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, Sujun; Shi, Changgui; Anbazhagan, Arivarasu Natarajan; Das, Vaskar; Arora, Vipin; Kc, Ranjan; Li, Xin; O-Sullivan, InSug; Wijnen, André J. van; Chintharlapalli, Sudhakar; Gott-Velis, Gina; Richard, Ripper; Mwale, Fackson; Shibuya, Masabumi; Min, Shaoxiong; Im, Hee-Jeong

doi:10.1002/jcp.29416

Cited by 19 publications

(12 citation statements)

References 55 publications

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“…These findings suggest that IA injection of pazopanib inhibits VEGFR1 at the level of peripheral sensory neurons to attenuate OA-induced neuronal plasticity, consequently blocking joint pain sensation. Consistent with results from our group and others, transgenic mice lacking an RTK signaling domain for VEGFR1 ( Vegfr1-Tk-/-), VEGFR1 signaling in nociceptive neurons ( SNS-Vegfr1-/-), or VEGFR1 signaling in sensory neurons ( Adv-Vegfr1-/- ) showed no thermal or mechanical hyperalgesia in response to joint degeneration or VEGFA stimulation 13 , 49 , 50 . Furthermore, intrathecal injection of a monoclonal antibody against VEGFR1, but not VEGFR2, reduced chronic OA joint pain 10 .…”

Section: Discussionsupporting

confidence: 90%

Targeting Vascular Endothelial Growth Factor Receptors as a Therapeutic Strategy for Osteoarthritis and Associated Pain

Singh

Wang

et al. 2023

Int. J. Biol. Sci.

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Pain is the major reason that patients suffering from osteoarthritis (OA) seek medical care. We found that vascular endothelial growth factors (VEGFs) mediate signaling in OA pain pathways. To determine the specific contributions of VEGFs and their receptors (VEGFRs) to joint pathology and pain transmission during OA progression, we studied intra-articular (IA) injections of VEGF ligands into murine knee joints. Only VEGF ligands specific for the activation of VEGFR1, but not VEGFR2, induced allodynia within 30 min. Interventions in OA by inhibitors of VEGFRs were done in vivo using a preclinical murine OA model by IA injections of selective inhibitors of VEGFR1/VEGFR2 kinase (pazopanib) or VEGFR2 kinase (vandetanib). OA phenotypes were evaluated using pain-associated murine behavioral tests and histopathologic analyses. Alterations in VEGF/VEGFR signaling by drugs were determined in knee joints, dorsal root ganglia, and spinal cord by immunofluorescence microscopy. Pazopanib immediately relieved OA pain by interfering with pain transmission pathways. Pain reduction by vandetanib was mainly due to the inhibition of cartilage degeneration by suppressing VEGFR2 expression. In conclusion, IA administration of pazopanib, which simultaneously inhibits VEGFR1 and VEGFR2, can be developed as an ideal OA disease-modifying drug that rapidly reduces joint pain and simultaneously inhibits cartilage degeneration.

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Section: Discussionsupporting

confidence: 90%

Targeting Vascular Endothelial Growth Factor Receptors as a Therapeutic Strategy for Osteoarthritis and Associated Pain

Singh

Wang

et al. 2023

Int. J. Biol. Sci.

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“…IDD is the underlying lesion of many spinal degenerative diseases, including cervical spondylosis, lumbar disc herniation, and lumbar spinal stenosis. 1 With the aging status of population and changes in lifestyles, the prevalence of spinal degenerative diseases kept increasing year by year; thus, it demonstrated the importance of IDD management. As spinal degenerative diseases would cause both serious influences of the life quality of patients and extreme healthy burden to society, it usually would need extensive medical management.…”

Section: Introductionmentioning

confidence: 99%

Epigallocatechin-3-Gallate Protects H2O2-Induced Nucleus Pulposus Cell Apoptosis and Inflammation by Inhibiting cGAS/Sting/NLRP3 Activation

Tian

Bao

et al. 2020

DDDT

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Background: Intervertebral disc degeneration (IDD) is the most common diagnosis of patients with lower back pain. IDD is the underlying lesion of many spinal degenerative diseases; however, the role of cGAS/Sting/NLRP3 pathway and epigallocatechin gallate (EGCG) in the development of IDD remained unclear. Methods: The expressions of cGAS, Sting and NLRP3 mRNA of intervertebral disc (IVD) samples from IDD patients and controls were detected by RT-PCR. The nucleus pulposus cells (NPCs) were induced by hydrogen peroxide (H 2 O 2 ) and used as an in-vitro model. Both 5 μM and 25 μM EGCG treatment were used to detect the effect of EGCG on the in-vitro model. Cell viability was detected by the MTT method, and cell apoptosis and cell cycle would be detected by flow cytometry. Western blot was used in the detection of the expression of cGAS/Sting/NLRP3 as well as apoptosis-related protein level. ELISA was used in the detection of pro-inflammatory factors, including IL-1β, TNF-α, IL-6 and IL-10. Results: The expressions of cGAS, Sting and NLRP3 mRNA were significantly increased in the IVD samples from IDD patients and NLRP3 was associated with cGAS and Sting. Advanced in-vitro study showed that H 2 O 2 significantly increased the expression of cGAS, Sting and NLRP3 protein levels. Advanced experiments showed that EGCG treatment demonstrated significant protective effects in cell viability, apoptosis, cell cycle arrest and inflammatory status through down-regulation of cGAS/Sting/NLRP3 pathway. Conclusion: It was shown that the cGAS, Sting and NLRP3 up-regulation was associated with the incidence of IDD. Our findings also suggest that EGCG treatment would provide anti-apoptosis, anti-inflammation and promote cell viability in H 2 O 2 treatment-incubated NPCs through inhibiting cGAS/Sting/NLRP3 pathway.

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“…The severity of mechanical sensitivity was used for testing the radiating leg pain. As previously described, the paw/foot withdrawal threshold was tested on the hindpaw plantar surface with the up-down method for von Frey filaments, and the tolerance level was expressed in grams (Stoelting, Wood Dale, IL, USA) ( Qiu et al, 2020 ). The von Pressure was applied to each hindpaw with Frey filaments for 4 s or until paw withdrawal.…”

Section: Methodsmentioning

confidence: 99%

Estrogen receptor β/substance P signaling in spinal cord mediates antinociceptive effect in a mouse model of discogenic low back pain

Song

Jin

et al. 2023

Front. Cell. Neurosci.

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IntroductionDiscogenic low back pain (DLBP) is the most commonly described form of back pain. Our previous studies indicated that estrogen-dependent DLBP mechanism was mediated by estrogen receptors (ERs) in the intervertebral disc (IVD) tissue, and the IVD degeneration degree is accompanied by downregulation of ERs, particularly ERβ. However, the neuropathological mechanisms underlying ERs modulation of DLBP are still not well understood. In this study, we investigated the antinociceptive effects of selective ERβ agonists on DLBP-related behavior by regulating substance P in spinal cord and dorsal root ganglia.MethodsTwo weeks after ovariectomies, 18-week-old female mice were randomly separated into four groups: control group; DLBP sham surgery plus vehicle group; DLBP plus vehicle group; DLBP plus ERβ-specific agonist diarylpropionitrile (DPN) group. Behavioral data was collected including behavioral measures of axial back pain (grip force and tail suspension tests) and radiating hypersensitivity (mechanical sensitivity and cold sensitivity test). Dual label scanning confocal immunofluorescence microscopy was used to observe spatial colocalization of ERβ and substance P in spinal cord. Substance P changes in spinal cord and dorsal root ganglia were measured by immunohistochemistry and real-time PCR.ResultsERβ activation could improve both axial and radiating behavioral disorders of DLBP. DPN facilitated the decrease of the amount of time in immobility 1 week after agonist administration. At the time point of 3 weeks, DPN group spent significantly less time in immobility than the vehicle group. In the grip strength tests, starting from postoperative week 1-week 3, DPN injection DLBP mice showed more resistance to stretch than the vehicle injection DLBP mice. Significant differences of cold withdrawal latency time were observed between the DLBP plus DPN injection and DLBP vehicle injection groups at 2- and 3-week injection time point. DPN significantly reversed the paw withdrawal threshold of DLBP mice at the time point of 1, 2, and 3 weeks. Substance P colocalized with ERβ in spinal dorsal horn, mainly in laminae I and II, a connection site of pain transmission. Substance P levels in dorsal horn and dorsal root ganglia of DLBP group were distinctly increased compared with that of control and DLBP sham group. DPN therapy could decrease substance P content in the dorsal horn and the dorsal root ganglia of DLBP mice compared with that of vehicle-treated DLBP mice.DiscussionActivation of ERβ is antinociceptive in the DLBP model by controlling substance P in spinal cord and dorsal root ganglia, which might provide a therapeutic target to manage DLBP in the clinic.

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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

Cited by 19 publications

References 55 publications

Targeting Vascular Endothelial Growth Factor Receptors as a Therapeutic Strategy for Osteoarthritis and Associated Pain

Targeting Vascular Endothelial Growth Factor Receptors as a Therapeutic Strategy for Osteoarthritis and Associated Pain

<p>Epigallocatechin-3-Gallate Protects H<sub>2</sub>O<sub>2</sub>-Induced Nucleus Pulposus Cell Apoptosis and Inflammation by Inhibiting cGAS/Sting/NLRP3 Activation</p>

Estrogen receptor β/substance P signaling in spinal cord mediates antinociceptive effect in a mouse model of discogenic low back pain

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