Norepinephrine modulates osteoarthritic chondrocyte metabolism and inflammatory responses

Lorenz, Julia; Schäfer, Nicole; Bauer, Robert; Jenei-Lanzl, Zsuzsa; Springorum, R.; Grässel, Susanne

doi:10.1016/j.joca.2015.08.007

Cited by 49 publications

(62 citation statements)

References 39 publications

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“…Various degrees of local inflammation might therefore evoke changes in innervation pattern of OA synovium comparable to RA and might also induce TH expression in joint cells, providing a local source for NE as has been shown for synovial macrophages [49]. In this line, our group demonstrated that chondrocytes of OA cartilage express TH in all three cartilage zones with the weakest staining intensity in the deep zone [54]. With that, the cells possess the prerequisite to induce an anti-inflammatory response in their immediate environment, perhaps serving as a primarily protective measure in OA.…”

Section: Sensory and Sympathetic Nerve Fibers In Osteoarthritic Jomentioning

confidence: 82%

“…An earlier study performed by Lai et al confirmed only the expression of β2-AR on growth plate chondrocytes from ribs of embryonic E18.5 mice [72]. Studies on cartilage tissue explants isolated from OA patients after endoprothetic surgery and on chondrogenic progenitor cells obtained from human OA cartilage explants revealed that also under degenerative conditions, β2-AR and α2-AR are present [54,70]. As it is suggested that many biomechanical pathways in OA pathogenesis are altered, it is conceivable that β2-AR might contribute to disease development related to overloading of cartilage, because β2-adrenergic drugs have been shown to influence mechanical events in bone tissue [21,73].…”

Section: Sensory and Sympathetic Neurotransmitters And Their Recepmentioning

confidence: 99%

“…However, not so much is known about the effect of inflammation on chondrocyte function in OA. For instance, Lorenz and colleagues investigated the effects of NE together with an inflammatory stimulus like IL-1β, simulating an early OA microenvironment [54]. NE in high concentrations decreased chondrocyte proliferation via β2-AR signaling.…”

Section: Sensory and Sympathetic Neurotransmitters And Their Recepmentioning

confidence: 99%

“…On bone marrow-derived macrophages, osteoclasts (white circles), and chondrocytes from OA cartilage (red fluorescence, detection by Alexa568-coupled secondary antibody) as well as osteoblasts (green fluorescence, detection by Alexa488-coupled secondary antibody) we detected receptors for SP (neurokinin 1 receptor, NK1-R) and calcitonin gene-related peptide, CGRP (calcitonin receptor-like receptor, CRLR). Receptors for sympathetic neurotransmitters expressed in chondrocytes and bone marrow-derived macrophages (BMM)/osteoclasts were previously published [54,62]. SP = Substance P.…”

Section: Figurementioning

confidence: 99%

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Peripheral Nerve Fibers and Their Neurotransmitters in Osteoarthritis Pathology

Grässel

Muschter

2017

IJMS

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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.

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Section: Sensory and Sympathetic Nerve Fibers In Osteoarthritic Jomentioning

confidence: 82%

Section: Sensory and Sympathetic Neurotransmitters And Their Recepmentioning

confidence: 99%

Section: Sensory and Sympathetic Neurotransmitters And Their Recepmentioning

confidence: 99%

Section: Figurementioning

confidence: 99%

See 2 more Smart Citations

Peripheral Nerve Fibers and Their Neurotransmitters in Osteoarthritis Pathology

Grässel

Muschter

2017

IJMS

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“…These pathways consist of adrenaline signaling, alpha-linolenic acid and retinol metabolism, vitamin A deficiency, and amino acid degradation. Adrenaline signaling through norepinephrine (m/z: 170.0807, adduct: M+H + ) previously has been linked to increased apoptosis and the reduction of chondrocyte proliferation in OA cell cultures (Lorenz et al, 2016). Anti-inflammatory and tissue protective effects have been shown in 1:1 to 6:1 ratios of linoleic acid (LA) to alpha-linolenic acid (ALA) inhibiting the decomposition of connective tissue such as type II collagen compared to higher ratios ( e.g.…”

Section: Discussionmentioning

confidence: 99%

Metabolic responses induced by compression of chondrocytes in variable-stiffness microenvironments

McCutchen

Zignego

June

2017

Journal of Biomechanics

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Cells sense and respond to mechanical loads in a process called mechanotransduction. These processes are disrupted in the chondrocytes of cartilage during joint disease. A key driver of cellular mechanotransduction is the stiffness of the surrounding matrix. Many cells are surrounded by extracellular matrix that allows for tissue mechanical function. Although prior studies demonstrate that extracellular stiffness is important in cell differentiation, morphology and phenotype, it remains largely unknown how a cell’s biological response to cyclical loading varies with changes in surrounding substrate stiffness. Understanding these processes is important for understanding cells that are cyclically loaded during daily in vivo activities (e.g. chondrocytes and walking). This study uses high-performance liquid chromatography - mass spectrometry to identify metabolomic changes in primary chondrocytes under cyclical compression for 0–30 minutes in low- and high- stiffness environments. Metabolomic analysis reveals metabolites and pathways that are sensitive to substrate stiffness, duration of cyclical compression, and a combination of both suggesting changes in extracellular stiffness in vivo alter mechanosensitive signaling. Our results further suggest that cyclical loading minimizes matrix deterioration and increases matrix production in chondrocytes. This study shows the importance of modeling in vivo stiffness with in vitro models to understand cellular mechanotransduction.

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Neuropeptide Y Acts Directly on Cartilage Homeostasis and Exacerbates Progression of Osteoarthritis Through NPY2R

Kang

Liu

Feng

et al. 2020

Journal of Bone and Mineral Research

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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.

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Norepinephrine modulates osteoarthritic chondrocyte metabolism and inflammatory responses

Cited by 49 publications

References 39 publications

Peripheral Nerve Fibers and Their Neurotransmitters in Osteoarthritis Pathology

Peripheral Nerve Fibers and Their Neurotransmitters in Osteoarthritis Pathology

Metabolic responses induced by compression of chondrocytes in variable-stiffness microenvironments

Neuropeptide Y Acts Directly on Cartilage Homeostasis and Exacerbates Progression of Osteoarthritis Through NPY2R

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