Dataset Information

Targeting VEGF and Its Receptors for the Treatment of Osteoarthritis and Associated Pain.

ABSTRACT: Increased vascular endothelial growth factor (VEGF) levels are associated with osteoarthritis (OA) progression. Indeed, VEGF appears to be involved in OA-specific pathologies including cartilage degeneration, osteophyte formation, subchondral bone cysts and sclerosis, synovitis, and pain. Moreover, a wide range of studies suggest that inhibition of VEGF signaling reduces OA progression. This review highlights both the potential significance of VEGF in OA pathology and pain, as well as potential benefits of inhibition of VEGF and its receptors as an OA treatment. With the emergence of the clinical use of anti-VEGF therapy outside of OA, both as high-dose systemic treatments and low-dose local treatments, these particular therapies are now more widely understood. Currently, there is no established disease-modifying drug available for patients with OA, which warrants continued study of the inhibition of VEGF signaling in OA, as stand-alone or adjuvant therapy. © 2016 American Society for Bone and Mineral Research.

SUBMITTER: Hamilton JL

PROVIDER: S-EPMC4863467 | biostudies-literature | 2016 May

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Targeting VEGF and Its Receptors for the Treatment of Osteoarthritis and Associated Pain.

Hamilton John L JL Nagao Masashi M Levine Brett R BR Chen Di D Olsen Bjorn R BR Im Hee-Jeong HJ

Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 20160408 5

Increased vascular endothelial growth factor (VEGF) levels are associated with osteoarthritis (OA) progression. Indeed, VEGF appears to be involved in OA-specific pathologies including cartilage degeneration, osteophyte formation, subchondral bone cysts and sclerosis, synovitis, and pain. Moreover, a wide range of studies suggest that inhibition of VEGF signaling reduces OA progression. This review highlights both the potential significance of VEGF in OA pathology and pain, as well as potential ...[more]

PMID: 27163679

Similar Datasets

Project description:Osteoarthritis (OA) of the joint is a prevalent disease accompanied by chronic, debilitating pain. Recent clinical evidence has demonstrated that central sensitization contributes to OA pain. An improved understanding of how OA joint pathology impacts upon the central processing of pain is crucial for the identification of novel analgesic targets/new therapeutic strategies. Inhibitory cannabinoid 2 (CB2) receptors attenuate peripheral immune cell function and modulate central neuro-immune responses in models of neurodegeneration. Systemic administration of the CB2 receptor agonist JWH133 attenuated OA-induced pain behaviour, and the changes in circulating pro- and anti-inflammatory cytokines exhibited in this model. Electrophysiological studies revealed that spinal administration of JWH133 inhibited noxious-evoked responses of spinal neurones in the model of OA pain, but not in control rats, indicating a novel spinal role of this target. We further demonstrate dynamic changes in spinal CB2 receptor mRNA and protein expression in an OA pain model. The expression of CB2 receptor protein by both neurones and microglia in the spinal cord was significantly increased in the model of OA. Hallmarks of central sensitization, significant spinal astrogliosis and increases in activity of metalloproteases MMP-2 and MMP-9 in the spinal cord were evident in the model of OA pain. Systemic administration of JWH133 attenuated these markers of central sensitization, providing a neurobiological basis for analgesic effects of the CB2 receptor in this model of OA pain. Analysis of human spinal cord revealed a negative correlation between spinal cord CB2 receptor mRNA and macroscopic knee chondropathy. These data provide new clinically relevant evidence that joint damage and spinal CB2 receptor expression are correlated combined with converging pre-clinical evidence that activation of CB2 receptors inhibits central sensitization and its contribution to the manifestation of chronic OA pain. These findings suggest that targeting CB2 receptors may have therapeutic potential for treating OA pain.

Project description:BackgroundC-C chemokine receptor 2 (CCR2) signaling plays a key role in pain associated with experimental murine osteoarthritis (OA) after destabilization of the medial meniscus (DMM). Here, we aimed to assess if CCR2 expressed by intra-articular sensory neurons contributes to knee hyperalgesia in the early stages of the model.MethodsDMM surgery was performed in the right knee of 10-week-old male wild-type (WT), Ccr2 null, or Ccr2RFP C57BL/6 mice. Knee hyperalgesia was measured using a Pressure Application Measurement device. CCR2 receptor antagonist (CCR2RA) was injected systemically (i.p.) or intra-articularly (i.a.) at different times after DMM to test its ability to reverse knee hyperalgesia. In vivo Ca2+ imaging of the dorsal root ganglion (DRG) was performed to assess sensory neuron responses to CCL2 injected into the knee joint cavity. CCL2 protein in the knee was measured by ELISA. Ccr2RFP mice and immunohistochemical staining for the pan-neuronal marker, protein gene product 9.5 (PGP9.5), or the sensory neuron marker, calcitonin gene-related peptide (CGRP), were used to visualize the location of CCR2 on intra-articular afferents.ResultsWT, but not Ccr2 null, mice displayed knee hyperalgesia 2-16 weeks after DMM. CCR2RA administered i.p. alleviated established hyperalgesia in WT mice 4 and 8 weeks after surgery. Intra-articular injection of CCL2 excited sensory neurons in the L4-DRG, as determined by in vivo calcium imaging; responses to CCL2 increased in mice 20 weeks after DMM. CCL2, but not vehicle, injected i.a. rapidly caused transient knee hyperalgesia in naïve WT, but not Ccr2 null, mice. Intra-articular CCR2RA injection also alleviated established hyperalgesia in WT mice 4 and 7 weeks after surgery. CCL2 protein was elevated in the knees of both WT and Ccr2 null mice 4 weeks after surgery. Co-expression of CCR2 and PGP9.5 as well as CCR2 and CGRP was observed in the lateral synovium of naïve mice; co-expression was also observed in the medial compartment of knees 8 weeks after DMM.ConclusionsThe findings suggest that CCL2-CCR2 signaling locally in the joint contributes to knee hyperalgesia in experimental OA, and it is in part mediated through direct stimulation of CCR2 expressed by intra-articular sensory afferents.

Project description:Osteoarthritis is a common presentation in primary care, and non-selective non-steroidal anti-inflammatory drugs (sometimes also referred to as traditional NSAIDs or tNSAIDs) and selective cyclo-oxygenase 2 inhibitors (COX-2 inhibitors) are commonly used to treat it. The UK's National Institute for Health and Clinical Excellence (NICE) recommends taking patient risk factors into account when selecting a tNSAID or a COX-2 inhibitor, but GPs have lacked practical guidance on assessing patient risk.A multi-disciplinary group that included primary care professionals (PCPs) developed an evidence-based consensus statement with an accompanying flowchart that aimed at providing concise and specific guidance on NSAID use in osteoarthritis treatment. An open invitation to meet and discuss the issue was made to relevant healthcare professionals in South Yorkshire. A round table meeting was held that used a modified nominal group technique, aimed at generating opinions and ideas from all stakeholders in the consensus process. A draft developed from this meeting went through successive revisions until a consensus was achieved.Four statements on the use of tNSAIDs and COX-2 inhibitors (and an attached category of evidence) were agreed: 1) tNSAIDs are effective drugs in relieving pain and immobility associated with osteoarthritis. COX-2 inhibitors are equally effective; 2) tNSAIDs and COX-2 inhibitors vary in their potential gastrointestinal, liver, and cardio-renal toxicity. This risk varies between individual treatments within both groups and is increased with dose and duration of treatment; 3) COX-2 inhibitors are associated with a significantly lower gastrointestinal toxicity compared to tNSAIDs. Co-prescribing of aspirin reduces this advantage; 4) PPIs should always be considered with a tNSAID and with a COX-2 inhibitor in higher GI risk patients. An accompanying flowchart to guide management was also agreed.Individual patient risk is an important factor in choice of treatment for patients with osteoarthritis and the consensus statement developed offers practical guidance for GPs and others in primary care. Where there are clinical uncertainties, guidance developed and agreed by local clinicians has a role to play in improving patient management.

Dataset Information

Targeting VEGF and Its Receptors for the Treatment of Osteoarthritis and Associated Pain.

Publications

Targeting VEGF and Its Receptors for the Treatment of Osteoarthritis and Associated Pain.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets