Suppression of Peripheral Pain by Blockade of Voltage‐Gated Calcium 2.2 Channels in Nociceptors Induces RANKL and Impairs Recovery From Inflammatory Arthritis in a Mouse Model

Baddack, Uta; Frahm, Silke; Antolin-Fontes, Beatriz; Grobe, Jenny; Lipp, Martin; Müller, Gerd; Ibañez–Tallon, Inés

doi:10.1002/art.39094

Cited by 11 publications

(10 citation statements)

References 43 publications

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“…How nociceptive fibers could influence the biology of bone is largely unknown, although there exists the possibility that they could regulate bone remodeling. Relative to this, blockage of Cav2.2 channels in nociceptors was shown to induce the osteoclast activator RANKL in a preclinical joint inflammation model generated in mice (Baddack et al 2015). The connection between SLC2A2 and bone fragility is much clear since hypophosphatemia and rickets are key clinical features of FBS and low phosphate levels result in deficient bone mineralization.…”

Section: Discussionmentioning

confidence: 99%

Molecular spectrum and differential diagnosis in patients referred with sporadic or autosomal recessive osteogenesis imperfecta

Caparrós-Martín

Aglan

Temtamy

et al. 2016

Molec Gen & Gen Med

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BackgroundOsteogenesis imperfecta (OI) is a heterogeneous bone disorder characterized by recurrent fractures. Although most cases of OI have heterozygous mutations in COL1A1 or COL1A2 and show autosomal dominant inheritance, during the last years there has been an explosion in the number of genes responsible for both recessive and dominant forms of this condition. Herein, we have analyzed a cohort of patients with OI, all offspring of unaffected parents, to determine the spectrum of variants accounting for these cases. Twenty patients had nonrelated parents and were sporadic, and 21 were born to consanguineous relationships.MethodsMutation analysis was performed using a next‐generation sequencing gene panel, homozygosity mapping, and whole exome sequencing (WES).ResultsPatients offspring of nonconsanguineous parents were mostly identified with COL1A1 or COL1A2 heterozygous changes, although there were also a few cases with IFITM5 and WNT1 heterozygous mutations. Only one sporadic patient was a compound heterozygote for two recessive mutations. Patients offspring of consanguineous parents showed homozygous changes in a variety of genes including CRTAP,FKBP10,LEPRE1,PLOD2,PPIB,SERPINF1,TMEM38B, and WNT1. In addition, two patients born to consanguineous parents were found to have de novo COL1A1 heterozygous mutations demonstrating that causative variants in the collagen I structural genes cannot be overlooked in affected children from consanguineous couples. Further to this, WES analysis in probands lacking mutations in OI genes revealed deleterious variants in SCN9A,NTRK1, and SLC2A2, which are associated with congenital indifference to pain (CIP) and Fanconi–Bickel syndrome (FBS).ConclusionThis work provides useful information for clinical and genetic diagnosis of OI patients with no positive family history of this disease. Our data also indicate that CIP and FBS are conditions to be considered in the differential diagnosis of OI and suggest a positive role of SCN9A and NTRK1 in bone development.

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Section: Discussionmentioning

confidence: 99%

Molecular spectrum and differential diagnosis in patients referred with sporadic or autosomal recessive osteogenesis imperfecta

Caparrós-Martín

Aglan

Temtamy

et al. 2016

Molec Gen & Gen Med

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“…A blockade of Cav2.2 using ω-conotoxin MVIIA has been shown to alleviate both inflamed and neuropathic pain [256,257]. However, regarding other VGCCs such as Cav3.1, Cav3.2, and Cav3.3, which are targets for CBD [95], it is still not known whether they are channels that are important targets in the treatment of pain.…”

Section: Cbd Ion Channel Targets In Painmentioning

confidence: 99%

Molecular Targets of Cannabidiol in Neurological Disorders

Bih

Chen

Nunn³

et al. 2015

Neurotherapeutics

447

323

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Cannabis has a long history of anecdotal medicinal use and limited licensed medicinal use. Until recently, alleged clinical effects from anecdotal reports and the use of licensed cannabinoid medicines are most likely mediated by tetrahydrocannabinol by virtue of: 1) this cannabinoid being present in the most significant quantities in these preparations; and b) the proportion:potency relationship between tetrahydrocannabinol and other plant cannabinoids derived from cannabis. However, there has recently been considerable interest in the therapeutic potential for the plant cannabinoid, cannabidiol (CBD), in neurological disorders but the current evidence suggests that CBD does not directly interact with the endocannabinoid system except in vitro at supraphysiological concentrations. Thus, as further evidence for CBD's beneficial effects in neurological disease emerges, there remains an urgent need to establish the molecular targets through which it exerts its therapeutic effects. Here, we conducted a systematic search of the extant literature for original articles describing the molecular pharmacology of CBD. We critically appraised the results for the validity of the molecular targets proposed. Thereafter, we considered whether the molecular targets of CBD identified hold therapeutic potential in relevant neurological diseases. The molecular targets identified include numerous classical ion channels, receptors, transporters, and enzymes. Some CBD effects at these targets in in vitro assays only manifest at high concentrations, which may be difficult to achieve in vivo, particularly given CBD's relatively poor bioavailability. Moreover, several targets were asserted through experimental designs that demonstrate only correlation with a given target rather than a causal proof. When the molecular targets of CBD that were physiologically plausible were considered for their potential for exploitation in neurological therapeutics, the results were variable. In some cases, the targets identified had little or no established link to the diseases considered. In others, molecular targets of CBD were entirely consistent with those already actively exploited in relevant, clinically used, neurological treatments. Finally, CBD was found to act upon a number of targets that are linked to neurological therapeutics but that its actions were not consistent withmodulation of such targets that would derive a therapeutically beneficial outcome. Overall, we find that while >65 discrete molecular targets have been reported in the literature for CBD, a relatively limited number represent plausible targets for the drug's action in neurological disorders when judged by the criteria we set. We conclude that CBD is very unlikely to exert effects in neurological diseases through modulation of the endocannabinoid system. Moreover, a number of other molecular targets of CBD reported in the literature are unlikely to be of relevance owing to effects only being observed at supraphysiological concentrations. Of interest and after excludin...

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“…Additionally, inhibition of store operated Ca 2+ channels with YM-58483 prevents and reverses CIA-induced pain-like behavior in male mice [57]. In a combination of the AIA and CIA models, nociceptor expression of MVIIA, which blocks the voltage gated calcium 2.2 channel, reduces abnormal weight bearing, but also increased joint destruction [8].…”

Section: Calcium Channelsmentioning

confidence: 99%

Pain pathogenesis in rheumatoid arthritis—what have we learned from animal models?

Krock

Jurczak²,

Svensson³

2018

Pain

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Rheumatoid arthritis (RA) is a systemic autoimmune disease characterized by joint inflammation and joint pain. Much of RA treatment is focused on suppressing inflammation, with the idea being that if inflammation is controlled other symptoms, such as pain, will disappear. However, pain is the most common complaint of RA patients, is often still present following the resolution of inflammation, and can develop prior to the onset of inflammation. Thus, further research is needed to better understand RA-associated pain mechanisms. A number of preclinical rodent models commonly used in rheumatology research have been developed based on bedside-to-bench and reverse translational approaches. These models include collagen-induced arthritis, antigen-induced arthritis, streptococcal

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Suppression of Peripheral Pain by Blockade of Voltage‐Gated Calcium 2.2 Channels in Nociceptors Induces RANKL and Impairs Recovery From Inflammatory Arthritis in a Mouse Model

Cited by 11 publications

References 43 publications

Molecular spectrum and differential diagnosis in patients referred with sporadic or autosomal recessive osteogenesis imperfecta

Molecular spectrum and differential diagnosis in patients referred with sporadic or autosomal recessive osteogenesis imperfecta

Molecular Targets of Cannabidiol in Neurological Disorders

Pain pathogenesis in rheumatoid arthritis—what have we learned from animal models?

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