoarthritis (OA) of the knee (n = 12) and post-TKA AF of the knee (n = 12) were included. Along evaluation of typical clinical signs and symptoms by using the Knee Society Clinical Rating System (KSS), the Knee Injury and Osteoarthritis Outcome Score (KOOS), and the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC index), the innervation of joint tissue was studied by semiquantitative immunofluorescence of nerve fibers. RESULTS: Patients with AF compared to OA had a lower KSS and lower KOOS. In all compartments (anterior, medial, and lateral recesses), the density of synovial sympathetic nerve fibers was significantly higher in OA compared to AF, which was also true for the density of sensory nerve fibers in the medial and lateral recesses. In synovial tissue of the anterior recess of patients with AF compared to OA, the density of nociceptive sensory nerve fibers was significantly higher relative to sympathetic nerve fibers. This was similarly observed in the neighboring infrapatellar fat pad of the knee. CONCLUSIONS: Similar as in many painful musculoskeletal diseases, this study indicates that patients with arthrofibrosis of the knee after TKA demonstrate a preponderance of profibrotic sensory nerve fibers over antifibrotic sympathetic nerve fibers. This could serve as a starting point for AF therapy with specific antifibrotic pain medication or regional anesthetic techniques.

Vitamin D deficiency leads to sensory and sympathetic denervation of the rat synovium.

Vitamin D deficiency is associated with increased susceptibility to inflammatory arthritis. Sensory and sympathetic synovial nerves are critical to the development of inflammatory arthritis and spontaneously degenerate in the early phases of disease. These nerves contain vitamin D receptors and vitamin D influences nerve growth and neurotrophin expression. We therefore examined the density of synovial nerves and neurotrophin-containing cells in vitamin D-deficient rats. Seven-week-old Sprague-Dawley rats were fed either control or vitamin D-deficient diets for 4weeks. Knee synovium sections extending from the patella to the meniscus were immunostained for total nerves, myelinated and unmyelinated nerves, sympathetic nerves, peptidergic and non-peptidergic sensory nerves, and neurotrophins and immune cell markers. In control rats, intimal innervation by unmyelinated sensory fibers was denser than subintimal innervation. In contrast, sympathetic innervation was confined to the subintima. Many sensory axons contained markers for both peptidergic and non-peptidergic nerves. Nerve growth factor (NGF) was primarily expressed by intimal CD163-negative type B synoviocytes, while neurturin, a ligand selective for non-peptidergic sensory neurons, was expressed by synovial mast cells. In vitamin D-deficient rats, there were significant reductions in sensory nerves in the intima and sympathetic nerves in the subintima. While there was no significant change in NGF-immunoreactivity, the number of neurturin-expressing mast cells was significantly reduced in the intima, suggesting that intimal reductions in sensory nerves may be related to reductions in neurturin. Vitamin D deficiency therefore may increase susceptibility to inflammatory arthritis by depleting sensory and sympathetic synovial nerves as a result of reduced synovial neurotrophin content.

Acute inflammation in the joint: its control by the sympathetic nervous system and by neuroendocrine systems.

Inflammation of tissues is under neural control involving neuroendocrine, sympathetic and central nervous systems. Here we used the acute experimental inflammatory model of bradykinin-induced plasma extravasation (BK-induced PE) of the rat knee joint to investigate the neural and neuroendocrine components controlling this inflammation. 1. BK-induced PE is largely dependent on the sympathetic innervation of the synovium, but not on activity in these neurons and not on release of norepinephrine. 2. BK-induced PE is under the control of the hypothalamo-pituitary-adrenal (HPA) system and the sympatho-adrenal (SA) system, activation of both leading to depression of BK-induced PE. The inhibitory effect of the HPA system is mediated by corticosterone and dependent on the sympathetic innervation of the synovium. The inhibitory effect of the SA system is mediated by epinephrine and ß2-adrenoceptors. 3. BK-induced PE is inhibited during noxious stimulation of somatic or visceral tissues and is mediated by the neuroendocrine systems. The nociceptive-neuroendocrine reflex circuits are (for the SA system) spinal and spino-bulbo-spinal. 4. The nociceptive-neuroendocrine reflex circuits controlling BK-induced PE are under powerful inhibitory control of vagal afferent neurons innervating the defense line (connected to the gut-associated lymphoid tissue) of the gastrointestinal tract. This inhibitory link between the visceral defense line and the central mechanisms controlling inflammatory mechanisms in body tissues serves to co-ordinate protective defensive mechanisms of the body. 5. The circuits of the nociceptive-neuroendocrine reflexes are under control of the forebrain. In this way, the defensive mechanisms of inflammation in the body are co-ordinated, optimized, terminated as appropriate, and adapted to the behavior of the organism.

The innervation of synovium of human osteoarthritic joints in comparison with normal rat and sheep synovium.

OBJECTIVE: To study whether osteoarthritis (OA) in the knee is associated with a change of the innervation pattern in the synovial layer. DESIGN: In synovial tissue from the normal knee joint of rat and sheep we studied the presence of vessels and of nerve fibres using transmission electron microscopy and immunohistochemistry. Synovial material was also obtained from patients who underwent total knee replacement surgery. This material was examined for inflammatory changes, and the presence of vessels and nerve fibres was assessed. RESULTS: The synovium in the parapatellar region of the normal knee joint of rat and sheep exhibited a dense capillary and neuronal network. It was entered by calcitonin gene-related peptide containing sensory fibres and tyrosine hydroxylase-positive sympathetic nerve fibres. Synovial material from patients with knee OA exhibited different degrees of inflammation. Synovial material without inflammation exhibited a similar vascular and neuronal network as the normal knee joint from rat and sheep. However, in synovium with inflammatory changes we found a significant decrease of nerve fibres in depth ranges close to the synovial lining layer depending on the degree of inflammation whereas deeper regions were less affected. CONCLUSIONS: Inflammatory changes in the synovium of OA joints are associated with a massive destruction of the capillary and neuronal network which is present in normal synovium. Due to the disappearance of the sensory fibres it is unlikely that OA pain is initiated directly in the synovium. The loss of normally innervated vascularisation may have multiple consequences for the physiological functions of the synovium.

Loss of sympathetic nerve fibers in vital intertrochanteric bone cylinders lateral to osteonecrosis of the femoral head.

OBJECTIVES: Although etiology in osteonecrosis of the femoral head mainly depends on alterations of bone blood flow, vasoregulatory nerve fibers of the sympathetic and sensory nervous system have never been investigated in bone of osteonecrosis patients. This study aimed to demonstrate density of sympathetic and sensory nerve fibers in femoral head and, for comparison, adjacent periosteum, and synovium of the hip joint in patients with osteonecrosis. METHODS: Immunofluorescence staining techniques were applied using specific nerve fiber markers. A total of 10 patients with early femoral head osteonecrosis (ARCO I-II), 10 with late femoral head osteonecrosis (ARCO III-IV), and 10 patients with osteoarthritis of the hip were investigated. RESULTS: In the bone of the femoral head, density of sympathetic nerve fibers was lower in early and late osteonecrosis compared to osteoarthritis. There was a marked preponderance of sympathetic over sensory nerve fibers in bone of osteoarthritis patients, which was opposite in early and late femoral head osteonecrosis. In periosteum, density of sympathetic nerve fibers was similar in all three groups but density of sensory nerve fibers and cellularity were higher in early osteonecrosis compared to the other two groups. DISCUSSION/CONCLUSIONS: Due to the different affinity of norepinephrine for α-adrenoceptors (high affinity) and ß-adrenoceptors (low affinity), the loss of sympathetic nerve fibers relative to sensory nerve fibers in femoral head osteonecrosis might change the femoral head blood flow (towards α-adrenergic vasoconstriction). Higher density of sensory nerve fibers and cellularity in periosteum might indicate an inflammatory response in early osteonecrosis.

Sensory innervation and inflammatory cytokines in hypertrophic synovia associated with pain transmission in osteoarthritis of the hip: a case-control study.

OBJECTIVE: To clarify the sensory innervation and inflammatory cytokines in hypertrophic synovia associated with pain transmission in OA of the hip. METHODS: A piece of the synovium was extracted during reconstruction surgery in 50 patients with OA of the hip as an inflammatory synovium and in 12 patients with femoral neck fracture as a normal synovium. Each sample was immersed in fixative solution, sectioned on a cryostat, and then processed for immunohistochemistry using antibodies as follows: neuron-specific class III ß-tubulin (TuJ-1) as a general marker for nerve fibres, calcitonin gene-related peptide (CGRP) for sensory nerve fibres, nuclear factor κB (NF-κB) for the protein complex controlling the transcription of DNA in cellular responses to painful stimuli, and TNF-α for cytokines involved in acute inflammation. The number of immunopositive cells and fibres were counted using a fluorescence microscope. RESULTS: In the inflammatory synovium of OA of the hip, TuJ-1 was positive in 46% (23 hips). Of those positive for TuJ-1, 78% (18 hips) were also positive for CGRP, but 22% (5 hips) were negative for CGRP. NF-κB was positive in 68% (34 hips). Of those positive for NF-κB, 76% (26 hips) were also positive for TNF-α, but 24% (8 hips) were negative for TNF-α. In normal synovia, all four substances were negative. CONCLUSION: We suggest sensory innervation and inflammatory cytokines in hypertrophic synovia are associated with nociception in OA of the hip. TRIAL REGISTRATION: University Hospital Medical Information Network, www.umin.ac.jp, UMIN000001335.

Increased density of sympathetic nerve fibers in metabolically activated fat tissue surrounding human synovium and mouse lymph nodes in arthritis.

OBJECTIVE: To investigate the density of sympathetic nerve fibers in and the metabolic activation of fat tissue surrounding human synovium in rheumatoid arthritis (RA)/osteoarthritis (OA) and in the draining lymph nodes of arthritic and normal mice. METHODS: Using immunofluorescence and immunohistochemistry, the density of sympathetic nerve fibers and the presence of nerve repellent factors were investigated. The metabolic activation of fat tissue was estimated by the occurrence of small-vacuole adipocytes, expression of ß3-adrenoceptors, and adipose tissue weight. RESULTS: The density of sympathetic nerve fibers was markedly increased in fat tissue surrounding RA synovium compared with that in fat tissue surrounding OA synovium. In adipose tissue adjacent to draining lymph nodes, the density of sympathetic nerve fibers was higher in arthritic mice compared with normal mice. In human synovium and mouse draining lymph nodes, the 2 sympathetic nerve repellent factors, semaphorin 3C and semaphorin 3F, were highly expressed. In arthritic compared with normal mice, the fat tissue around lymph nodes was markedly lighter, adipocytes had more fragmented lipid droplets, and fat tissue demonstrated high expression of ß3-adrenoceptors. CONCLUSION: This study demonstrated an increased density of sympathetic nerve fibers in metabolically activated fat tissue surrounding human RA synovium and the draining lymph nodes of arthritic mice. Because sympathetic neurotransmitters stimulate lipolysis, the repulsion of sympathetic nerve fibers from inflamed regions and their increased occurrence in fat tissue probably represent an adaptive program to support the proinflammatory process by releasing energy-rich substrates.

Surgical synovectomy decreases density of sensory nerve fibers in synovial tissue of non-inflamed controls and rheumatoid arthritis patients.

Surgical synovectomy is a technique to treat synovitis and pain in patients with rheumatoid arthritis (RA) resistant to DMARDs or therapy with biologics. Indication to synovectomy is subject to tight cooperation of orthopaedic surgeons and rheumatologists. It was thought that synovectomy leads to a reduction of sensory nerve fibers, called sensory denervation. Since sensory denervation after synovectomy has never been histologically tested, we aimed to investigate sensory and sympathetic innervation in synovial tissue before and after synovectomy. Eight non-inflamed control subjects and eight patients with RA were included in this study with a two-stage synovectomy approach (interval 40­50 days). Nerve fibers and cells in synovial tissue were detected and counted using immunofluorescence. Density of sympathetic nerve fibers did not change after synovectomy, whereas density of sensory nerve fibers decreased in all control subjects and seven of eight patients with RA. In parallel, the density of synovial cells increased after synovectomy in all control subjects and six of eight RA patients, which is indicative of a wound healing response. In one female RA patient, density of sensory nerve fibers increased and a very marked rise of cellular density was observed, too. This indicates that probably not all patients profit from surgical synovectomy. The majority of patients (94%) demonstrated sensory denervation after surgical synovectomy accompanied by a wound healing cell response. This study can help to explain the positive effects of surgical synovectomy which usually leads to pain reduction and improved mobility.

Synovial folds - a pain in the neck?

The synovial folds of the cervical spine are regarded as a potential source of neck pain and headache, especially following whiplash injury. Damage to the synovial folds following motor vehicle trauma has been well documented in post-mortem studies. However, methods of identifying injury to the synovial folds in the survivors of motor vehicle trauma have proven elusive to date. Recently, it has been made possible to image the synovial folds in vivo using magnetic resonance imaging. This now makes it feasible to investigate the potential involvement of synovial folds in the generation of neck pain and headache and its relief using spinal manipulation. This paper reviews critically the morphology of the synovial folds of the cervical spine that underpins the hypotheses proposed to explain their functional and clinical significance and a new system of naming and classifying the synovial folds is presented. Although there is some evidence to support the contribution of the synovial folds to neck pain, several theories have little or no support and require investigation and further evaluation. These findings have implications for understanding the anatomical basis of neck pain and headache and the rationale for the use of spinal manipulation in their management.

Catecholamine-producing cells in the synovial tissue during arthritis: modulation of sympathetic neurotransmitters as new therapeutic target.

BACKGROUND: The proinflammatory and anti-inflammatory role of the sympathetic nervous system in early and late inflammation is an unresolved paradox. A drastic loss of sympathetic nerve fibres in the synovial tissue of patients with rheumatoid arthritis (RA) has previously been demonstrated. The presence of tyrosine hydroxylase (TH)-positive cells in RA and osteoarthritis (OA) has been determined, but the role of these cells in inflammation is still unclear. OBJECTIVE: To characterise TH-positive cells in inflamed RA and OA synovial tissue and to study their role in inflammation. METHODS: Synovial samples were obtained from 32 patients with OA and 19 patients with RA and from 10 control patients. Synovial tissue samples were used for immunofluorescence staining. Synovial cells were isolated by tissue digestion and immediately used for cell culture. For in vivo experiments, collagen type-II arthritis in DBA/1J mice was induced. RESULTS: TH+ cells were present only in inflamed tissue and not in controls. Catecholamine-storing vesicles and vesicular monoamine transporter 2 (VMAT2) were identified in the synovial tissue. Experimental increase of cytoplasmic catecholamines by VMAT2 blockade strongly reduced tumour necrosis factor (TNF) independently of canonical extracellular ß-adrenergic signalling. In addition, VMAT2 blockade increased cyclic AMP (cAMP) and cAMP responsive element binding protein, responsible for TNF inhibition. In vivo, appearance of VMAT2 positive cells was confirmed. VMAT2 blockade ameliorated inflammation also in vivo. CONCLUSIONS: This study demonstrates that local catecholamine-producing cells start to replace sympathetic nerve fibres around the onset of disease, and modulation of locally produced catecholamines has strong anti-inflammatory effects in vivo and in vitro.

The unifying articular (synovial) origin of intraneural ganglia: evolution-revelation-revolution.

The pathogenesis of intraneural ganglia has been an issue of curiosity, controversy, and contention for 200 years. Three major theories have been proposed to explain their existence, namely, 1) degenerative, 2) synovial (articular), and 3) tumoral theories, each of which only partially explains the observations made by a number of investigators. As a result, differing operative strategies have been described; these generally meet with incomplete neurological recoveries and high rates of recurrence. Recent advances in magnetic resonance imaging and critical analysis of the literature have clarified the mechanisms underlying the formation and propagation of these cysts, thereby confirming the unifying articular (synovial) theory. By identifying the shared features of the typical cases and explaining atypical examples or clinical outliers, several fundamental principles have been described. These include: 1) a joint origin; 2) dissection of fluid from that joint along an articular nerve branch, extension occurring via a path of least resistance; and 3) cyst size, extent, and directionality being influenced by pressures and pressure fluxes. We believe that understanding the pathogenesis of these cysts will be reflected in optimal surgical approaches, improved outcomes, and decreased frequency, if not elimination, of recurrences. This article describes the ongoing process of critically analyzing and challenging previous observations and evidence in an effort to prove a concept and a theory.

Immunohistochemical and histological study of human uncovertebral joints: a preliminary investigation.

STUDY DESIGN: A descriptive cadaveric study. OBJECTIVE: To investigate the anatomy and innervation of the uncovertebral joint to determine if it is synovial in nature and capable of generating pain. SUMMARY OF BACKGROUND DATA: There is controversy with regard to the anatomic and histological makeup of the uncovertebral interface with some authors considering it a joint and others disc tissue. No research has investigated the presence of pain generating neurotransmitters within the uncovertebral cartilaginous and capsular tissue. METHODS: Tissue from uncovertebral capsule and cartilage was harvested for each uncovertebral surface starting at the C2-C3 to the C6-C7 cervical segment. The tissue was placed in 4% paraformaldehyde fixative, then dehydrated and embedded in paraffin. Ten micron sections were cut through the tissue blocks and mounted on slides. The tissue was rehydrated and either stained with hematoxylin and eosin (H and E) or immunostained with antisera against protein gene product 9.5 (PGP 9.5), substance P (SP), neuropeptide Y (NPY), and calcitonin gene-related peptide (CGRP). RESULTS: The sample consisted of 2 unembalmed fresh male human cadavers of a mean age of 83 years. Chondrocytes and synoviocytes were identified at the capsular tissue of each uncovertebral interface from C2-C3-C6-C7. Immunoreactivity for PGP 9.5, SP, CGRP, and NPY was observed at all uncovertebral interface levels in capsular tissue. CONCLUSION: The presence of both synoviocytes and chondrocytes has been recorded in the present study, suggesting that the uncovertebral interface is synovial in nature. Immunoreactivity to PGP 9.5, SP, CGRP, and NPY indicates the presence of nerve fibers from both the somatic and autonomic nervous systems. These findings suggest that the uncovertebral joints are potential pain generators in the cervical spine.

Adherence of intraneural ganglia of the upper extremity to the principles of the unifying articular (synovial) theory.

OBJECT: Intraneural ganglia are nonneoplastic mucinous cysts contained within the epineurium of peripheral nerves. Their pathogenesis has been controversial. Historically, the majority of authors have favored de novo formation (degenerative theory). Because of their rarity, intraneural ganglia affecting the upper limb have been misunderstood. This study was designed to critically analyze the literature and to test the hypothesis that intraneural ganglia of the upper limb act analogously to those in the lower limb, being derived from an articular source (synovial theory). METHODS: Two patients with digital intraneural cysts were included in the study. An extensive literature review of intraneural ganglia of the upper limb was undertaken to provide the historical basis for the study. RESULTS: In both cases, the digital intraneural ganglia were demonstrated to have joint connections; the one patient in whom an articular branch was not appreciated initially had evidence on postoperative MR images of persistence of intraneural cyst after simple decompression was performed. Eighty-six cases of intraneural lesions were identified in varied locations of the upper limb: the most common sites were the ulnar nerve at the elbow and wrist, occurring 38 and 22 times, respectively. Joint connections were present in only 20% of the cases published by other groups. CONCLUSIONS: The authors believe that the fundamental principles of the unifying articular (synovial) theory (that is, articular branch connections, cyst fluid following a path of least resistance, and the role of pressure fluxes) previously described to explain intraneural ganglia in the lower limb apply to those cases in the upper limb. In their opinion, the joint connection is often not identified because of the cysts' rarity, radiologists' and surgeons' inexperience, and the difficulty visualizing and demonstrating it because of the small size of the cysts. Furthermore, they believe that recurrence (subclinical or clinical) is not only underreported but also predictable after simple decompression that fails to address the articular branch. In contrast, intraneural recurrence can be eliminated with disconnection of the articular branch.

Intraneural ganglia: a clinical problem deserving a mechanistic explanation and model.

Intraneural ganglion cysts have been considered a curiosity for 2 centuries. Based on a unifying articular (synovial) theory, recent evidence has provided a logical explanation for their formation and propagation. The fundamental principle is that of a joint origin and a capsular defect through which synovial fluid escapes following the articular branch, typically into the parent nerve. A stereotypical, reproducible appearance has been characterized that suggests a shared pathogenesis. In the present report the authors will provide a mechanistic explanation that can then be mathematically tested using a preliminary model created by finite element analysis.