vasoactive-intestinal-peptide and Osteoarthritis

The importance of the nociceptive nervous system for maintaining tissue homeostasis has been known for some time, and it has also been suggested that organogenesis and tissue repair are under neuronal control. Changes in peripheral joint innervation are supposed to be partly responsible for degenerative alterations in joint tissues which contribute to development of osteoarthritis. Various resident cell types of the musculoskeletal system express receptors for sensory and sympathetic neurotransmitters, allowing response to peripheral neuronal stimuli. Among them are mesenchymal stem cells, synovial fibroblasts, bone cells and chondrocytes of different origin, which express distinct subtypes of adrenoceptors (AR), receptors for vasoactive intestinal peptide (VIP), substance P (SP) and calcitonin gene-related peptide (CGRP). Some of these cell types synthesize and secrete neuropeptides such as SP, and they are positive for tyrosine-hydroxylase (TH), the rate limiting enzyme for biosynthesis of catecholamines. Sensory and sympathetic neurotransmitters are involved in the pathology of inflammatory diseases such as rheumatoid arthritis (RA) which manifests mainly in the joints. In addition, they seem to play a role in pathogenesis of priori degenerative joint disorders such as osteoarthritis (OA). Altogether it is evident that sensory and sympathetic neurotransmitters have crucial trophic effects which are critical for joint tissue and bone homeostasis. They modulate articular cartilage, subchondral bone and synovial tissue properties in physiological and pathophysiological conditions, in addition to their classical neurological features.

Topics: Calcitonin Gene-Related Peptide; Chondrocytes; Humans; Neuropeptides; Neurotransmitter Agents; Osteoarthritis; Peripheral Nerves; Receptors, Adrenergic; Substance P; Vasoactive Intestinal Peptide

Vasoactive intestinal peptide (VIP) plays important roles in many biological functions, such as, stimulation of contractility in the heart, vasodilation, promoting neuroendocrine-immune communication, lowering arterial blood pressure, and anti-inflammatory and immune-modulatory activity. Osteoarthritis (OA) is a chronic and degenerative bone disease, which is one of the most common causes of disability and most common in both sexes as people become older. Interestingly VIP can prevent chronic cartilage damage and joint remodeling. This review article provides update information on the association of VIP and OA and its treatment. Evidences suggest that VIP is down-regulated in synovial fluid of OA, and VIP down-regulation leads to increase in the production of pro-inflammatory cytokines that might contribute to the pathogenesis of OA; however contradictory reports also exist suggesting that accumulation of VIP in joints can also contribute OA. A number of studies indicated that up-regulation of VIP can counteract the action of pro-inflammatory stimuli and alleviate the pain in OA. More clinical investigations are necessary to determine the biology of VIP and its therapeutic potential in OA that might represent the future standards of care for OA.

Topics: Cytokines; Down-Regulation; Humans; Osteoarthritis; Synovial Fluid; Up-Regulation; Vasoactive Intestinal Peptide

Bone cells respond in specific ways to various hormones and growth factors, but the biology of skeletal innervation and its physiologic significance in bone metabolism is poorly understood. With the introduction of immunohistochemical staining techniques and new molecular biology tools, the knowledge in this field has significantly improved. In this review, we update current understanding of the effects of neuropeptides on bone metabolism, specifically vasoactive intestinal peptide (VIP) and calcitonin-gene related peptide (CGRP). In addition, new information concerning the role of growth factors, such as neurotrophins, is also discussed. There is strong evidence to suggest that bone can be a target of the nervous system. Further investigations in this field will allow us to answer questions related to pre-natal development, bone growth, fracture healing, osteoporosis, osteoarthritis or neoplasias of mesoderm origin.

Topics: Bone and Bones; Bone Development; Calcitonin Gene-Related Peptide; Embryonic and Fetal Development; Fracture Healing; Humans; Immunohistochemistry; Molecular Biology; Neoplasms; Nerve Growth Factors; Neuropeptides; Osteoarthritis; Osteoporosis; Vasoactive Intestinal Peptide

Loss and dysfunction of articular chondrocytes, which disrupt the homeostasis of extracellular matrix formation and breakdown, promote the onset of osteoarthritis (OA). Targeting inflammatory pathways is an important therapeutic strategy for OA. Vasoactive intestinal peptide (VIP) is an immunosuppressive neuropeptide with potent anti-inflammatory effects; however, its role and mechanism in OA remain unclear. In this study, microarray expression profiling from the Gene Expression Omnibus database and integrative bioinformatics analyses were performed to identify differentially expressed lncRNAs in OA samples. qRT-PCR validation of the top ten different expressed lncRNAs indicated that the expression level of intergenic non-protein coding RNA 2203 (LINC02203, also named LOC727924) was the highest in OA cartilage compared to normal cartilage. Hence, the LOC727924 function was further investigated. LOC727924 was upregulated in OA chondrocytes, with a dominant sub-localization in the cytoplasm. In OA chondrocytes, LOC727924 knockdown boosted cell viability, suppressed cell apoptosis, reactive oxygen species (ROS) accumulation, increased aggrecan and collagen II, decreased matrix metallopeptidase (MMP)-3/13 and ADAM metallopeptidase with thrombospondin type 1 motif (ADAMTS)-4/5 levels, and reduced the levels of tumor necrosis factor alpha (TNF-α), interleukin 1 beta (IL-1β), and interleukin 6 (IL-6). LOC727924 could interact with the microRNA 26a (miR-26a)/ karyopherin subunit alpha 3 (KPNA3) axis by competitively targeting miR-26a for KPNA3 binding, therefore down-regulating miR-26a and upregulating KPNA3; in OA chondrocytes, miR-26a inhibition partially abolished LOC727924 knockdown effects on chondrocytes. miR-26a inhibited the nuclear translocation of p65 through targeting KPNA3 and p65 transcriptionally activated LOC727924, forming a p65-LOC727924-miR-26a/KPNA3-p65 regulatory loop to modulate OA chondrocyte phenotypes. In vitro, VIP improved OA chondrocyte proliferation and functions, down-regulated LOC727924, KPNA3, and p65 expression, and upregulated miR-26a expression; in vivo, VIP ameliorated destabilization of the medial meniscus (DMM)-induced damages on the mouse knee joint, down-regulated KPNA3, inhibited the nuclear translocation of p65. In conclusion, the p65-LOC727924-miR-26a/KPNA3-p65 regulatory loop modulates OA chondrocyte apoptosis, ROS accumulation, extracellular matrix (ECM) deposition, and inflammatory response in vitro and OA development

Topics: Animals; Apoptosis; Cartilage, Articular; Chondrocytes; Interleukin-1beta; Mice; MicroRNAs; Osteoarthritis; Reactive Oxygen Species; RNA, Long Noncoding; Vasoactive Intestinal Peptide

Osteoarthritis (OA) is the most common musculoskeletal disorder causing a great disability and a reduction in the quality of life. In OA, articular chondrocytes (AC) and synovial fibroblasts (SF) release innate-derived immune mediators that initiate and perpetuate inflammation, inducing cartilage extracellular matrix (ECM) degradation. Given the lack of therapies for the treatment of OA, in this study, we explore biomarkers that enable the development of new therapeutical approaches. We analyze the set of secreted proteins in AC and SF co-cultures by stable isotope labeling with amino acids (SILAC). We describe, for the first time, 115 proteins detected in SF-AC co-cultures stimulated by fibronectin fragments (Fn-fs). We also study the role of the vasoactive intestinal peptide (VIP) in this secretome, providing new proteins involved in the main events of OA, confirmed by ELISA and multiplex analyses. VIP decreases proteins involved in the inflammatory process (CHI3L1, PTX3), complement activation (C1r, C3), and cartilage ECM degradation (DCN, CTSB and MMP2), key events in the initiation and progression of OA. Our results support the anti-inflammatory and anti-catabolic properties of VIP in rheumatic diseases and provide potential new targets for OA treatment.

Topics: Biomarkers; Chondrocytes; Coculture Techniques; Cytokines; Disease Susceptibility; Extracellular Matrix; Fibroblasts; Humans; Inflammation Mediators; Osteoarthritis; Proteome; Proteomics; Synovial Membrane; Vasoactive Intestinal Peptide

To explore the relationship between the distribution of neuropeptides, cancellous bone microstructure and joint pain in postmenopausal women with osteoarthritis (OA) and osteoporosis (OP).. Cancellous bone of the femoral head was obtained at the time of hip arthroplasty from 20 postmenopausal women, 10 with OA and 10 with OP. Pain intensity was evaluated using the visual analog scale (VAS) before the operation. The microstructural parameters were measured with micro-CT and the neuropeptides of the cancellous bone were stained by an immunohistochemical method.. We observed that BV/TV, Tb.Th and Th.N values in the OP were significantly decreased compared to those in the OA. Immunohistochemical analysis revealed that the mean optical density (MOD) values for SP, CGRP, and VIP in the OA group were significantly higher than those in the OP, and the MOD value for NPY in the OA was significantly lower than that in the OP. We also observed that the MOD values for SP were positively correlated with AD, BV/TV, Tb.Th, Tb.N and Conn.D and negatively with MD, Tb.Sp and SMI in all patients. The MOD values for CGRP were positively correlated with AD, BV/TV and Tb.Th. MOD values for VIP were positively correlated with BV/TV and Tb.Th and negatively with SMI. The VAS score was correlated positively with the MOD values for SP, CGRP, VIP and negatively with NPY in all patients.. Neuropeptides play an important role in the pathogenesis of OA and OP, which may cause pain and influence the bone microstructure.

Topics: Aged; Arthralgia; Calcitonin Gene-Related Peptide; Cancellous Bone; Female; Humans; Middle Aged; Neuropeptide Y; Neuropeptides; Osteoarthritis; Osteoporosis, Postmenopausal; Pain Measurement; Pain Perception; Postmenopause; Substance P; Vasoactive Intestinal Peptide

ADAMTS (a disintegrin and metalloproteinase with thrombospondin motifs) family is known to play an important role in the pathogenesis of osteoarthritis (OA), working on aggrecan degradation or altering the integrity of extracellular matrix (ECM). Thus, the main purpose of our study was to define the role of vasoactive intestinal peptide (VIP) and corticotrophin-releasing factor (CRF), as immunoregulatory neuropeptides, on ADAMTS production in synovial fibroblasts (SF) from OA patients and healthy donors (HD). OA- and HD-SF were stimulated with pro-inflammatory mediators and treated with VIP or CRF. Both neuropeptides decreased ADAMTS-4, -5, -7 and -12 expressions, aggrecanase activity, glycosaminoglycans (GAG), and cartilage oligomeric matrix protein (COMP) degradation after stimulation with fibronectin fragments (Fn-fs) in OA-SF. After stimulation with interleukin-1β, VIP reduced ADAMTS-4 and -5, and both neuropeptides decreased ADAMTS-7 production and COMP degradation. Moreover, VIP and CRF reduced Runx2 and β-catenin activation in OA-SF. Our data suggest that the role of VIP and CRF on ADAMTS expression and cartilage degradation could be related to the OA pathology since scarce effects were produced in HD-SF. In addition, their effects might be greater when a degradation loop has been established, given that they were higher after stimulation with Fn-fs. Our results point to novel OA therapies based on the use of neuropeptides, since VIP and CRF are able to stop the first critical step, the loss of cartilage aggrecan and the ECM destabilization during joint degradation.

Topics: ADAMTS Proteins; Aged; Aged, 80 and over; beta Catenin; Cartilage Oligomeric Matrix Protein; Cartilage, Articular; Case-Control Studies; Core Binding Factor Alpha 1 Subunit; Corticotropin-Releasing Hormone; Endopeptidases; Female; Fibroblasts; Fibronectins; Gene Expression Regulation; Glycosaminoglycans; Humans; Interleukin-1beta; Joint Capsule; Male; Middle Aged; Osteoarthritis; Signal Transduction; Vasoactive Intestinal Peptide

Rheumatoid arthritis (RA) and osteoarthritis are two rheumatic diseases whose progression is associated with a chronic synovitis. Fibroblast-like synoviocytes (FLS) have been shown to play a pivotal role in initiating and perpetuating inflammatory and destructive processes in the rheumatoid joint. Recently, the stimulating role of IL-22 has been reported on RA-FLS contribution to joint destruction by means of the increase of proliferation and matrix-metalloproteinase-1 (MMP-1) and alarmin S100A8/A9 production. Besides, mediators potentially present in inflamed joints have been shown to increase the expression of IL-22/IL-22R1 axis, amplifying the capacity of FLS to respond to IL-22 signalling. Since targeting cytokines that govern FLS activation would allow controlling their contribution to synovial inflammation, the present study was designed to analyze the potential immunoregulatory capacity of vasoactive intestinal peptide (VIP) to counterbalance IL-22 effects on FLS behavior. Our results showed that VIP is able to downregulate the augmented expression of IL-22 specific receptor in FLS subjected to a proinflammatory milieu. Moreover, this study revealed the ability of VIP to inhibit the IL-22 stimulatory effects on proliferation as well as on expression of both MMP-1 and alarmins in RA-FLS. The present findings reinforce the potential of this neuroimmunopeptide as a therapeutic agent in rheumatic diseases.

Topics: Arthritis, Rheumatoid; Calgranulin A; Cells, Cultured; Fibroblasts; Humans; Interleukin-22; Interleukins; Joint Capsule; Matrix Metalloproteinase 1; Osteoarthritis; Receptors, Interleukin; Synovitis; Vasoactive Intestinal Peptide

Plasminogen activators are specific proteolytic enzymes implicated in a variety of basic biological processes. The expression of the urokinase plasminogen activator system components is increased in some human diseases, including osteoarthritis. We sought to study the effect of two components of the inflamed synovial microenvironment on this system, IL-1β and fibronectin fragments, elucidating whether corticotropin-releasing factor (CRF) and vasoactive intestinal peptide (VIP) neuropeptides modulate it, and analyzing the physiological consequences in joint destruction by measuring matrix metalloproteinases-9 and metalloproteinases-13 levels in osteoarthritis fibroblast-like synoviocytes. We showed that IL-1β and fibronectin fragments stimulated urokinase system contributing to the perpetuation of the destructive cascade in joint. VIP modulated, even at constitutive level, this system, also counteracting the effect of both inflammatory stimuli. However, CRF seemed to be ineffective in controlling the production of these proteinases. Moreover, VIP was able to reduce the constitutive expression of matrix metalloproteinase-13 and the levels of both matrix metalloproteinases after stimulation with the pro-inflammatory stimuli. Our results suggest that the presence of early and later inflammatory mediators, such as IL-1β and fibronectin fragments, increases the urokinase system and the matrix metalloproteinases levels. Whereas CRF did not affect this system, VIP counteracts these actions supporting its therapeutic potential for the treatment of osteoarthritis.

Topics: Cells, Cultured; Corticotropin-Releasing Hormone; Fibroblasts; Fibronectins; History, 18th Century; Humans; Inflammation Mediators; Interleukin-1beta; Joint Capsule; Matrix Metalloproteinase 13; Osteoarthritis; Urokinase-Type Plasminogen Activator; Vasoactive Intestinal Peptide

Neuropeptide Y (NPY) and vasoactive intestinal peptide (VIP) have their biological half-lives controlled by dipeptidyl peptidase IV (DPP IV/CD26). Several lines of evidence suggest the involvement of NPY in the regulation of rheumatoid arthritis (RA), and VIP has already been identified as a potent anti-inflammatory factor that reduces joint inflammation. The role of DPP IV/CD26 in the pathogenesis of RA has been indicated, but its mediator actions involving NPY and VIP have not been well investigated, so the aim of this study was to find an association between NPY, VIP, and DPP IV/CD26 in RA patients. Assessment of NPY, VIP, DPP IV/CD26 as well as some other inflammatory markers was carried out in 20 RA patients being treated with different types of drugs. Control group consisted of 18 osteoarthritis patients. Synovial fluid and serum content of investigated molecules was determined by ELISA and DPP IV/CD26 activity was measured spectrophotometrically. Immunodetection showed elevated levels of NPY and VIP in RA patients, with a significant increase in synovial fluid, while concentration and activity of DPP IV/CD26 were significantly decreased in both synovial fluid and serum. Positive correlations between serum DPP IV/CD26 concentration and activity (R = 0.6961), as well as between serum and synovial fluid concentration of VIP (R = 0.7029) were found. In RA group, NPY, VIP, and DPP IV/CD26 concentrations were not affected by the administration of drugs. The results of this study indicate a connection between elevated concentration of NPY and VIP and decreased DPP IV/CD26 activity and concentration, suggesting a potential role of these molecules in the immunomodulation of RA.

Topics: Adult; Aged; Aged, 80 and over; Arthritis, Rheumatoid; Biomarkers; Dipeptidyl Peptidase 4; Female; Humans; Male; Middle Aged; Neuropeptide Y; Osteoarthritis; Synovial Fluid; Vasoactive Intestinal Peptide

To assess the contribution of fibroblast-like synoviocytes (FLS) to the inflammatory joint microenvironment under different pathogenic stimuli and their potential to respond to interleukin (IL)-17 and to determine whether the neuroimmunomodulatory vasoactive intestinal peptide (VIP) is able to modulate IL-17 receptor (IL-17R) and related cytokines.. The effect of proinflammatory cytokines [tumor necrosis factor α (TNFα) and IL-17] and Toll-like receptor (TLR) ligands [poly(I:C) and lipopolysaccharide (LPS)] on IL-17R expression and IL-12 and IL-23 production was studied in osteoarthritis (OA)- and rheumatoid arthritis (RA)-FLS, involved in Th1/Th17 differentiation. The effect of VIP was also determined. IL-17RA, IL-17RC, IL-12p35 and IL-23p19 expression was measured by real-time polymerase chain reaction. IL-12 and IL-23 protein levels were measured by ELISA in supernatant cultures.. TNFα, LPS and poly(I:C) induced an increase in IL-17RA in RA-FLS, whereas TNFα, TNFα plus IL-17 and poly(I:C) enhanced IL-17RC transcripts in FLS. VIP diminished the upregulated expression of IL-17RA in RA-FLS following TNFα and poly(I:C). TNFα, LPS and poly(I:C) increased IL-12 and IL-23 levels in cells derived from patients presenting both pathologies. However, IL-17A DECREASED IL-12 AND AUGMENTED IL-23. VIP DECREASED IL-12P35 MRNA UPREGULATION BY POLY(I:C) AND IL-23P19 TRANSCRIPTS IN LPS-TREATED FLS.. Inflammatory cytokines and TLR ligands modulate IL-17R, IL-12 and IL-23 possibly favoring the cross talk between FLS and Th1/Th17 cells. The ability of VIP to counteract the enhancing effect of proinflammatory molecules on IL-17R and the IL-12 family of cytokines corroborates and amplifies the beneficial effect of this endogenous neuroimmunopeptide in rheumatic diseases.

Topics: Analysis of Variance; Arthritis, Rheumatoid; Cells, Cultured; Cytokines; Fibroblasts; Gene Expression Regulation; Humans; Interleukin-12; Interleukin-23; Ligands; Lipopolysaccharides; Osteoarthritis; Polydeoxyribonucleotides; Receptors, Interleukin-17; RNA, Messenger; Vasoactive Intestinal Peptide

The aim of this study was to analyze both the constitutive and induced expression and function of double-stranded RNA (dsRNA; Toll-like receptor 3 [TLR-3], retinoic acid-inducible gene I [RIG-I], and melanoma differentiation-associated gene 5 [MDA5]) and single-stranded RNA (ssRNA; TLR-7) receptors in osteoarthritis (OA) and rheumatoid arthritis (RA) fibroblast-like synoviocytes (FLS), by studying the transcription factors involved and the subsequent effects on antiviral interferon-β (IFNβ), the proinflammatory CXCL8 chemokine, and matrix metalloproteinase 3 (MMP-3). An additional goal was to study the effect of vasoactive intestinal peptide (VIP).. The expression of TLR-3, TLR-7, RIG-I, and MDA5 in cultured FLS was studied by reverse transcription-polymerase chain reaction (RT-PCR), enzyme-linked immunosorbent assay (ELISA), immunofluorescence, and Western blotting. Transcription factors were studied using the ELISA-based TransAM transcription factor kit. The expression of IFNβ, CXCL8 (interleukin-8), and MMP-3 was analyzed by RT-PCR and ELISA.. FLS expressed TLR-3, TLR-7, RIG-I, and MDA5. The expression of TLR-3 and RIG-I was higher in RA FLS, while the expression of TLR-7 and MDA5 was higher in OA FLS. Stimulation with poly(I-C) induced the activation of IFN regulatory factor 3 (IRF-3), NF-κB, and activator protein 1 (AP-1) c-Jun as well as the subsequent production of IFNβ, CXCL8, and MMP-3. VIP reduced the activation of IRF-3 and the production of IFNβ in both OA and RA FLS. Imiquimod induced the activation of NF-κB, AP-1 c-Fos, and AP-1 c-Jun and the synthesis of CXCL8 and MMP-3. VIP significantly diminished MMP-3 production only in imiquimod-treated RA FLS.. The results of this study revealed a prominent function of FLS in the recognition of both dsRNA and ssRNA, which may be present in the joint microenvironment. This study also advances the healing function of the endogenous neuroimmune peptide VIP, which inhibited TLR-3-, RIG-I-, MDA5-, and TLR-7-mediated stimulation of antiviral, proinflammatory, and joint destruction mediators.

Topics: Aminoquinolines; Arthritis, Rheumatoid; Cells, Cultured; DEAD-box RNA Helicases; Fibroblasts; Humans; Imiquimod; Interferon Inducers; Interferon Regulatory Factor-3; Interferon-beta; Interferon-Induced Helicase, IFIH1; Interleukin-8; Matrix Metalloproteinase 3; Osteoarthritis; Receptors, Retinoic Acid; RNA, Double-Stranded; Synovial Fluid; Toll-Like Receptor 3; Toll-Like Receptor 7; Transcription Factors; Vasoactive Intestinal Peptide

Since recent evidences point out the potential involvement of Toll-like receptors (TLRs) in the therapeutic effect of vasoactive intestinal peptide (VIP), the purpose of this study is to elucidate the role of VIP as a negative regulator of TLR-signaling. To this aim, we analyzed in fibroblast-like synoviocytes (FLS) from patients with rheumatoid arthritis (RA) or osteoarthritis (OA), the expression profile of TLR-pathway related molecules, as well as the alterations induced by LPS stimulation in RA-FLS and the effect of VIP treatment. Cultured FLS were obtained from patients with RA or OA. RA-FLS were next stimulated with lipopolysaccharide (LPS) in presence or absence of VIP. The gene expression profiling of molecules involved in LPS-mediated TLR4-signaling was studied by cRNA microarray analysis. Twenty three molecules involved in TLR signaling resulted over-expressed at mRNA level in basal RA-FLS compared to OA-FLS. Moreover, in RA-FLS, 23 of the analyzed genes were found to be up-regulated by LPS stimulation whereas 30 were not affected. VIP down-regulated the LPS-induced RNA expression of molecules involved in TLR signaling pathway. Up-regulation of RNA expression of CD14, MD2, TRAM, TRIF, IRAK4, TAB2, TRAF6 and TBK1 was corroborated by RT-PCR as well as the VIP regulatory effect. Increased protein levels of TRAF6, TBK1 and pIRAK1 after exposure to LPS, and the inhibitory effect of VIP, were described by Western blotting. As functional consequences, it was observed the VIP-induced impaired production of IL-6 and RANTES/CCL5 after LPS stimulation. In conclusion, VIP acts as a negative modulator of the TLR4-signaling by overturning the production of several checkpoints molecules of the cascade and thus, widening its potential therapeutic effects.

Topics: Arthritis, Rheumatoid; Chemokine CCL5; Down-Regulation; Fibroblasts; Gene Expression Profiling; Humans; Interleukin-1 Receptor-Associated Kinases; Interleukin-6; Lipopolysaccharides; Models, Immunological; Osteoarthritis; Protein Serine-Threonine Kinases; RNA, Complementary; RNA, Messenger; Signal Transduction; Synovial Membrane; TNF Receptor-Associated Factor 6; Toll-Like Receptor 4; Vasoactive Intestinal Peptide

The present study examined whether local administration of the neuropeptide vasoactive intestinal polypeptide (VIP) could modulate joint nociception in normal rat knee joints and if the VIP antagonist VIP(6-28) could ameliorate joint mechanosensitivity in an animal model of osteoarthritis (OA).. OA was induced in male Wistar rats by intra-articular injection of 3mg sodium monoiodo-acetate with a recovery period of 14 days. Electrophysiological recordings were made from knee joint primary afferents in response to normal rotation and noxious hyper-rotation of the joint both before and following close intra-arterial injection of different doses of VIP and VIP(6-28).. Local application of VIP to normal knees caused afferent firing rate to be significantly enhanced during normal rotation (up to 180% P<0.01; n=17) and during hyper-rotation (up to 37% P<0.01; n=17) of the knee. VIP-induced sensitization was blocked by pre-administration of the VIP receptor antagonist VIP(6-28). In the OA group, application of VIP(6-28) caused afferent firing rate to be significantly reduced during normal rotation (up to 45% P<0.05; n=17) and during hyper-rotation (up to 34% P<0.01; n=15) of the knee joint.. These findings indicate that VIP is involved in peripheral sensitization of knee joint afferents especially in response to normal joint movements. OA-induced sensitization of knee joint afferents was inhibited by local administration of VIP(6-28), indicating that VIP is released into OA knee joints, potentially contributing to joint pain. As such, VIP(6-28) may prove to be a beneficial agent for the treatment of arthritis pain.

Topics: Animals; Disease Models, Animal; Dose-Response Relationship, Drug; Electrophysiology; Hindlimb; Injections, Intra-Arterial; Joints; Male; Movement; Nerve Fibers; Neurons, Afferent; Osteoarthritis; Pain; Peptide Fragments; Rats; Rats, Wistar; Receptors, Vasoactive Intestinal Peptide; Rotation; Vasoactive Intestinal Peptide

In the present study, we have investigated the in vitro effect of calcitonin-related peptide (CGRP), neuropeptide Y (NPY), substance P (SP) and vasoactive intestinal peptide (VIP) at concentrations of 10(-8), 10(-9) and 10(-10) M on the production of different proinflammatory cytokines or chemokines such as IL-1beta, IL-6 and TNFalpha by peripheral whole blood cells from patients with rheumatoid arthritis, as well as from osteoarthritis patients studied as a control group without immunoinflammatory background. We have found that CGRP, NPY, SP and VIP stimulated significantly the production of those cytokines and chemokines in rheumatoid arthritis patients. In general, the stimulation was higher at the 10(-9) M concentration, with SP and VIP, and in rheumatoid arthritis patients compared to osteoarthritis ones. Neuropeptides did not significantly modify the LPS-induced cytokine production by whole blood cells. The results indicate that physiological concentrations of the neuropeptides studied can modulate the inflammatory and immunological response, stimulating significantly the production of inflammatory cytokines by human whole blood cells in rheumatoid arthritis patients, as well as, in a minor way, in osteoarthritis patients.

Topics: Aged; Arthritis, Rheumatoid; Calcitonin Gene-Related Peptide; Cytokines; Dose-Response Relationship, Drug; Female; Humans; Interleukin-1; Interleukin-6; Lipopolysaccharides; Male; Middle Aged; Neuropeptide Y; Osteoarthritis; Peptides; Substance P; Tumor Necrosis Factor-alpha; Vasoactive Intestinal Peptide

To study the effect of experimentally induced osteoarthrosis, or non-inflammatory degenerative changes, on the innervation of the sheep temporomandibular joint (TMJ) through the use of indirect immunohistochemistry and image analysis quantification.. Bilateral condylar scarification was performed in 8 sheep, which were killed at 16 weeks post-operation; 3 unoperated sheep served as controls. Tissues from 8 osteoarthrotic joints and 4 control joints were processed for the immunostaining with antisera for protein gene product 9.5 (PGP 9.5), substance P (SP), calcitonin gene-related peptide (CGRP), neuropeptide Y (NPY), vasoactive intestinal peptide (VIP), and tyrosine hydroxylase (TH). An additional 10 joints were decalcified to study the morphologic changes induced by the condylar abrasion.. Osteoarthrotic changes were commonly seen in the anterior and lateral regions of the joint and included fibrosis, peripheral osteophyte formation, cysts, and erosion of articular surfaces. In the osteoarthrotic joints, the distribution of PGP 9.5-, CGRP-, and SP-immunoreactive (IR) nerve fibers was similar to that observed for control joints in the capsule, synovium, and capsule/disc junction. There were statistically detectable decreases in the percent surface area of IR nerve fibers in the capsule for both PGP 9.5 and CGRP in arthrotic joints compared with control joints. The lateral and anterior regions of the capsule had greater density of PGP 9.5- and CGRP-IR nerve fibers than other parts of the capsule in both control and arthrotic joints, and the medial capsule was poorly innervated in all joints. Immunostaining for substance P was always weaker.. This study suggests that while inflammatory arthritis has a marked influence on the density of sensory and autonomic nerve fibers in synovium in a variety of joints in different species, experimentally induced non-inflammatory osteoarthrosis in the sheep TMJ also leads to a depletion of the density of nerve fibers in the capsule, especially in the lateral part of the joint. Further work is required to determine whether other parts of the joint, such as synovium and marrow, respond differently to experimentally induced osteoarthrosis.

Topics: Analysis of Variance; Animals; Autonomic Nervous System; Calcitonin Gene-Related Peptide; Cicatrix; Cysts; Disease Models, Animal; Fibrosis; Image Processing, Computer-Assisted; Immunohistochemistry; Joint Capsule; Male; Mandibular Condyle; Nerve Fibers; Nerve Tissue Proteins; Neurons, Afferent; Neuropeptide Y; Osteoarthritis; Sheep; Statistics, Nonparametric; Substance P; Synovial Membrane; Temporomandibular Joint; Temporomandibular Joint Disc; Temporomandibular Joint Disorders; Thiolester Hydrolases; Tyrosine 3-Monooxygenase; Ubiquitin Thiolesterase; Vasoactive Intestinal Peptide

Immunoreactive plasma and synovial fluid concentrations of calcitonin gene-related peptide II (CGRP II), substance P and vasoactive intestinal peptide (VIP) were measured in patients with osteoarthritis, gout and rheumatoid arthritis. Significantly higher levels of CGRP II and substance P-like immunoreactivity levels in synovial fluid were found in gout as well as CGRP II, substance P and VIP-like immunoreactivities in rheumatoid arthritis when compared to those in osteoarthritis. Plasma CGRP II, substance P and VIP-like immunoreactivity levels showed no significant differences among patients in the three different groups of arthritis. Our results suggest that these neuropeptides released from peripheral nerve endings into the synovial cavity probably play a pathogenic role in human joint inflammation.

Topics: Adult; Aged; Aged, 80 and over; Arthritis, Rheumatoid; Calcitonin Gene-Related Peptide; Female; Gout; Humans; Male; Middle Aged; Osteoarthritis; Radioimmunoassay; Substance P; Synovial Fluid; Vasoactive Intestinal Peptide

Arthroscopy was performed on 18 patients (19 joints) with temporomandibular joint arthropathy. Arthroscopic investigation revealed that 12 patients had disk derangement, including 3 patients with rheumatoid arthritis. Six patients had osteoarthrosis, including one patient with rheumatoid arthritis. Synovial fluid content of substance P-like immunoreactivity (SP-LI), neurokinin A (NKA-LI), calcitonin gene-related peptide (CGRP-LI), neuropeptide Y (NPY-LI) and vasoactive intestinal polypeptide (VIP-LI) were analysed using radioimmunoassay technique. All peptides analysed were found, although in various concentrations, in the different joints. There were no significant differences in concentrations of the peptides in the synovial fluid between patients in the various groups. No significant correlation was found between clinical symptoms and signs, arthroscopic findings, or use of analgesic/anti-inflammatory medication versus concentrations of peptides in the synovial fluid. In comparison with earlier findings in the knee joint significantly higher concentrations of SP-LI, CGRP-LI and NPY-LI were found in the TMJ.

Topics: Adult; Aged; Aged, 80 and over; Arthritis, Rheumatoid; Arthroscopy; Calcitonin Gene-Related Peptide; Cartilage, Articular; Female; Humans; Male; Middle Aged; Neurokinin A; Neuropeptide Y; Neuropeptides; Osteoarthritis; Substance P; Synovial Fluid; Synovitis; Temporomandibular Joint; Temporomandibular Joint Disorders; Vasoactive Intestinal Peptide