neuropeptide-y and Osteoarthritis

Neuropeptide Y (NPY) is known to regulate bone homeostasis; however, its functional role as a risk factor during osteoarthritis (OA) remains elusive. In this study, we aim to investigate the direct effect of NPY on degradation of cartilage and progression of OA and explore the molecular events involved. NPY was overexpressed in human OA cartilage accompanied with increased expression of NPY1 receptor (NPY1R) and NPY2 receptor (NPY2R). Stressors such as cold exposure resulted in the peripheral release of NPY from sympathetic nerves, which in turn promoted upregulation of NPY and NPY2R in articular cartilage in vivo. Intra-articular administration of NPY significantly promoted chondrocyte hypertrophy and cartilage matrix degradation, with a higher OARSI score than that of control mice, whereas inhibition of NPY2R but not NPY1R with its specific antagonist remarkably ameliorated NPY-mediated effects. Moreover, NPY activated mTORC1 pathway in articular chondrocytes, whereas the administration of rapamycin (an mTORC1 inhibitor) in vitro abrogated NPY-mediated effects. Mechanistically, mTORC1 downstream kinase S6K1 interacted with and phosphorylated SMAD1/5/8 and promoted SMAD4 nuclear translocation, resulting in upregulation of Runx2 expression to promote chondrocyte hypertrophy and cartilage degradation. In conclusion, our findings provided the direct evidence and the crucial role of NPY in cartilage homeostasis. © 2020 American Society for Bone and Mineral Research.

Topics: Animals; Cartilage, Articular; Chondrocytes; Homeostasis; Mice; Neuropeptide Y; Osteoarthritis; Receptors, Neuropeptide Y

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

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

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

Forty-one patients (37 female and four male) with signs and symptoms of temporomandibular joint arthritis, were separated into two diagnostic groups (group I: inflammatory; group II: degenerative/non-specific joint disease). They were examined clinically, fluid was aspirated from the joint with saline and venous blood samples were collected at the same time. The joint fluid and plasma samples were analysed for neuropeptide-like immunoreactivity, i.e. neuropeptide Y (NPY-LI), calcitonin gene-related peptide (CGRP-LI), substance P (SP-LI) and neurokinin A (NKA-LI), using competitive radioimmunoassays. The aim was to investigate any co-variation of the peptides in the joint fluid and plasma. In group I, the median values of peptide concentrations in joint fluid were SP-LI = 129, CGRP-LI = 75, NKA-LI = 36 and NPY-LI = 676 pmol/l and in group II, SP-LI = 52, CGRP-LI = 64, NKA-LI = 45 and NPY-LI = 318 pmol/l. There were no significant differences between the groups for peptide concentrations. In group I, all the neuropeptides were strongly correlated. In group II, SP-LI and NKA-LI were strongly correlated while CGRP-LI was weakly correlated with NPY-LI and NKA-LI. Multiple step-wise regression analysis showed that most of the variation in NPY-LI, CGRP-LI and SP-LI in group I was explained by NKA-LI, but the regression did not reach statistical significance in group II.

Topics: Adult; Aged; Arthritis; Arthritis, Psoriatic; Arthritis, Rheumatoid; Calcitonin Gene-Related Peptide; Female; Humans; Male; Middle Aged; Neurokinin A; Neuropeptide Y; Osteoarthritis; Regression Analysis; Spondylitis, Ankylosing; Substance P; Synovial Fluid; Temporomandibular Joint Disorders

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