Blockade of vascular endothelial growth factor receptor-1 (Flt-1), reveals a novel analgesic for osteoarthritis-induced joint pain

Das, Vaskar; Kc, Ranjan; Li, Xin; O-Sullivan, InSug; Wijnen, André J. van; Pytowski, Bronislaw; Applegate, Daniel T.; Votta-Velis, Gina; Ripper, Richard; Park, Thomas J.; Im, Hee Jeong

doi:10.1016/j.genrep.2018.03.008

Cited by 19 publications

(34 citation statements)

References 22 publications

(66 reference statements)

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“…For example, NGF is a well‐known potent inducer of VEGF and VEGF strongly arguments the expression of NGF. For instance, the NGF/TrkA axis highly stimulates VEGFR‐1 expression in the DRG sensory neurons (Das et al, ). VEGF is capable of directly modulating the excitability of primary sensory neurons (Selvaraj et al, ); it is likely that stimulation of one of these factors: either NGF or VEGF signaling may be sufficient enough to trigger and develop back pain sensation in the injured discs.…”

Section: Discussionmentioning

confidence: 99%

“…For example, Selvaraj et al (2015) demonstrated that VEGFR-1/Flt-1 could directly regulate the excitability of sensory neurons and the expression of neuropeptides associated with pain in the dorsal root ganglia (DRG). More recently, Das et al (2018) showed the distinct role of VEGFR-1, but not VEGFR-2, in knee OA pain transmission. Therefore, we hypothesize that VEGFR-1 contributes to the nociceptive pain signal transduction during intervertebral disc (IVD) degeneration.…”

Section: Introductionmentioning

confidence: 99%

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Absence of VEGFR‐1/Flt‐1 signaling pathway in mice results in insensitivity to discogenic low back pain in an established disc injury mouse model

Qiu

Shi

Anbazhagan

et al. 2019

Journal Cellular Physiology

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Although degenerative disc disease (DDD) and related low back pain (LBP) are growing public health problems, the underlying disease mechanisms remain unclear. An increase in the vascular endothelial growth factor (VEGF) levels in DDD has been reported. This study aimed to examine the role of VEGF receptors (VEGFRs) in DDD, using a mouse model of DDD. Progressive DDD was induced by anterior stabbing of lumbar intervertebral discs in wild type (WT) and VEGFR‐1 tyrosine‐kinase deficient mice (vegfr‐1TK−/−). Pain assessments were performed weekly for 12 weeks. Histological and immunohistochemical assessments were made for discs, dorsal root ganglions, and spinal cord. Both vegfr‐1TK−/− and WT mice presented with similar pathological changes in discs with an increased expression of inflammatory cytokines and matrix‐degrading enzymes. Despite the similar pathological patterns, vegfr‐1TK−/− mice showed insensitivity to pain compared with WT mice. This insensitivity to discogenic pain was related to lower levels of pain factors in the discs and peripheral sensory neurons and lower spinal glial activation in the vegfr‐1TK−/− mice than in the WT mice. Exogenous stimulation of bovine disc cells with VEGF increased inflammatory and cartilage degrading enzyme. Silencing vegfr‐1 by small‐interfering‐RNA decreased VEGF‐induced expression of pain markers, while silencing vegfr‐2 decreased VEGF‐induced expression of inflammatory and metabolic markers without changing pain markers. This suggests the involvement of VEGFR‐1 signaling specifically in pain transmission. Collectively, our results indicate that the VEGF signaling is involved in DDD. Particularly, VEGFR‐1 is critical for discogenic LBP transmission independent of the degree of disc pathology.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Absence of VEGFR‐1/Flt‐1 signaling pathway in mice results in insensitivity to discogenic low back pain in an established disc injury mouse model

Qiu

Shi

Anbazhagan

et al. 2019

Journal Cellular Physiology

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“… 77 Notably, systemic anti-Flt-1 antibody treatment reversed mechanical and thermal hyperalgesia. 77 In a mouse knee OA model, IT inhibition of Flt-1 reduced mechanical hyperalgesia, 21 indicating a CNS role of Flt-1 in pain transmission.…”

Section: Discussionmentioning

confidence: 99%

Differential expression of cerebrospinal fluid neuroinflammatory mediators depending on osteoarthritis pain phenotype

Bjurström

Bodelsson

Montgomery

et al. 2020

Pain

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Neuroinflammation is implicated in the development and maintenance of persistent pain states, but there are limited data linking cerebrospinal fluid (CSF) inflammatory mediators with neurophysiological pain processes in humans. In a prospective observational study, CSF inflammatory mediators were compared between patients with osteoarthritis (OA) who were undergoing total hip arthroplasty due to disabling pain symptoms (n = 52) and pain-free comparison controls (n = 30). In OA patients only, detailed clinical examination and quantitative sensory testing were completed. Cerebrospinal fluid samples were analyzed for 10 proinflammatory mediators using Meso Scale Discovery platform. Compared to controls, OA patients had higher CSF levels of interleukin 8 (IL-8) (P = 0.002), intercellular adhesion molecule 1 (P = 0.007), and vascular cell adhesion molecule 1 (P = 0.006). Osteoarthritis patients with central sensitization possibly indicated by arm pressure pain detection threshold <250 kPa showed significantly higher CSF levels of Fms-related tyrosine kinase 1 (Flt-1) (P = 0.044) and interferon gamma-induced protein 10 (IP-10) (P = 0.024), as compared to subjects with PPDT above that threshold. In patients reporting pain numerical rating scale score ≥3/10 during peripheral venous cannulation, Flt-1 was elevated (P = 0.025), and in patients with punctate stimulus wind-up ratio ≥2, CSF monocyte chemoattractant protein 1 was higher (P = 0.011). Multiple logistic regression models showed that increased Flt-1 was associated with central sensitization, assessed by remote-site PPDT and peripheral venous cannulation pain, and monocyte chemoattractant protein-1 with temporal summation in the area of maximum pain. Multiple proinflammatory mediators measured in CSF are associated with persistent hip OA-related pain. Pain phenotype may be influenced by specific CSF neuroinflammatory profiles.

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“…In the knee OA, mAbs have shown promising results on mice models and in vitro studies. Targeting of the VEGF monoclonal antibody, including MF-1 (mAb to VEGFR1) and DC101 (mAb to VEGFR2), showed modulatory effects in OA knee pain in mice when applied intraarticularly [ 241 ]. A potential therapeutic option for treating chronic pain, in patients with symptomatic knee OA, could be Tanezumab, a mAb that blocks the Nerve Growth Factor (NGF) from activating Tropomyosin-receptor-kinase (Trk) receptors on nociceptive neurons [ 242 ].…”

Section: Future Strategies For Oa Managementmentioning

confidence: 99%

Knee Osteoarthritis: A Review of Pathogenesis and State-Of-The-Art Non-Operative Therapeutic Considerations

Primorac

Molnar

Rod

et al. 2020

Genes

258

176

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Being the most common musculoskeletal progressive condition, osteoarthritis is an interesting target for research. It is estimated that the prevalence of knee osteoarthritis (OA) among adults 60 years of age or older is approximately 10% in men and 13% in women, making knee OA one of the leading causes of disability in elderly population. Today, we know that osteoarthritis is not a disease characterized by loss of cartilage due to mechanical loading only, but a condition that affects all of the tissues in the joint, causing detectable changes in tissue architecture, its metabolism and function. All of these changes are mediated by a complex and not yet fully researched interplay of proinflammatory and anti-inflammatory cytokines, chemokines, growth factors and adipokines, all of which can be measured in the serum, synovium and histological samples, potentially serving as biomarkers of disease stage and progression. Another key aspect of disease progression is the epigenome that regulates all the genetic expression through DNA methylation, histone modifications, and mRNA interference. A lot of work has been put into developing non-surgical treatment options to slow down the natural course of osteoarthritis to postpone, or maybe even replace extensive surgeries such as total knee arthroplasty. At the moment, biological treatments such as platelet-rich plasma, bone marrow mesenchymal stem cells and autologous microfragmented adipose tissue containing stromal vascular fraction are ordinarily used. Furthermore, the latter two mentioned cell-based treatment options seem to be the only methods so far that increase the quality of cartilage in osteoarthritis patients. Yet, in the future, gene therapy could potentially become an option for orthopedic patients. In the following review, we summarized all of the latest and most important research in basic sciences, pathogenesis, and non-operative treatment.

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Blockade of vascular endothelial growth factor receptor-1 (Flt-1), reveals a novel analgesic for osteoarthritis-induced joint pain

Cited by 19 publications

References 22 publications

Absence of VEGFR‐1/Flt‐1 signaling pathway in mice results in insensitivity to discogenic low back pain in an established disc injury mouse model

Absence of VEGFR‐1/Flt‐1 signaling pathway in mice results in insensitivity to discogenic low back pain in an established disc injury mouse model

Differential expression of cerebrospinal fluid neuroinflammatory mediators depending on osteoarthritis pain phenotype

Knee Osteoarthritis: A Review of Pathogenesis and State-Of-The-Art Non-Operative Therapeutic Considerations

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